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| Publications of Richard S. Keefe :recent first alphabetical combined listing:%% Journal Articles @article{fds273531, Author = {Davidson, M and Keefe, RS and Mohs, RC and Siever, LJ and Losonczy, MF and Horvath, TB and Davis, KL}, Title = {L-dopa challenge and relapse in schizophrenia.}, Journal = {The American Journal of Psychiatry}, Volume = {144}, Number = {7}, Pages = {934-938}, Year = {1987}, Month = {July}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/ajp.144.7.934}, Abstract = {Neuroleptic administration has been shown to be superior to placebo in prolonging schizophrenic remission. However, individual patients are able to maintain long periods of remission in the absence of neuroleptic treatment, while others relapse soon after neuroleptic withdrawal. This study attempted to predict time to relapse in 28 schizophrenic patients withdrawn from neuroleptics and challenged with L-dopa for 7 days, then followed until relapse. Time to relapse correlated significantly with L-dopa-induced increase in BPRS score (p = .006). Five of six patients who responded to L-dopa relapsed within 4 weeks after L-dopa administration, while only four of 22 who did not respond relapsed in a comparable period.}, Doi = {10.1176/ajp.144.7.934}, Key = {fds273531} } @article{fds273533, Author = {Keefe, RS and Mohs, RC and Losonczy, MF and Davidson, M and Silverman, JM and Kendler, KS and Horvath, TB and Nora, R and Davis, KL}, Title = {Characteristics of very poor outcome schizophrenia.}, Journal = {The American Journal of Psychiatry}, Volume = {144}, Number = {7}, Pages = {889-895}, Year = {1987}, Month = {July}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/ajp.144.7.889}, Abstract = {The authors compared 21 "Kraepelinian" schizophrenic patients who had been ill and dependent on others for the past 5 years with 76 chronic schizophrenic patients in remission or with exacerbations requiring hospitalization. The Kraepelinian patients met the criteria for schizophrenia by more diagnostic systems than the exacerbated patients, were less responsive to haloperidol, had more severe negative symptoms, and had similarly severe positive symptoms. They had cerebral ventricles that were more asymmetrical and a greater family history of schizophrenia spectrum disorders than the other chronic patients. These data suggest that patients with 5 years of illness and complete dependency on others may represent a subgroup of schizophrenia.}, Doi = {10.1176/ajp.144.7.889}, Key = {fds273533} } @article{fds273532, Author = {Silverman, JM and Mohs, RC and Davidson, M and Losonczy, MF and Keefe, RS and Breitner, JC and Sorokin, JE and Davis, KL}, Title = {Familial schizophrenia and treatment response.}, Journal = {The American Journal of Psychiatry}, Volume = {144}, Number = {10}, Pages = {1271-1276}, Year = {1987}, Month = {October}, url = {http://dx.doi.org/10.1176/ajp.144.10.1271}, Abstract = {Thirty-nine patients with chronic schizophrenia for whom hospitalization was clinically indicated received haloperidol for 4 to 6 weeks in a standardized dose schedule. Responders were compared with nonresponders for family history, baseline symptom factors, and ventricle-brain ratio (VBR). The lifetime risk for schizophrenia spectrum disorders was higher among first-degree relatives of nonresponders than among first-degree relatives of responders. Treatment responders had higher baseline scores on the factors of activation and hostile-suspiciousness, but the groups did not differ in any other baseline symptom factor or in VBR. The authors suggest that there is an association between failure to respond to drugs and genetic loading for schizophrenia spectrum disorders.}, Doi = {10.1176/ajp.144.10.1271}, Key = {fds273532} } @article{fds273535, Author = {Keefe, RS and Mohs, RC and Davidson, M and Losonczy, MF and Silverman, JM and Lesser, JC and Horvath, TB and Davis, KL}, Title = {Kraepelinian schizophrenia: a subgroup of schizophrenia?}, Journal = {Psychopharmacology Bulletin}, Volume = {24}, Number = {1}, Pages = {56-61}, Year = {1988}, Key = {fds273535} } @article{fds273534, Author = {Keefe, RS and Siever, LJ and Mohs, RC and Peterson, AE and Mahon, TR and Bergman, RL and Davis, KL}, Title = {Eye tracking, schizophrenic symptoms, and schizotypal personality disorder.}, Journal = {European Archives of Psychiatry and Neurological Sciences}, Volume = {239}, Number = {1}, Pages = {39-42}, Year = {1989}, ISSN = {0175-758X}, url = {http://dx.doi.org/10.1007/BF01739742}, Abstract = {Schizophrenic patients and patients with schizotypal personality disorder were significantly more likely than normal controls to demonstrate impaired eye tracking performance. Fifteen of 27 schizophrenics and 15 of 27 schizotypals had impaired eye tracking, compared with 11 of 39 normal controls. In the schizophrenic group, including 10 out-patients in a stable state of relative remission, impaired eye tracking was associated with more severe formal thought disorder and more time spent in psychiatric hospitals. Among stable schizophrenic out-patients, poor eye tracking was related to more severe formal thought disorder and greater overall psychopathology. This pattern of results suggests a possible relation between eye tracking impairment and more severe enduring symptoms across the spectrum of schizophrenic and schizophrenia-related disorders.}, Doi = {10.1007/BF01739742}, Key = {fds273534} } @article{fds273537, Author = {Silverman, JM and Keefe, RS and Mohs, RC and Davis, KL}, Title = {A study of the reliability of the family history method in genetic studies of Alzheimer disease.}, Journal = {Alzheimer Disease and Associated Disorders}, Volume = {3}, Number = {4}, Pages = {218-223}, Year = {1989}, Abstract = {The reliability between 2 raters conducting independent family history interviews for Alzheimer disease-like and other dementias was investigated. The interviews were conducted at least 1 year apart with the second rater blind to the data collected by the first rater. Raters agreed on the presence and type of dementia in 153 relatives age 45 or older of 30 AD probands, the age at onset in secondary cases, and the age of nonaffected relatives.}, Key = {fds273537} } @article{fds273536, Author = {Keefe, RS and Mohs, RC and Losonczy, MF and Davidson, M and Silverman, JM and Horvath, TB and Davis, KL}, Title = {Premorbid sociosexual functioning and long-term outcome in schizophrenia.}, Journal = {The American Journal of Psychiatry}, Volume = {146}, Number = {2}, Pages = {206-211}, Year = {1989}, Month = {February}, url = {http://dx.doi.org/10.1176/ajp.146.2.206}, Abstract = {Chronic schizophrenic patients with the most severe social deterioration have been shown to differ from other chronic schizophrenic patients with respect to measures of left-to-right ventricular asymmetry, negative symptoms, and response to haloperidol treatment. In the current study, the authors investigated the social antecedents of these characteristics of very poor outcome schizophrenia in 69 chronic schizophrenic patients. Poor premorbid sociosexual functioning was associated with more severe left-to-right ventricular asymmetry, greater severity of negative symptoms, fewer positive symptoms, and worse current social functioning. These data suggest that factors associated with severe social deterioration in the end stage of schizophrenia are also associated with premorbid sociosexual impairment.}, Doi = {10.1176/ajp.146.2.206}, Key = {fds273536} } @article{fds327117, Author = {KEEFE, RSE and MOHS, RC and SILVERMAN, JM and LOSONCZY, MF and DAVIDSON, M and HORVATH, TB and DAVIS, KL}, Title = {CHARACTERISTICS OF KRAEPELINIAN SCHIZOPHRENIA AND THEIR RELATION TO PREMORBID SOCIOSEXUAL FUNCTIONING}, Journal = {NEUROLEPTIC-NONRESPONSIVE PATIENT : CHARACTERIZATION AND TREATMENT}, Volume = {27}, Pages = {1-+}, Publisher = {AMER PSYCHIATRIC PRESS}, Editor = {ANGRIST, B and SCHULZ, SC}, Year = {1990}, Month = {January}, ISBN = {0-88048-461-6}, Key = {fds327117} } @article{fds273538, Author = {Siever, LJ and Keefe, R and Bernstein, DP and Coccaro, EF and Klar, HM and Zemishlany, Z and Peterson, AE and Davidson, M and Mahon, T and Horvath, T}, Title = {Eye tracking impairment in clinically identified patients with schizotypal personality disorder.}, Journal = {The American Journal of Psychiatry}, Volume = {147}, Number = {6}, Pages = {740-745}, Year = {1990}, Month = {June}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/ajp.147.6.740}, Abstract = {Eye tracking accuracy, which has been found to be impaired in schizophrenic patients and their relatives, was assessed in 26 patients with schizotypal personality disorder, 17 control subjects with other non-schizophrenia-related personality disorders, 29 normal control subjects, and 44 schizophrenic patients. Both schizotypal and schizophrenic patients, but not control subjects with other personality disorders, demonstrated significantly more impaired tracking than the normal control subjects. These results suggest that patients with clinically defined schizotypal personality disorder may be biologically related to schizophrenic patients as part of a spectrum of schizophrenia-related disorders.}, Doi = {10.1176/ajp.147.6.740}, Key = {fds273538} } @article{fds273540, Author = {Siever, LJ and Silverman, JM and Horvath, TB and Klar, H and Coccaro, E and Keefe, RS and Pinkham, L and Rinaldi, P and Mohs, RC and Davis, KL}, Title = {Increased morbid risk for schizophrenia-related disorders in relatives of schizotypal personality disordered patients.}, Journal = {Archives of General Psychiatry}, Volume = {47}, Number = {7}, Pages = {634-640}, Year = {1990}, Month = {July}, ISSN = {0003-990X}, url = {http://dx.doi.org/10.1001/archpsyc.1990.01810190034005}, Abstract = {To evaluate whether probands from a clinical sample diagnosed as having DSM-III schizotypal and/or paranoid personality disorder have a familial relationship to the schizophrenia-related disorders, the morbid risk for schizophrenia-related disorders and other psychiatric disorders were evaluated in the first-degree relatives of patients with schizotypal and/or paranoid personality disorder and compared with the corresponding risk for these disorders in the first-degree relatives of patients with other non-schizophrenia-related personality disorders. The morbid risk for all schizophrenia-related disorders, and specifically for schizophrenia-related personality disorders, was significantly greater among the relatives of the probands with schizotypal and/or paranoid personality disorder than among the relatives of probands with other personality disorder. The morbid risk for other psychiatric disorders did not differ significantly between the first-degree relatives of the schizotypal/paranoid personality disorder and the other personality disorder control proband samples. These results suggest a specific familial association between schizophrenia-related disorders, particularly schizophrenia-related personality disorders, and clinically diagnosed schizotypal patients.}, Doi = {10.1001/archpsyc.1990.01810190034005}, Key = {fds273540} } @article{fds273539, Author = {Harvey, PD and Keefe, RS and Moskowitz, J and Putnam, KM and Mohs, RC and Davis, KL}, Title = {Attentional markers of vulnerability to schizophrenia: performance of medicated and unmedicated patients and normals.}, Journal = {Psychiatry Research}, Volume = {33}, Number = {2}, Pages = {179-188}, Year = {1990}, Month = {August}, ISSN = {0165-1781}, url = {http://dx.doi.org/10.1016/0165-1781(90)90072-d}, Abstract = {Medicated and unmedicated schizophrenic patients (both n's = 14) were compared to a normal control sample (n = 15) on two attentional tasks hypothesized to be markers of vulnerability to schizophrenia. These tasks, the continuous performance test and the visual backward masking task, were found to be more deviant in schizophrenic patients than in normals. In addition, the group mean levels of performance did not differ consistently across medication status within the medicated patients. It was found, however, that the association between these tasks varied as a function of medication status, with unmedicated patients more similar to normals than to medicated patients. The implications of these results for the two tasks as markers are discussed, with special focus on those earlier studies that did not evaluate unmedicated patients.}, Doi = {10.1016/0165-1781(90)90072-d}, Key = {fds273539} } @article{fds273541, Author = {Keefe, RS and Lobel, DS and Mohs, RC and Silverman, JM and Harvey, PD and Davidson, M and Losonczy, MF and Davis, KL}, Title = {Diagnostic issues in chronic schizophrenia: kraepelinian schizophrenia, undifferentiated schizophrenia, and state-independent negative symptoms.}, Journal = {Schizophrenia Research}, Volume = {4}, Number = {2}, Pages = {71-79}, Year = {1991}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/0920-9964(91)90026-n}, Abstract = {Data are presented concerning three recent clinical distinctions in schizophrenia: kraepelinian versus non-kraepelinian patients; mixed versus simple undifferentiated subtypes; and state-dependent versus state-independent negative symptoms. Schizophrenic patients who have been ill and dependent on others for the past 5 years ('kraepelinians') were compared to other chronic schizophrenics. The kraepelinian patients met the criteria for schizophrenia by more diagnostic systems than other patients, were less responsive to haloperidol, had more severe negative symptoms and formal thought disorder, and had similarly severe positive symptoms. They also had cerebral ventricles that demonstrated more left-to-right asymmetry and a greater family history of schizophrenia spectrum disorders. Mixed undifferentiated schizophrenic patients, who met criteria for more than one schizophrenic subtype, were compared to simple undifferentiated schizophrenic patients, who met criteria for no subtype. The mixed group was characterized by more severe positive and negative symptoms and formal thought disorder, worse social functioning, and a worse response to haloperidol. In a subgroup of patients who were studied once while in a state of exacerbation and once while in a state of relative remission, the negative symptoms of inattention and affective flattening were state-dependent, while anhedonia-asociality was state-independent.}, Doi = {10.1016/0920-9964(91)90026-n}, Key = {fds273541} } @article{fds273543, Author = {Keefe, RS and Silverman, JM and Siever, LJ and Cornblatt, BA}, Title = {Refining phenotype characterization in genetic linkage studies of schizophrenia.}, Journal = {Social Biology}, Volume = {38}, Number = {3-4}, Pages = {197-218}, Year = {1991}, url = {http://dx.doi.org/10.1080/19485565.1991.9988788}, Abstract = {A definitive replicable genetic linkage for a major locus underlying the susceptibility to schizophrenia has not been identified to date. Although there are several possible explanations for the failure to find linkage in schizophrenia, one major problem is that the range of phenotypic expressions of the genes for schizophrenia has not been clarified. A more refined understanding of the various phenotypic expressions of a gene related to schizophrenia would enhance the power of studies designed to detect a genetic linkage with a major chromosomal locus and would benefit other strategies for understanding the etiology of schizophrenia. The genes for schizophrenia may be frequently expressed in relatives of schizophrenic patients, although with less severe symptoms than those of chronic schizophrenia. Two series of findings support this notion. Nonschizophrenic relatives of schizophrenic patients demonstrate an increased incidence of nonpsychotic schizophrenia-like symptoms and traits, and they manifest deficit performances on several different laboratory tests of neurocognitive functioning. A more refined phenotypic expression of a schizophrenia-related gene may thus be indicated by personality traits and subclinical neurocognitive deficits. These personality traits and neurocognitive deficits are considered here as possible aids in the identification of affected cases in genetic linkage studies of schizophrenia. Terminology for different indicators of neurocognitive deficits is introduced, and the relative utility of personality traits and indicators of neurocognitive deficit for genetic linkage studies is discussed. As specific examples, schizophrenia-related personality traits that are unrelated to affective symptoms and performance deficits on tasks of eye tracking and continuous attention are considered for strategies for broadening phenotype characterization without reducing the specificity of affected case identification.}, Doi = {10.1080/19485565.1991.9988788}, Key = {fds273543} } @article{fds327115, Author = {Harvey, PD and Davidson, M and Mohs, RC and Keefe, RSE and Moskowitz, J and Knott, P and Duffelmeyer, M}, Title = {Plasma HVA correlates of attentional performance in unmedicated schizophrenics}, Journal = {Schizophrenia Research}, Volume = {4}, Number = {3}, Pages = {345-346}, Publisher = {Elsevier BV}, Year = {1991}, Month = {May}, url = {http://dx.doi.org/10.1016/0920-9964(91)90258-s}, Doi = {10.1016/0920-9964(91)90258-s}, Key = {fds327115} } @article{fds327116, Author = {Frecska, E and Losonczy, M and Keefe, RSE and Silverman, JM and Davidson, M and Harvey, P and McQueeney, RT and Lobel, D and Apter, S and Davis, KL}, Title = {Kraepelinian schizophrenia: A replication in an independent sample}, Journal = {Schizophrenia Research}, Volume = {4}, Number = {3}, Pages = {257-257}, Publisher = {Elsevier BV}, Year = {1991}, Month = {May}, url = {http://dx.doi.org/10.1016/0920-9964(91)90108-4}, Doi = {10.1016/0920-9964(91)90108-4}, Key = {fds327116} } @article{fds273542, Author = {Thaker, G and Moran, M and Cassady, S and Adami, H and Tamminga, C}, Title = {Normal smooth pursuit eye movements in volunteer subjects meeting schizotypal personality disorder criteria.}, Journal = {The American Journal of Psychiatry}, Volume = {148}, Number = {8}, Pages = {1096-1097}, Year = {1991}, Month = {August}, Key = {fds273542} } @article{fds273544, Author = {Harvey, PD and Putnam, KM and Davidson, M and Kahn, RS and Powchik, P and McQueeney, R and Keefe, RS and Davis, KL}, Title = {Brief neuroleptic discontinuation and clinical symptoms in Kraepelinian and non-Kraepelinian chronic schizophrenic patients.}, Journal = {Psychiatry Research}, Volume = {38}, Number = {3}, Pages = {285-292}, Year = {1991}, Month = {September}, ISSN = {0165-1781}, url = {http://dx.doi.org/10.1016/0165-1781(91)90018-k}, Abstract = {Neuroleptic medication was abruptly discontinued in 24 male chronic schizophrenic patients who were subdivided on the basis of their history of illness into Kraepelinian (n = 8) and non-Kraepelinian (n = 16) subgroups. These patients were kept drug free for 6 weeks and then returned to treatment with haloperidol, 20 mg/day. Half of the non-Kraepelinian patients developed exacerbations of their symptoms, which quickly resolved when they were returned to medication, while none of the Kraepelinian patients showed a worsening of symptomatology. On-medication clinical severity failed to predict risk for exacerbation, with severity of exacerbation predicting the amount of improvement when returned to medication. The Kraepelinian patients were found to be much less variable than the non-Kraepelinian patients in their symptoms during both medication manipulations, suggesting that medication truly has a negligible effect on them.}, Doi = {10.1016/0165-1781(91)90018-k}, Key = {fds273544} } @article{fds327114, Author = {CORNBLATT, BA and KEEFE, RSE}, Title = {THE GENETICS OF MENTAL-ILLNESS - AN OVERVIEW}, Journal = {Social Biology}, Volume = {38}, Number = {3-4}, Pages = {R1-R5}, Publisher = {SOC STUDY SOCIAL BIOLOGY}, Year = {1991}, Month = {September}, Key = {fds327114} } @article{fds273546, Author = {Davidson, M and Kahn, RS and Stern, RG and Harvey, PD and Keefe, R and Knott, P and Apter, S and Webster, L and Davis, KL}, Title = {Measurements of plasma homovanillic acid in schizophrenic patients.}, Journal = {Clinical Neuropharmacology}, Volume = {15 Suppl 1 Pt A}, Pages = {521A-522A}, Year = {1992}, url = {http://dx.doi.org/10.1097/00002826-199201001-00271}, Doi = {10.1097/00002826-199201001-00271}, Key = {fds273546} } @article{fds327112, Author = {Keefe, RSE and Silverman, JM and Amin, F and Lees, SE and Duncan, A and Harvey, PD and Davidson, M and Siever, LJ and Mohs, RC and Davis, KL}, Title = {Frontal functioning and plasma HVA in the relatives of schizophrenic patients}, Journal = {Schizophrenia Research}, Volume = {6}, Number = {2}, Pages = {158-158}, Publisher = {Elsevier BV}, Year = {1992}, Month = {January}, url = {http://dx.doi.org/10.1016/0920-9964(92)90244-y}, Doi = {10.1016/0920-9964(92)90244-y}, Key = {fds327112} } @article{fds327113, Author = {Harvey, PD and Kahn, RS and Davidson, M and Mohs, RC and Keefe, RSE and Davis, KL}, Title = {Dopaminergic correlates of attentional performance in unmedicated schizophrenic patients}, Journal = {Schizophrenia Research}, Volume = {6}, Number = {2}, Pages = {136-136}, Publisher = {Elsevier BV}, Year = {1992}, Month = {January}, url = {http://dx.doi.org/10.1016/0920-9964(92)90194-a}, Doi = {10.1016/0920-9964(92)90194-a}, Key = {fds327113} } @article{fds273545, Author = {Keefe, RS and Harvey, PD and Lenzenweger, MF and Davidson, M and Apter, SH and Schmeidler, J and Mohs, RC and Davis, KL}, Title = {Empirical assessment of the factorial structure of clinical symptoms in schizophrenia: negative symptoms.}, Journal = {Psychiatry Research}, Volume = {44}, Number = {2}, Pages = {153-165}, Year = {1992}, Month = {November}, ISSN = {0165-1781}, url = {http://dx.doi.org/10.1016/0165-1781(92)90049-9}, Abstract = {The factor structure of the Scale for the Assessment of Negative Symptoms (SANS) was examined in a confirmatory factor analysis that used the LISREL procedure. Four models of negative symptom factors were tested in 130 hospitalized schizophrenic patients. A three-factor model of diminished expression, social dysfunction, and disorganization generated by the authors yielded a superior fit to the data relative to the two-factor model of Liddle (1987b) and a unifactorial severity model. A four-factor model based on the original subscale formulation of the SANS failed to fit the data.}, Doi = {10.1016/0165-1781(92)90049-9}, Key = {fds273545} } @article{fds273547, Author = {Harvey, PD and Lenzenweger, MF and Keefe, RS and Pogge, DL and Serper, MR and Mohs, RC}, Title = {Empirical assessment of the factorial structure of clinical symptoms in schizophrenic patients: formal thought disorder.}, Journal = {Psychiatry Research}, Volume = {44}, Number = {2}, Pages = {141-151}, Year = {1992}, Month = {November}, ISSN = {0165-1781}, url = {http://dx.doi.org/10.1016/0165-1781(92)90048-8}, Abstract = {Male schizophrenic patients (n = 142) were examined with a clinical assessment of their language dysfunctions with the Scale for the Assessment of Thought, Language, and Communication (TLC). Confirmatory factor analyses were conducted to test the relative fit of several differential theoretical models of the factorial structure of thought disorders. The models examined were positive-negative thought disorder, a three-factor model based on the results of an earlier exploratory factor analysis, and a simpler verbal productivity-disconnection model that can be extracted from other exploratory analyses and empirical studies. The positive-negative thought disorder model failed to fit the data, while the three-factor model fit the data, but no better than the simpler verbal productivity-disconnection model.}, Doi = {10.1016/0165-1781(92)90048-8}, Key = {fds273547} } @article{fds273548, Author = {Frecska, E and Losonczy, MF and Keefe, RSE and Silverman, JM and Davidson, M and Davis, KL}, Title = {The characteristics of poor outcome, 'Kraepelinian' schizophrenia}, Journal = {European Neuropsychopharmacology}, Volume = {3}, Number = {3}, Pages = {400}, Publisher = {Elsevier BV}, Year = {1993}, Month = {January}, ISSN = {0924-977X}, url = {http://dx.doi.org/10.1016/0924-977X(93)90193-P}, Doi = {10.1016/0924-977X(93)90193-P}, Key = {fds273548} } @article{fds327110, Author = {DEVEGVAR, ML and KEEFE, RSE and MOSKOWITZ, J and LEES, S and KALUS, O and KNOTT, P and TRESTMAN, RL and SIEVER, LJ}, Title = {PERFORMANCE ON TESTS SENSITIVE TO FRONTAL-LOBE DYSFUNCTION AND DEFICIT-LIKE SYMPTOMS IN SCHIZOTYPAL PERSONALITY-DISORDER}, Journal = {Biological Psychiatry}, Volume = {33}, Number = {6A}, Pages = {A101-A101}, Publisher = {ELSEVIER SCIENCE INC}, Year = {1993}, Month = {March}, Key = {fds327110} } @article{fds327111, Author = {KEEFE, RSE and BLUM, C and MERHIGE, DM and LEES, SE and ZOLOT, DM and DAVIDSON, M and HARVEY, PD and DAVIS, KL}, Title = {TASKS FROM MONKEY CORTEX STUDIES AND SPECIFIC PREFRONTAL DYSFUNCTION IN SCHIZOPHRENIA}, Journal = {Biological Psychiatry}, Volume = {33}, Number = {6A}, Pages = {A92-A92}, Publisher = {ELSEVIER SCIENCE INC}, Year = {1993}, Month = {March}, Key = {fds327111} } @article{fds273549, Author = {Siever, LJ and Kalus, OF and Keefe, RS}, Title = {The boundaries of schizophrenia.}, Journal = {The Psychiatric Clinics of North America}, Volume = {16}, Number = {2}, Pages = {217-244}, Year = {1993}, Month = {June}, url = {http://dx.doi.org/10.1016/s0193-953x(18)30171-0}, Abstract = {Evidence from a variety of domains including the phenomenologic, genetic, psychological, neuropsychological, psychophysiologic, neurochemical, imaging, outcome, and treatment response suggests that schizotypal personality disorder is related closely to chronic schizophrenia and that this disorder may be part of a continuum of schizophrenia-related disorders. Questions remain as to how the boundaries of schizophrenia should be defined. The commonalities across the schizophrenia spectrum as well as the differences between disorders on the spectrum need to be clarified further. A multidimensional approach to the pathogenesis of the schizophrenia-related disorders offers a beginning opportunity for such a clarification. The study of patients with schizotypal personality disorder suggest that a dimension of deficit-like or "negative" symptoms of asociality and interpersonal impairment may be associated with neuropsychological and psychophysiologic correlates of altered cortical, particularly frontal, function and raise the possibility in structural changes as reflected in increased ventricular size in frontal and third ventricle areas. On the other hand, the psychotic-like or "positive" symptoms seem to be more related to increases in dopaminergic activity that may be partially responsive to neuroleptic treatment. It is conceivable that these two dimensions may represent partially distinct but potentially interactive pathophysiologic processes that may converge and interact to result in chronic schizophrenia. In this way, the study of the boundaries of schizophrenia and the milder schizophrenia-related personality disorders may provide important clues as to the genetic and pathophysiology of chronic schizophrenia itself, as well as to illuminate a set of disorders that are clinically underrecognized but probably more prevalent than more severe forms of schizophrenia.}, Doi = {10.1016/s0193-953x(18)30171-0}, Key = {fds273549} } @article{fds354411, Author = {DAVIDSON, M and BERMAN, I and KEEFE, RS and DUVVI, K and PONTECORVO, M}, Title = {RISPERIDONE IN ELDERLY SCHIZOPHRENIC-PATIENTS}, Journal = {Schizophrenia Research}, Volume = {11}, Number = {2}, Pages = {197-197}, Year = {1994}, Key = {fds354411} } @article{fds327108, Author = {KEEFE, RSE and BLUM, C and HARVEY, PD and DAVIDSON, M and ROITMAN, SE and DAVIS, KL}, Title = {WORKING-MEMORY DEFICITS IN SCHIZOPHRENICS WITH SEVERE SELF-CARE DYSFUNCTION}, Journal = {Schizophrenia Research}, Volume = {11}, Number = {2}, Pages = {158-158}, Publisher = {ELSEVIER SCIENCE BV}, Year = {1994}, Month = {January}, Key = {fds327108} } @article{fds327109, Author = {EPSTEIN, JI and KEEFE, RSE and HARVEY, PD and MOHS, RC and ROITMAN, SEL and DAVIDSON, M and SIEVER, LJ}, Title = {THE EXTENT OF WORKING-MEMORY DEMANDS PREDICTS RESPONSE TO NEUROLEPTIC MEDICATION ON CONTINUOUS PERFORMANCE TESTS}, Journal = {Schizophrenia Research}, Volume = {11}, Number = {2}, Pages = {153-154}, Publisher = {ELSEVIER SCIENCE BV}, Year = {1994}, Month = {January}, Key = {fds327109} } @article{fds273550, Author = {Kahn, RS and Harvey, PD and Davidson, M and Keefe, RS and Apter, S and Neale, JM and Mohs, RC and Davis, KL}, Title = {Neuropsychological correlates of central monoamine function in chronic schizophrenia: relationship between CSF metabolites and cognitive function.}, Journal = {Schizophrenia Research}, Volume = {11}, Number = {3}, Pages = {217-224}, Year = {1994}, Month = {February}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/0920-9964(94)90015-9}, Abstract = {Schizophrenia is associated with multiple cognitive deficits which in turn may be related to abnormal dopamine (DA) function. To examine possible associations between cognitive dysfunction and central DA activity in schizophrenia, neuropsychological measures (visuospatial and verbal recall; performance on the Wisconsin Card Sort Test (WCST); visuospatial perception) were examined in 17 drug-free male schizophrenic patients and related to cerebrospinal fluid concentrations of the metabolites of dopamine (homovanillic acid (HVA)), serotonin, and norepinephrine. CSF HVA concentrations were correlated with the ability to recall visuospatial information, with attention to verbal tasks, and with WCST performance (low CSF HVA concentrations predicting poor performance on these tests) but not with the ability to recall verbally presented material and visuospatial perception. These data are consistent with earlier results suggesting that (cortical) DA function is associated with recall and retrieval of visuospatial information and with WCST performance.}, Doi = {10.1016/0920-9964(94)90015-9}, Key = {fds273550} } @article{fds327104, Author = {Frecska, E and Losonczy, MF and Keefe, RSE and Apter, S and Davidson, M and Mohs, RC and Davis, KL}, Title = {Age dependent change of ventricular measures in schizophrenia: Cross-sectional analysis}, Journal = {Biological Psychiatry}, Volume = {35}, Number = {9}, Pages = {704-705}, Publisher = {Elsevier BV}, Year = {1994}, Month = {May}, url = {http://dx.doi.org/10.1016/0006-3223(94)90980-6}, Doi = {10.1016/0006-3223(94)90980-6}, Key = {fds327104} } @article{fds327105, Author = {Keefe, RSE and Blum, C and Roitman, SL and Harvey, PD and Davidson, M and Mohs, RC and Davis, KL}, Title = {Working memory dysfunction in Kraepelinian schizophrenics}, Journal = {Biological Psychiatry}, Volume = {35}, Number = {9}, Pages = {660-660}, Publisher = {Elsevier BV}, Year = {1994}, Month = {May}, url = {http://dx.doi.org/10.1016/0006-3223(94)90820-6}, Doi = {10.1016/0006-3223(94)90820-6}, Key = {fds327105} } @article{fds327106, Author = {Epstein, JI and Keefe, RSE and Lees Roitman and SE and Harvey, PD and Davidson, M and Siever, LJ and Mohs, RC}, Title = {Neuroleptic effects on CPT and eye tracking in schizophrenia}, Journal = {Biological Psychiatry}, Volume = {35}, Number = {9}, Pages = {674-674}, Publisher = {Elsevier BV}, Year = {1994}, Month = {May}, url = {http://dx.doi.org/10.1016/0006-3223(94)90872-9}, Doi = {10.1016/0006-3223(94)90872-9}, Key = {fds327106} } @article{fds327107, Author = {Apter, SH and Keefe, RSE and Hirschowitz, J and Davidson, M and Macaluso, JM and Amato, R and Davis, KL}, Title = {Longitudinal classification in schizophrenia: The relationship between kraepelinian and deficit syndrome subtypologies}, Journal = {Biological Psychiatry}, Volume = {35}, Number = {9}, Pages = {695-695}, Publisher = {Elsevier BV}, Year = {1994}, Month = {May}, url = {http://dx.doi.org/10.1016/0006-3223(94)90944-x}, Doi = {10.1016/0006-3223(94)90944-x}, Key = {fds327107} } @article{fds273551, Author = {Keefe, RS and Silverman, JM and Roitman, SE and Harvey, PD and Duncan, MA and Alroy, D and Siever, LJ and Davis, KL and Mohs, RC}, Title = {Performance of nonpsychotic relatives of schizophrenic patients on cognitive tests.}, Journal = {Psychiatry Research}, Volume = {53}, Number = {1}, Pages = {1-12}, Year = {1994}, Month = {July}, ISSN = {0165-1781}, url = {http://dx.doi.org/10.1016/0165-1781(94)90091-4}, Abstract = {We tested 54 nonpsychotic first degree relatives of 23 schizophrenic probands and 18 control subjects matched for age and education on several neuropsychological tests. The tests were selected to assess overall intellectual ability or because previous work indicated that they are particularly sensitive measures of cognitive dysfunction in schizophrenic patients. The relatives of schizophrenic patients performed significantly worse than the control subjects on tests of verbal fluency and on Trailmaking, part B. Each of these tests contributed unique variance to the discrimination between groups. The groups did not differ significantly on the number of perseverative errors on the Wisconsin Card Sorting Test, Wechsler Adult Intelligence Scale-Revised block design or vocabulary, or Trailmaking, part A. Eight relatives who met DSM-III-R criteria for schizotypal personality disorder were more impaired than the remaining 46 relatives on letter fluency, but otherwise their performance was similar to that of nonschizotypal relatives. These data suggest that close relatives of schizophrenic patients may have subtle neuropsychological impairments that are not necessarily associated with clinical symptoms of schizophrenia spectrum disorders.}, Doi = {10.1016/0165-1781(94)90091-4}, Key = {fds273551} } @article{fds273552, Author = {Siever, LJ and Friedman, L and Moskowitz, J and Mitropoulou, V and Keefe, R and Roitman, SL and Merhige, D and Trestman, R and Silverman, J and Mohs, R}, Title = {Eye movement impairment and schizotypal psychopathology.}, Journal = {The American Journal of Psychiatry}, Volume = {151}, Number = {8}, Pages = {1209-1215}, Year = {1994}, Month = {August}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/ajp.151.8.1209}, Abstract = {OBJECTIVE: Eye movement dysfunction in relation to a smooth pursuit task has been documented in schizophrenic patients and in patients with the related personality disorder, schizotypal personality disorder. To investigate which quantitative measures are associated with the eye movement dysfunction and whether the dysfunction is more related to the psychotic-like or the deficit-like symptoms of schizotypal personality disorder, ratings of eye movements in several groups of subjects were compared. METHOD: The study groups consisted of 26 patients with schizotypal personality disorder, 42 patients with other personality disorders (22 who also had two or more schizotypal personality traits and 20 who had fewer than two), and 37 normal comparison subjects. Smooth pursuit eye tracking of sinusoidal and constant velocity targets was recorded by an infrared eye tracking system. Two raters evaluated pursuit gain and large and small saccades in the direction of the target and in the direction opposite to that of the target (quantitative ratings) and constant velocity (qualitative rating). RESULTS: Patients with schizotypal personality disorder and patients with other personality disorders and two or more schizotypal traits, but not those with fewer than two schizotypal traits, had significantly poorer qualitative ratings of tracking than the normal comparison subjects. Neither gain nor any of the saccadic measures significantly differed between groups. The number of large saccades in the direction of the target was the only quantitative variable that predicted low qualitative ratings. Qualitatively poor tracking was associated with the deficit-like, but not the psychotic-like, symptoms of schizotypal personality disorder. CONCLUSIONS: Patients with schizotypal personality disorder demonstrate qualitatively poorer tracking than comparison groups, and the impaired tracking is associated with deficit-like symptoms.}, Doi = {10.1176/ajp.151.8.1209}, Key = {fds273552} } @article{fds273383, Author = {Keefe, RS}, Title = {The contribution of neuropsychology to psychiatry.}, Journal = {The American Journal of Psychiatry}, Volume = {152}, Number = {1}, Pages = {6-15}, Year = {1995}, Month = {January}, url = {http://dx.doi.org/10.1176/ajp.152.1.6}, Abstract = {OBJECTIVE: Neuropsychological test data are applied with increasing frequency in research studies and clinical practice in psychiatry. This article addresses three popular assumptions about neuropsychological test data and describes the limitations and contributions of neuropsychological assessment of patients with psychiatric disorders. METHOD: All research articles from major journals in psychiatry and clinical psychology since 1991 that focused on neuropsychological assessment of psychiatric patients were reviewed. Other journals and earlier studies were reviewed selectively. RESULTS: Neuropsychological test data have made significant contributions to the development of hypotheses about abnormal brain structure and function in patients with psychiatric disorders, yet many findings from neuropsychological assessments of psychiatric patients are misinterpreted. The extent to which neuropsychological test data in psychiatric populations can be interpreted to reflect abnormalities in brain structure and function is frequently exaggerated, as is the ability of neuropsychological measures to serve as specific cognitive probes in imaging studies of physiological activation. On the other hand, the utility of neuropsychological test batteries as measures of the patterns of cognitive strength and deficit in individuals with specific psychiatric disorders is frequently underestimated. CONCLUSIONS: In addition to testing models of regional brain dysfunction in psychiatric disorders, neuropsychological tests can provide researchers in psychiatry with an improved understanding of the relation between central cognitive impairments and symptoms and serve to identify cognitive predictors of course of illness, and they may provide a method for discriminating among heterogeneous forms of some psychiatric disorders. Clinically, neuropsychological test data can be used to develop treatment strategies tailored for an individual's specific cognitive strengths and deficits.}, Doi = {10.1176/ajp.152.1.6}, Key = {fds273383} } @article{fds273554, Author = {Yehuda, R and Keefe, RS and Harvey, PD and Levengood, RA and Gerber, DK and Geni, J and Siever, LJ}, Title = {Learning and memory in combat veterans with posttraumatic stress disorder.}, Journal = {The American Journal of Psychiatry}, Volume = {152}, Number = {1}, Pages = {137-139}, Year = {1995}, Month = {January}, url = {http://dx.doi.org/10.1176/ajp.152.1.137}, Abstract = {OBJECTIVE: The authors investigated a broad range of memory functions for stimuli unrelated to trauma to determine whether symptoms such as intrusive memories might reflect an underlying cognitive deficit unrelated to the psychological content of the traumatic memory in patients with posttraumatic stress disorder (PTSD). METHOD: The authors measured the intellectual functioning of 20 male combat veterans with PTSD and 12 normal comparison subjects using the WAIS and evaluated them for performance on memory using the California Verbal Learning Test. RESULTS: Veterans with PTSD showed normal abilities in the functions of initial attention, immediate memory, cumulative learning, and active interference from previous learning. However, these veterans showed a circumscribed cognitive deficit, manifested by the presence of substantial retroactive interference and revealed by a significant decrement in retention following exposure to an intervening word list. CONCLUSIONS: The data suggest that patients with PTSD may have fairly specific deficits in the monitoring and regulation of memory information.}, Doi = {10.1176/ajp.152.1.137}, Key = {fds273554} } @article{fds273384, Author = {Davidson, M and Harvey, PD and Powchik, P and Parrella, M and White, L and Knobler, HY and Losonczy, MF and Keefe, RS and Katz, S and Frecska, E}, Title = {Severity of symptoms in chronically institutionalized geriatric schizophrenic patients.}, Journal = {The American Journal of Psychiatry}, Volume = {152}, Number = {2}, Pages = {197-207}, Year = {1995}, Month = {February}, url = {http://dx.doi.org/10.1176/ajp.152.2.197}, Abstract = {OBJECTIVE: The goal of this study was to characterize the symptoms of geriatric, chronically ill, institutionalized schizophrenic patients and investigate age-related differences in schizophrenic symptoms and cognitive performance from early adulthood to late senescence. METHOD: The Positive and Negative Syndrome Scale and the Mini-Mental State examination were used to assess the schizophrenic symptoms and cognitive performance, respectively, of 393 institutionalized schizophrenic patients stratified into seven groups designated by 10-year age intervals from 25 years to over 85 years. RESULTS: In the comparisons of the seven age groups, significant differences between groups in positive and negative subscale scores on the Positive and Negative Syndrome Scale and in Mini-Mental State scores were revealed. Significant correlations between Mini-Mental State scores and Positive and Negative Syndrome Scale negative symptom scores, but not positive symptom scores, were found for all age groups, except for the youngest patients studied. Current treatment with neuroleptics and prior treatment with ECT, insulin coma, or leukotomy could not account for the poor cognitive performance of the older schizophrenic patients. CONCLUSIONS: The older schizophrenic patients continued to experience psychotic and nonpsychotic symptoms in senescence. Their positive symptoms were moderately less severe and their negative symptoms and cognitive impairment were significantly more severe than those of the younger patients. Somatic treatment appeared not to be responsible for the severe cognitive impairment and negative symptoms of the older patients. These data are relevant to chronically hospitalized geriatric schizophrenic patients but not necessarily to all geriatric schizophrenic patients.}, Doi = {10.1176/ajp.152.2.197}, Key = {fds273384} } @article{fds327103, Author = {Keefe, RSE and Lees Roitman and S and Dupre, RL and Harvey, PD and Davis, KL and Mohs, RC}, Title = {The relationship between working memory deficits and other measures sensitive to prefrontal dysfunction}, Journal = {Schizophrenia Research}, Volume = {15}, Number = {1-2}, Pages = {123-123}, Publisher = {Elsevier BV}, Year = {1995}, Month = {April}, url = {http://dx.doi.org/10.1016/0920-9964(95)95378-m}, Doi = {10.1016/0920-9964(95)95378-m}, Key = {fds327103} } @article{fds273553, Author = {Davidson, M and Keefe, RS}, Title = {Cognitive impairment as a target for pharmacological treatment in schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {17}, Number = {1}, Pages = {123-129}, Year = {1995}, Month = {September}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/0920-9964(95)00037-m}, Doi = {10.1016/0920-9964(95)00037-m}, Key = {fds273553} } @article{fds273555, Author = {Keefe, RS and Roitman, SE and Harvey, PD and Blum, CS and DuPre, RL and Prieto, DM and Davidson, M and Davis, KL}, Title = {A pen-and-paper human analogue of a monkey prefrontal cortex activation task: spatial working memory in patients with schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {17}, Number = {1}, Pages = {25-33}, Year = {1995}, Month = {September}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/0920-9964(95)00027-j}, Abstract = {In order to pursue the hypothesis that the dorsolateral prefrontal cortex is a source of cognitive deficit in schizophrenia, we developed an easily administered pen-and-paper human analogue of a visuospatial working memory task that in non-human primates activates the neurons of Walker area 46 (Goldman-Rakic, 1987). Compared to normal controls, schizophrenic patients made significantly greater errors in identifying where a visuospatial stimulus had been presented to them 30 and 60 seconds earlier, and these differences were significantly greater than in an immediate recall condition. These data suggest that schizophrenic patients have visuospatial working memory deficits that are sensitive to pen-and-paper versions of the tasks that activate the Walker area 46 in non-human primates. The availability of an easily administered test that may be associated with the functioning of the prefrontal cortex may enable more specific assessment of this brain region in humans.}, Doi = {10.1016/0920-9964(95)00027-j}, Key = {fds273555} } @article{fds273381, Author = {Trestman, RL and Keefe, RS and Mitropoulou, V and Harvey, PD and deVegvar, ML and Lees-Roitman, S and Davidson, M and Aronson, A and Silverman, J and Siever, LJ}, Title = {Cognitive function and biological correlates of cognitive performance in schizotypal personality disorder.}, Journal = {Psychiatry Research}, Volume = {59}, Number = {1-2}, Pages = {127-136}, Year = {1995}, Month = {November}, ISSN = {0165-1781}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:A1995TY65800014&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Abstract = {There is evidence that some schizophrenic patients have deficits on tests of cognitive function, particularly tests of executive function, including the Wisconsin Card Sorting Test (WCST) and the Trail-making Test, Part B. This study was conducted to determine the generalizability of these findings across the schizophrenia spectrum to schizotypal personality disorder (SPD). Forty DSM-III SPD patients, 56 nonschizophrenia-related other personality disorder (OPD) patients, and 32 normal volunteers from two medical centers performed tests of executive function such as the WCST, Trail-making Part B, Stroop Word-Color Test, and Verbal Fluency, as well as tests of more general intellectual functioning such as the Wechsler Intelligence Scale-Revised Vocabulary and Block Design subtests, and Trail-making Part A. SPD patients performed more poorly on the WCST and on Trail-making Part B than did OPD patients or normal subjects; the groups did not differ on tests of general intellectual functioning. SPD patients may share some of the cognitive deficits observed in schizophrenia.}, Doi = {10.1016/0165-1781(95)02709-2}, Key = {fds273381} } @article{fds327102, Author = {Keefe, RSE and Roitman, SEL and Dupre, RL and Harvey, PD}, Title = {Laboratory and clinical tests of spatial working memory}, Journal = {Schizophrenia Research}, Volume = {18}, Number = {2-3}, Pages = {XIII7-XIII7}, Publisher = {ELSEVIER SCIENCE BV}, Year = {1996}, Month = {February}, Key = {fds327102} } @article{fds273385, Author = {Vocisano, C and Klein, DN and Keefe, RS and Dienst, ER and Kincaid, MM}, Title = {Demographics, family history, premorbid functioning, developmental characteristics, and course of patients with deteriorated affective disorder.}, Journal = {The American Journal of Psychiatry}, Volume = {153}, Number = {2}, Pages = {248-255}, Year = {1996}, Month = {February}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/ajp.153.2.248}, Abstract = {OBJECTIVE: This exploratory study examined the characteristics of a group of unusual and previously undescribed patients with major affective disorder who not only had been continuously symptomatic for prolonged periods of time but were also so functionally impaired that they required years of continuous care in psychiatric facilities or by family members. METHOD: Twenty-seven inpatients with major mood disorders and 29 inpatients with schizophrenia were recruited from a large state hospital; 27 outpatients with major mood disorders were recruited from an affiliated outpatient facility. The research battery included the Structured Clinical Interview for DSM-III-R--Patient Version, the Premorbid Adjustment Scale, and a semistructured interview designed to assess demographic, family history, developmental, and course information. RESULTS: Inpatients with deteriorated affective disorder differed from outpatients with nondeteriorated affective disorder along several important dimensions, including family history of mental illness, birth-related problems, physical disorders in infancy, premorbid functioning, presence of mixed episodes and rapid cycling, and medication non-compliance between hospitalizations. Inpatients with deteriorated affective disorder differed from inpatients with schizophrenia on the Premorbid Adjustment Scale. Patients with bipolar affective disorder differed from those with unipolar disorder on many of the variables associated with deterioration of functioning. CONCLUSIONS: Birth-related problems, physical disorders in infancy, and poor premorbid adjustment in childhood and adolescence appear to play an important role in deterioration of functioning among patients with unipolar depression. Disruption in treatment because of medication noncompliance and the appearance of mixed episodes and rapid cycling are associated with functional decline in bipolar affective disorder. Several characteristics previously considered specific to deterioration of functioning in schizophrenia, such as a high rate of birth complications and poor premorbid adjustment, appear to be associated with functional deterioration among patients with major depression as well.}, Doi = {10.1176/ajp.153.2.248}, Key = {fds273385} } @article{fds273388, Author = {Harvey, PD and Keefe, RSE and Mitroupolou, V and DuPre, R and Roitman, SL and Mohs, RC and Siever, LJ}, Title = {Information-processing markers of vulnerability to schizophrenia: Performance of patients with schizotypal and nonschizotypal personality disorders}, Journal = {Psychiatry Research}, Volume = {60}, Number = {1}, Pages = {49-56}, Publisher = {Elsevier BV}, Year = {1996}, Month = {February}, url = {http://dx.doi.org/10.1016/0165-1781(95)02764-5}, Abstract = {Deficits in performance on tests of information processing have been proposed to be markers of vulnerability to schizophrenia. Very few of the previous studies of these information-processing deficits, however, have examined subjects who have clinical diagnoses of schizotypal personality disorders; most studies instead have focused on schizophrenic patients and their relatives or subjects selected on the basis of psychometric evidence of schizotypal traits. In this study, patients with DSM-III schizotypal (n = 29) and non-odd cluster (n = 33) personality disorders were examined With the Continuous Performance Test (CPT) and a backward masking test and compared with a group of normal volunteers (n = 31). Patients with schizotypal personality disorder manifested a specific deficit in performance, making significantly more errors of omission in the degraded stimulus condition of the CPT compared with the nondegraded condition, whereas non-odd cluster patients and the normal volunteers performed the same in both conditions. No differences in performance between the groups were found for any of the backward-masking measures. These data suggest that specific deficits in CPT performance, possibly reflecting reduced processing capacity or load responsiveness of the vigilance system, are associated with schizotypal personality disorder and fail to replicate previous studies finding backward-masking deficits in various nonclinical schizotypal populations.}, Doi = {10.1016/0165-1781(95)02764-5}, Key = {fds273388} } @article{fds327101, Author = {Roitman, SEL and Keefe, RSE and Dupre, RL and Siever, LJ}, Title = {Visuospatial working memory in schizotypal personality disorder}, Journal = {Biological Psychiatry}, Volume = {39}, Number = {7}, Pages = {266-266}, Publisher = {ELSEVIER SCIENCE INC}, Year = {1996}, Month = {April}, Key = {fds327101} } @article{fds273386, Author = {Siegel, BV and Trestman, RL and O'Flaithbheartaigh, S and Mitropoulou, V and Amin, F and Kirrane, R and Silverman, J and Schmeidler, J and Keefe, RS and Siever, LJ}, Title = {D-amphetamine challenge effects on Wisconsin Card Sort Test. Performance in schizotypal personality disorder.}, Journal = {Schizophrenia Research}, Volume = {20}, Number = {1-2}, Pages = {29-32}, Year = {1996}, Month = {May}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/0920-9964(95)00002-x}, Abstract = {The authors assessed the effects on Wisconsin Card Sort (WCST) performance and psychiatric symptoms of 30 mg d-amphetamine, a dopamine and norepinephrine agonist, vs placebo in nine patients with schizotypal personality disorder (SPD). Patients, particularly those who made more perseverative errors, demonstrated amphetamine-associated improvement on WCST performance. The data in this preliminary study suggest that some of the cognitive dysfunction present in SPD may improve with amphetamine challenge.}, Doi = {10.1016/0920-9964(95)00002-x}, Key = {fds273386} } @article{fds273387, Author = {Epstein, JI and Keefe, RS and Roitman, SL and Harvey, PD and Mohs, RC}, Title = {Impact of neuroleptic medications on continuous performance test measures in schizophrenia.}, Journal = {Biological Psychiatry}, Volume = {39}, Number = {10}, Pages = {902-905}, Year = {1996}, Month = {May}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/0006-3223(95)00588-9}, Doi = {10.1016/0006-3223(95)00588-9}, Key = {fds273387} } @article{fds273389, Author = {Keefe, RS and Frescka, E and Apter, SH and Davidson, M and Macaluso, JM and Hirschowitz, J and Davis, KL}, Title = {Clinical characteristics of Kraepelinian schizophrenia: replication and extension of previous findings.}, Journal = {The American Journal of Psychiatry}, Volume = {153}, Number = {6}, Pages = {806-811}, Year = {1996}, Month = {June}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/ajp.153.6.806}, Abstract = {OBJECTIVE: Subtypologies of schizophrenia based on cross-sectional criteria, such as the nomenclature of the DSMs, have not been successful in identifying valid diagnostic subgroups among patients with schizophrenia. A subtypology that uses criteria to classify individuals on the basis of longitudinal deficits in self-care may identify a more valid subgroup of schizophrenic patients. METHOD: This study describes the clinical characteristics of a group of schizophrenic patients identified on the basis of a longitudinal criterion: at least 5 years of continuous and complete dependence on others for obtaining and maintaining the basic necessities of life, including food, clothing, and shelter. RESULTS: Sixty-one "Kraepelinian" schizophrenic inpatients, when compared to 80 non-Kraepelinian schizophrenic inpatients who were similar in years of illness, age, and education, demonstrated more severe negative symptoms and more severe formal thought disorder; yet the severity of their delusions, hallucinations, and bizarre behavior did not differ significantly. None of the Kraepelinian patients and eight non-Kraepelinian patients met DSM-III-R criteria for schizoaffective disorder. CONCLUSIONS: Data from this replication study suggest that Kraepelinian schizophrenic patients, identified on the basis of a longitudinal course characterized by severe dysfunctions in self-care, may represent an alternative, and possibly more valid, method of subtyping schizophrenia.}, Doi = {10.1176/ajp.153.6.806}, Key = {fds273389} } @article{fds327100, Author = {Keefe, RSE and Cornblatt, BA}, Title = {The neuropsychology of schizophrenia - David,AS, Cutting,JC}, Journal = {Contemporary Psychology: a Journal of Reviews}, Volume = {41}, Number = {9}, Pages = {900-902}, Publisher = {AMER PSYCHOLOGICAL ASSOC}, Year = {1996}, Month = {September}, Key = {fds327100} } @article{fds273390, Author = {Harvey, PD and Davidson, M and White, L and Keefe, RS and Hirschowitz, J and Mohs, RC and Davis, KL}, Title = {Empirical evaluation of the factorial structure of clinical symptoms in schizophrenia: effects of typical neuroleptics on the brief psychiatric rating scale.}, Journal = {Biological Psychiatry}, Volume = {40}, Number = {8}, Pages = {755-760}, Year = {1996}, Month = {October}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/0006-3223(95)00486-6}, Abstract = {There has been little investigation of the effect of neuroleptic medication on the structure of symptoms in schizophrenia. In this study, 135 male schizophrenic patients were rated with the Brief Psychiatric Rating Scale (BPRS) after 4 weeks of treatment with typical neuroleptic medication and after 2 weeks free of neuroleptics, with the order of assessment varying across patients. Confirmatory factor analyses (CFA) found that there were no differences in symptom structure across medication status and no differences in the structure of symptoms in treatment responders and nonresponders. The typical 5-factor BPRS model fit the data poorly and the fit improved considerably through deletion of items measuring symptoms not associated with schizophrenia, suggesting that some of the symptoms that contribute to a total BPRS score may be adding primarily error variance. Although the sample size in this study is limited, the results suggest that using total BPRS scores to measure severity of schizophrenic symptoms should be reconsidered.}, Doi = {10.1016/0006-3223(95)00486-6}, Key = {fds273390} } @article{fds273391, Author = {Harvey, PD and Keefe, RSE}, Title = {Cognitive impairment in schizophrenia and implications of atypical neuroleptic treatment}, Journal = {Cns Spectrums}, Volume = {2}, Number = {8}, Pages = {41-55}, Year = {1997}, ISSN = {1092-8529}, url = {http://dx.doi.org/10.1017/S1092852900005034}, Abstract = {Cognitive impairment is considered a central feature of schizophrenia. Many aspects of cognition are impaired in schizophrenia. Careful evaluation of the relationship between cognitive impairment and the other symptoms of schizophrenia has revealed several important findings. In this article, we discuss these findings, the effects of typical neuroleptic therapy on cognitive impairment, and important issues to address in cognitive enhancement studies in schizophrenia.}, Doi = {10.1017/S1092852900005034}, Key = {fds273391} } @article{fds327099, Author = {Keefe, RSE and Courtney, M and McEvoy, JM}, Title = {Self-monitoring deficits in schizophrenia: Autonoetic agnosia}, Journal = {Schizophrenia Research}, Volume = {24}, Number = {1-2}, Pages = {110-110}, Publisher = {Elsevier BV}, Year = {1997}, Month = {January}, url = {http://dx.doi.org/10.1016/s0920-9964(97)82306-7}, Doi = {10.1016/s0920-9964(97)82306-7}, Key = {fds327099} } @article{fds273392, Author = {Keefe, RS and Silverman, JM and Mohs, RC and Siever, LJ and Harvey, PD and Friedman, L and Roitman, SE and DuPre, RL and Smith, CJ and Schmeidler, J and Davis, KL}, Title = {Eye tracking, attention, and schizotypal symptoms in nonpsychotic relatives of patients with schizophrenia.}, Journal = {Archives of General Psychiatry}, Volume = {54}, Number = {2}, Pages = {169-176}, Year = {1997}, Month = {February}, ISSN = {0003-990X}, url = {http://dx.doi.org/10.1001/archpsyc.1997.01830140081014}, Abstract = {BACKGROUND: Biological relatives of patients with schizophrenia demonstrate an increased prevalence of schizotypal personality disorder symptoms, eye tracking deficits, and attentional disturbances. We investigated whether these hypothesized components of a schizophrenia-related phenotype are associated with one another or are independent in nonpsychotic relatives of patients with schizophrenia. METHODS: Eighty-three nonpsychotic first-degree relatives of 38 patients with schizophrenia and 45 control subjects without a psychiatric diagnosis underwent clinical evaluation, eye tracking evaluation, and the Continuous Performance Test (CPT) of visual attention. RESULTS: Eye tracking qualitative rating was more powerful than quantitative eye tracking measures or CPT measures in discriminating relatives of patients with schizophrenia from control subjects. Correlations between neurocognitive variables and DSM-III-R schizotypal personality disorder symptom clusters suggested that CPT errors of omission are associated with positive schizotypal symptoms. Eye tracking measures were not significantly correlated with schizotypal symptoms or CPT errors in relatives of patients with schizophrenia. CONCLUSIONS: Eye tracking deficits in the relatives of patients with schizophrenia are unrelated to CPT deficits and schizotypal symptoms. Eye tracking deficits and disturbances in visual attention may be separate components of a schizophrenia-related phenotype and should be considered as independent factors in genetic studies of schizophrenia.}, Doi = {10.1001/archpsyc.1997.01830140081014}, Key = {fds273392} } @article{fds327098, Author = {Roitman, SEL and Keefe, RSE and Mitropoulou, V and Dupre, RL and Siever, LJ}, Title = {Visuospatial working memory in schizotypal personality disorder}, Journal = {Biological Psychiatry}, Volume = {41}, Pages = {355-355}, Publisher = {ELSEVIER SCIENCE INC}, Year = {1997}, Month = {April}, Key = {fds327098} } @article{fds273395, Author = {Roitman, SE and Cornblatt, BA and Bergman, A and Obuchowski, M and Mitropoulou, V and Keefe, RS and Silverman, JM and Siever, LJ}, Title = {Attentional functioning in schizotypal personality disorder.}, Journal = {The American Journal of Psychiatry}, Volume = {154}, Number = {5}, Pages = {655-660}, Year = {1997}, Month = {May}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/ajp.154.5.655}, Abstract = {OBJECTIVE: Previous research has shown biological, phenomenological, and cognitive similarities between schizophrenic patients and individuals with schizophrenia-related personality disorders and features. Evidence further suggests that of these common dysfunctions, abnormal attention is one of the most promising indicators of a biological susceptibility to schizophrenia-related disorders. Although attentional dysfunctions have been reliably detected in schizophrenic patients as well as in a variety of populations at risk for schizophrenia, few studies have investigated attention in clinical patients with schizotypal personality disorder. In this study, the extent of attentional impairment was assessed in subjects with schizotypal personality disorder, normal comparison subjects, patients with other personality disorders, and schizophrenic patients. METHOD: Thirty subjects with schizotypal personality disorder, 35 subjects with other personality disorders (i.e., clinic patients with non-odd cluster personality disorders), 36 subjects with schizophrenia, and 20 comparison subjects who did not meet criteria for any axis I or axis II disorder participated in this study. All subjects were diagnosed according to DSM-III criteria. Attention was assessed by using the Continuous Performance Test, Identical Pairs Version. RESULTS: Analyses indicated that subjects with schizotypal personality disorder, like schizophrenic subjects, performed significantly worse than comparison subjects on both the verbal and spatial tasks of the Continuous Performance Test, Identical Pairs Version. In contrast, patients with other personality disorders performed similarly to comparison subjects across conditions. CONCLUSIONS: These results suggest that patients with schizotypal personality disorder are impaired in their attentional functioning relative to normal comparison subjects and that they display deficits that are similar to the pattern characterizing schizophrenic patients.}, Doi = {10.1176/ajp.154.5.655}, Key = {fds273395} } @article{fds273393, Author = {Keefe, RS and Lees-Roitman, SE and Dupre, RL}, Title = {Performance of patients with schizophrenia on a pen and paper visuospatial working memory task with short delay.}, Journal = {Schizophrenia Research}, Volume = {26}, Number = {1}, Pages = {9-14}, Year = {1997}, Month = {July}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/S0920-9964(97)00037-6}, Abstract = {Human and nonhuman primate data suggest that visuospatial working memory is mediated by a neural network that includes the prefrontal cortex. Simple working memory tasks are less complex than standard neuropsychological tests of frontal dysfunction. As such, they are less vulnerable to general performance factors such as amotivation and uncooperativeness in schizophrenic patients. These tasks thus hold promise as potential measures of frontal dysfunction in schizophrenia. However, the specific parameters of visuospatial working memory deficit in schizophrenia have not been established. This study assessed working memory functions in 18 schizophrenic patients and 28 controls using a pen-and-paper analogue of a monkey prefrontal cortex activation task. Schizophrenic patients and controls performed similarly on a sensory-guided task that did not require working memory functions, yet schizophrenic patients performed significantly worse than controls on tasks that required subjects to retain visuospatial information for delay periods of 10 and 20 s. These data suggest that the working memory deficits in patients with schizophrenia begin to appear less than 10 s following encoding of visuospatial information and that these working memory deficits can be assessed with easily administered pen-and-paper tasks.}, Doi = {10.1016/S0920-9964(97)00037-6}, Key = {fds273393} } @article{fds273394, Author = {Roitman, SE and Keefe, RS and Harvey, PD and Siever, LJ and Mohs, RC}, Title = {Attentional and eye tracking deficits correlate with negative symptoms in schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {26}, Number = {2-3}, Pages = {139-146}, Year = {1997}, Month = {August}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/s0920-9964(97)00044-3}, Abstract = {Thirty patients with a DSM-III-R diagnosis of schizophrenia were assessed for severity of schizophrenic symptoms using the Brief Psychiatric Rating Scale (BPRS) and were tested on a Continuous Performance Test (CPT) and a smooth pursuit eye tracking task. Negative symptoms were significantly correlated with eye tracking impairment (r = 0.43, p < 0.01) and CPT deficits (r = 0.67, p < 0.001), but performance on neither task was correlated with positive symptoms. CPT performance and eye tracking performance were modestly correlated with each other (r = 0.39, p < 0.01) and CPT performance was found to be a stronger predictor of negative symptoms than eye tracking performance. These data indicate that neurocognitive markers of vulnerability to schizophrenia are associated with negative rather than positive symptoms.}, Doi = {10.1016/s0920-9964(97)00044-3}, Key = {fds273394} } @article{fds273396, Author = {Vocisano, C and Klein, DN and Keefe, RS}, Title = {Lifetime comorbidity, lifetime history of psychosis and suicide attempts, and current symptoms of patients with deteriorated affective disorder.}, Journal = {Psychiatry Research}, Volume = {73}, Number = {1-2}, Pages = {33-45}, Year = {1997}, Month = {November}, ISSN = {0165-1781}, url = {http://dx.doi.org/10.1016/s0165-1781(97)00114-5}, Abstract = {This study extends our prior research by examining the lifetime comorbidity, history of psychosis and suicide attempts, and current symptoms of an unusual group of patients with major affective disorders who have not only been symptomatic for prolonged periods but have also been so functionally impaired that they required years of care in psychiatric facilities or by family members. Twenty-seven of these deteriorated affective patients and 29 patients with deteriorated schizophrenia were recruited from a large state hospital; 27 patients with non-deteriorated affective disorder were recruited from an affiliated outpatient facility. Patients with deteriorated affective disorder, as compared to those with non-deteriorated affective disorder, were far more likely to have a history of psychotic symptoms with suicidal themes and a history of life-threatening suicide attempts and completed suicide. Deteriorated affective patients were also more likely to meet criteria for melancholia and to have attentional deficits, thought disorder and negative symptoms. The deteriorated and non-deteriorated affective groups had similar lifetime rates of psychotic symptoms (bizarre and non-bizarre) and lifetime psychiatric comorbidity. Functional deterioration in schizophrenia, as compared to functional deterioration in affective disorders, was distinguished by a virtual absence of psychotic symptoms with suicidal themes, lower lifetime rates of life-threatening suicide attempts, greater variety and severity of psychotic symptoms, and greater severity of current affective flattening, anhedonia-asociality and disorientation to time. The results of this study extend our previous research by demonstrating that patients with major mood disorders who have experienced extreme functional deterioration evidence a distinct constellation of symptoms that differentiates them from their better outcome peers with mood disorders, and from similarly functionally deteriorated patients with schizophrenia.}, Doi = {10.1016/s0165-1781(97)00114-5}, Key = {fds273396} } @article{fds327097, Author = {Keefe, RSE and Courtney, M and Bayan, UJ and Harvey, PD and McEvoy, JM}, Title = {Does autonoetic agnosia underlie specific psychotic symptoms in schizophrenia?}, Journal = {Schizophrenia Research}, Volume = {29}, Number = {1-2}, Pages = {36-36}, Publisher = {Elsevier BV}, Year = {1998}, Month = {January}, url = {http://dx.doi.org/10.1016/s0920-9964(97)88379-x}, Doi = {10.1016/s0920-9964(97)88379-x}, Key = {fds327097} } @article{fds273397, Author = {Davis, KL and Buchsbaum, MS and Shihabuddin, L and Spiegel-Cohen, J and Metzger, M and Frecska, E and Keefe, RS and Powchik, P}, Title = {Ventricular enlargement in poor-outcome schizophrenia.}, Journal = {Biological Psychiatry}, Volume = {43}, Number = {11}, Pages = {783-793}, Year = {1998}, Month = {June}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/s0006-3223(97)00553-2}, Abstract = {BACKGROUND: A subset of patients with schizophrenia, defined on the basis of longitudinal deficits in self-care, may show a classic ("Kraepelinian") degenerative course. An independent validator of the phenomenologically defined Kraepelinian subtype might be provided by a structural indicator of possible brain degeneration: ventricular size as measured by computed tomography (CT). METHODS: To examine whether Kraepelinian patients would show a differential increase in ventricular size over time, two CT scans were conducted at intervals separated by > 4 years, an average of 5 years. Fifty-three male patients with DSM-III-R diagnoses of chronic schizophrenia were subdivided into Kraepelinian (n = 22; mean age = 42 +/- 6 years) and non-Kraepelinian (n = 31; mean age = 38 +/- 12.2 years) subgroups. Kraepelinian patients were defined on the basis of longitudinal criteria: > 5 years of complete dependence on others for life necessities and care, lack of employment, and sustained symptomatology. Thirteen normal elderly volunteers (mean age = 60 +/- 17.8) were also scanned at 4-year intervals. CT measurements were made by raters without knowledge of subgroup membership. A semiautomated computer program was used to trace the anterior horn, lateral ventricles, and temporal horns for each slice level on which they were clearly seen. RESULTS: The ventricles showed a bilateral increase in size over the 4-year interval in the Kraepelinian subgroup, more marked in the left hemisphere than the right. By contrast, neither the non-Kraepelinian subgroup nor the normal volunteers showed significant CT changes from scan 1 to scan 2. CONCLUSIONS: Thus, the longitudinal dysfunctions in self-care that characterize the Kraepelinian patients were associated with an independent indicator of brain abnormality.}, Doi = {10.1016/s0006-3223(97)00553-2}, Key = {fds273397} } @article{fds273399, Author = {Keefe, RS and Silva, SG and Perkins, DO and Lieberman, JA}, Title = {The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis.}, Journal = {Schizophrenia Bulletin}, Volume = {25}, Number = {2}, Pages = {201-222}, Year = {1999}, ISSN = {0586-7614}, url = {http://www.ncbi.nlm.nih.gov/pubmed/10416727}, Abstract = {Cognitive deficits are a fundamental feature of the psychopathology of schizophrenia. Yet the effect of treatment on this dimension of the illness has been unclear. Atypical antipsychotic medications have been reported to reduce the neurocognitive impairment associated with schizophrenia. However, studies of the pattern and degree of cognitive improvement with these compounds have been methodologically limited and have produced variable results, and few findings have been replicated. To clarify our understanding of the effects of atypical antipsychotic drugs on neurocognitive deficits in patients with schizophrenia, we have (1) reported on newly established standards for research design in studies of treatment effects on cognitive function in schizophrenia, (2) reviewed the literature on this topic and determined the extent to which 15 studies on the effect of atypical antipsychotics met these standards, (3) performed a meta-analysis of the 15 studies, which suggested general cognitive enhancement with atypical antipsychotics, and (4) described the pharmacological profile of these agents and considered the pharmacological basis for their effects on neurocognition. Finally, we suggest directions for the development of new therapeutic strategies.}, Doi = {10.1093/oxfordjournals.schbul.a033374}, Key = {fds273399} } @article{fds273401, Author = {Keefe, RSE and Bollini, AM and Silva, SG}, Title = {Do novel antipsychotics improve cognition? A report of a meta-analysis}, Journal = {Psychiatric Annals}, Volume = {29}, Number = {11}, Pages = {623-629}, Publisher = {SLACK INC}, Year = {1999}, Month = {January}, url = {http://dx.doi.org/10.3928/0048-5713-19991101-08}, Doi = {10.3928/0048-5713-19991101-08}, Key = {fds273401} } @article{fds327096, Author = {Keefe, RSE and Bollini, AM and Courtney, MC and Wilson, WH and McEvoy, JP}, Title = {Successful treatment of self-monitoring deficits predicts psychotic symptom decrease}, Journal = {Schizophrenia Research}, Volume = {36}, Number = {1-3}, Pages = {172-172}, Publisher = {ELSEVIER SCIENCE BV}, Year = {1999}, Month = {April}, Key = {fds327096} } @article{fds273398, Author = {Keefe, RS and Arnold, MC and Bayen, UJ and Harvey, PD}, Title = {Source monitoring deficits in patients with schizophrenia; a multinomial modelling analysis.}, Journal = {Psychological Medicine}, Volume = {29}, Number = {4}, Pages = {903-914}, Year = {1999}, Month = {July}, ISSN = {0033-2917}, url = {http://dx.doi.org/10.1017/s0033291799008673}, Abstract = {BACKGROUND: Schizophrenia patients, particularly those with symptoms such as thought insertion, passivity experiences and hallucinations, may share an underlying cognitive deficit in monitoring the generation of their own thoughts. This deficit, which has been referred to as 'autonoetic agnosia', may result in the conclusion that self-generated thoughts come from an external source. Previous work supports this notion, yet the statistical approaches that have been used have not enabled a distinction between specific deficits suggesting autonoetic agnosia and more general cognitive dysfunction. METHODS: Autonoetic agnosia was assessed using source-monitoring paradigms in 28 patients with schizophrenia and 19 control subjects. Multinomial model analyses, which allow the distinction between deficits in recognizing information, remembering its source, and response biases, were applied to the data. RESULTS: Schizophrenia patients were impaired in discriminating between words that came from two external sources, from two internal sources, and one internal and one external source. In a condition requiring subjects to distinguish between words they had heard from those they had imagined hearing, when schizophrenic patients did not remember the source of the information, they showed a stronger bias than controls to report that it had come from an external source. CONCLUSIONS: The application of multinomial models to source monitoring data suggests that schizophrenia patients have source monitoring deficits that are not limited to the distinction between internally-generated and externally-perceived information. However, when schizophrenia patients do not remember the source of information, they may be more likely than controls to report that it came from an external source.}, Doi = {10.1017/s0033291799008673}, Key = {fds273398} } @article{fds273400, Author = {Roitman, SE and Mitropoulou, V and Keefe, RS and Silverman, JM and Serby, M and Harvey, PD and Reynolds, DA and Mohs, RC and Siever, LJ}, Title = {Visuospatial working memory in schizotypal personality disorder patients.}, Journal = {Schizophrenia Research}, Volume = {41}, Number = {3}, Pages = {447-455}, Year = {2000}, Month = {February}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/s0920-9964(99)00085-7}, Abstract = {BACKGROUND: Cognitive processing deficits have been identified as an abnormality that schizotypal personality disorder (SPD) individuals share with schizophrenic patients. It has been hypothesized that impaired working memory may be a critical component of several of the more complex cognitive deficits found in schizophrenia spectrum patients. METHOD: 18 DSM-III-R SPD patients, and 17 normal comparison subjects were compared on a pen and paper visuospatial working memory task. Moreover, we identified a second psychiatric comparison group comprised of nine patients with other, non-odd cluster personality disorder diagnoses who met no more than one of the SPD criteria and were also tested on the same task. Each person was given 14 immediate recall trials and 10 trials using a 10 s delay. RESULTS: SPD patients performed significantly worse than normal control subjects on the working memory task. SPD patients also performed significantly worse compared to the non-schizophrenia-related personality disorder psychiatric comparison group. CONCLUSIONS: Like schizophrenic patients, SPD patients demonstrate working memory impairment compared to normal controls. This impairment may be specific to the schizophrenia-related personality disorders.}, Doi = {10.1016/s0920-9964(99)00085-7}, Key = {fds273400} } @article{fds273402, Author = {Bollini, AM and Arnold, MC and Keefe, RS}, Title = {Test-retest reliability of the dot test of visuospatial working memory in patients with schizophrenia and controls.}, Journal = {Schizophrenia Research}, Volume = {45}, Number = {1-2}, Pages = {169-173}, Year = {2000}, Month = {September}, url = {http://dx.doi.org/10.1016/s0920-9964(99)00216-9}, Abstract = {To determine the test-retest reliability of the Dot Test of Visuospatial Working Memory, this task was administered to 29 patients with schizophrenia and 19 normal controls on two consecutive days. The test involved "copying" trials followed by "delay" recall trials. For "copying" trials, subjects saw a dot and then drew it on a blank sheet of paper. For "delay" trials, subjects drew the dot following a 10-, 20-, or 30-s delay. The distance between the stimulus and the drawn dot was measured for each trial. The composite score, termed "working memory deficit," is calculated by subtracting the average of the copying trials from the average of the delay trials. Pearson correlations revealed that overall performance in each group was comparable for days 1 and 2. Intra-class correlations of "working memory deficit" on days 1 and 2 were moderate in patients and controls, suggesting that task performance for each subject was similar on the testing days. Test-retest reliability tended to be higher for 10-s delay performance in patients and controls than for longer delay periods. Further analyses suggested that there was no significant learning effect on the task from day 1 to day 2 for either group on any measure. The Dot Test of Visuospatial Working Memory, especially the composite score, has moderate test-retest reliability and is a valuable tool that can be used to assess working memory functions in studies using a repeated-measures design.}, Doi = {10.1016/s0920-9964(99)00216-9}, Key = {fds273402} } @article{fds354410, Author = {Keefe, RS and Seidman, LJ and Christensen, BK and Yurgelun-Todd, DA and Lewine, RR and Sitskoorn, MM and Lieberman, JA}, Title = {Treatment of neurocognitive deficits with olanzapine or low-dose haloperidol in first episode psychosis}, Journal = {Schizophrenia Research}, Volume = {49}, Number = {1-2}, Pages = {234-234}, Year = {2001}, Key = {fds354410} } @article{fds273403, Author = {Harvey, PD and Keefe, RS}, Title = {Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment.}, Journal = {The American Journal of Psychiatry}, Volume = {158}, Number = {2}, Pages = {176-184}, Year = {2001}, Month = {February}, url = {http://dx.doi.org/10.1176/appi.ajp.158.2.176}, Abstract = {OBJECTIVE: Novel antipsychotic medications have been reported to have beneficial effects on cognitive functioning in patients with schizophrenia. However, these effects have been assessed in studies with considerable variation in methodology. A large number of investigator-initiated and industry-sponsored clinical trials are currently underway to determine the effect of various novel antipsychotics on cognitive deficits in patients with schizophrenia. The ability to discriminate between high- and low-quality studies will be required to understand the true implications of these studies and their relevance to clinical practice. METHOD: This article addresses several aspects of research on cognitive enhancement in schizophrenia, emphasizing how the assessment of cognitive function in clinical trials requires certain standards of study design to lead to interpretable results. RESULTS: Novel antipsychotic medications appear to have preliminary promise for the enhancement of cognitive functioning. However, the methodology for assessing the treatment of cognitive deficits is still being developed. CONCLUSIONS: Researchers and clinicians alike need to approach publications in this area with a watchful eye toward methodological weaknesses that limit the interpretability of findings.}, Doi = {10.1176/appi.ajp.158.2.176}, Key = {fds273403} } @article{fds273404, Author = {Conway, CR and Bollini, AM and Graham, BG and Keefe, RSE and Schiffman, SS and McEvoy, JP}, Title = {Sensory acuity and reasoning in delusional disorder.}, Journal = {Comprehensive Psychiatry}, Volume = {43}, Number = {3}, Pages = {175-178}, Year = {2002}, ISSN = {0010-440X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11994833}, Abstract = {Systematic research on delusional disorder (DD) is limited. The goal of this study was to assess DD patients in the following areas: sensory capacities, decision-making style, and complex reasoning. Ten DD patients and 10 matched normal controls completed the following (1) smell, taste, and vision testing; (2) a probabilistic inference test in which subjects made probability decisions; and (3) a gambling task assessing complex reasoning. No significant difference was found between DD subjects and normals for taste acuity, olfactory acuity, or olfactory discrimination. No difference in visual acuity was noted, but sample size was limited. In addition, DD subjects required significantly less data to make probability decisions than normal controls. Despite using less data, DD subjects were as certain as controls regarding the accuracy of their decisions. As for complex reasoning, DD subjects performed as well as normal controls, but tended to surmise the purpose of the task sooner than normals, a difference that approached significance. In conclusion, these results suggest no differences between DD and normal subjects regarding olfaction, taste, and vision. The reasoning studies suggest that DD subjects may have a "cognitive set" that predisposes them to make conclusions with significantly less data than normals. Further, the study suggests that this reasoning difference generalizes to events outside the DD subjects' delusional realm and can be evoked in an experimental environment.}, Doi = {10.1053/comp.2002.32358}, Key = {fds273404} } @article{fds273406, Author = {Keefe, RSE}, Title = {[The evaluation of cognitive dysfunctions in schizophrenia].}, Journal = {L'Encephale}, Volume = {28 Spec No 2 Pt 2}, Number = {5 II}, Pages = {S11-S13}, Year = {2002}, ISSN = {0013-7006}, Key = {fds273406} } @article{fds273405, Author = {Keefe, RSE and Arnold, MC and Bayen, UJ and McEvoy, JP and Wilson, WH}, Title = {Source-monitoring deficits for self-generated stimuli in schizophrenia: multinomial modeling of data from three sources.}, Journal = {Schizophrenia Research}, Volume = {57}, Number = {1}, Pages = {51-67}, Year = {2002}, Month = {September}, ISSN = {0920-9964}, url = {http://www.ncbi.nlm.nih.gov/pubmed/12165376}, Abstract = {INTRODUCTION: Schizophrenia patients, particularly those with specific types of hallucinations and delusions, may have a deficit in monitoring the generation of thought. This deficit, termed autonoetic agnosia, may result in the conclusion that self-generated thoughts come from an external source. METHODS: This study assessed autonoetic agnosia in 29 schizophrenic patients and 19 controls by applying a recently developed technique from cognitive science: multinomial modeling of source-monitoring data. RESULTS: Schizophrenic patients demonstrated deficits in monitoring the source of self-generated information, yet performed similarly to controls in monitoring the source of visual and auditory information. Schizophrenic patients with specific "target" symptoms such as auditory hallucinations and thought insertion had greater deficits than other patients in recognizing self-generated information. CONCLUSION: This study offers partial support for the notion that schizophrenic patients manifest autonoetic agnosia.}, Doi = {10.1016/s0920-9964(01)00306-1}, Key = {fds273405} } @article{fds273408, Author = {Keefe, RSE and Mohs, RC and Bilder, RM and Harvey, PD and Green, MF and Meltzer, HY and Gold, JM and Sano, M}, Title = {Neurocognitive assessment in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project schizophrenia trial: development, methodology, and rationale.}, Journal = {Schizophrenia Bulletin}, Volume = {29}, Number = {1}, Pages = {45-55}, Year = {2003}, url = {http://dx.doi.org/10.1093/oxfordjournals.schbul.a006990}, Abstract = {Patients with schizophrenia are severely impaired in crucial aspects of neurocognitive function. This impairment is the strongest clinical correlate of poor long-term outcome and adaptive dysfunction. Reports of neurocognitive enhancement with second generation antipsychotic medications have thus offered promise for improvement in the long-term outcome of patients with schizophrenia. However, the majority of these studies have had serious weaknesses in methodology, such as open-label design, small samples, or inappropriate dosing of medications. More recent studies have addressed these methodological issues but have been of short duration and have largely been sponsored by pharmaceutical companies. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project is a unique opportunity to address the comparative neurocognitive effectiveness of available antipsychotic medications. This article describes the neurocognitive methods used in the schizophrenia trial of the CATIE project, including the selection and training of neurocognitive raters, patient inclusion criteria for assessment, rationale for the choice of neurocognitive instruments, and methodology for each neurocognitive test.}, Doi = {10.1093/oxfordjournals.schbul.a006990}, Key = {fds273408} } @article{fds354407, Author = {Yurgelun-Todd, DA and Renshaw, PF and Wei, H and Keefe, RS and Charles, HC and Tohen, M and Liebermann, JA}, Title = {Improved attention is associated with reductions in frontal lobe lactate levels in first episode psychosis}, Journal = {Schizophrenia Research}, Volume = {60}, Number = {1}, Pages = {318-318}, Publisher = {Elsevier BV}, Year = {2003}, Month = {March}, url = {http://dx.doi.org/10.1016/s0920-9964(03)80271-2}, Doi = {10.1016/s0920-9964(03)80271-2}, Key = {fds354407} } @article{fds354408, Author = {Keefe, R and Seidman, LJ and Christensen, B and Hamer, RM and Yurgelun-Todd, D and Lewine, R and Sitskoorn, M and Sharma, T and Tohen, M and Lieberman, JA}, Title = {Neurocognitive effects of olanzapine and low-dose haloperidol: A two-year treatment study in first episode psychosis}, Journal = {Schizophrenia Research}, Volume = {60}, Number = {1}, Pages = {289-289}, Publisher = {Elsevier BV}, Year = {2003}, Month = {March}, url = {http://dx.doi.org/10.1016/s0920-9964(03)80477-2}, Doi = {10.1016/s0920-9964(03)80477-2}, Key = {fds354408} } @article{fds354409, Author = {Breier, A and Keefe, RS and Young, CA and Purdon, SE and Gold, JM and Davis, KL}, Title = {A one-year double-blind comparison of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in patients with schizophrenia}, Journal = {Schizophrenia Research}, Volume = {60}, Number = {1}, Pages = {274-275}, Publisher = {Elsevier BV}, Year = {2003}, Month = {March}, url = {http://dx.doi.org/10.1016/s0920-9964(03)80434-6}, Doi = {10.1016/s0920-9964(03)80434-6}, Key = {fds354409} } @article{fds327095, Author = {Keefe, RSE and Seidman, LJ and Christensen, BK and Hamer, RM and Yurgelun-Todd, DA and Lewine, RRJ and Sitskoorn, MM and Sharma, T and Tohen, M and Lieberman, JA}, Title = {Neurocognitive effects of olanzapine and low-dose haloperidol: A two-year treatment study in first episode psychosis}, Journal = {Biological Psychiatry}, Volume = {53}, Number = {8}, Pages = {26S-26S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2003}, Month = {April}, Key = {fds327095} } @article{fds326768, Author = {Yurgelun-Todd, DA and Renshaw, PF and Wei, H and Keefe, RSE and Charles, HC and Tohen, M and Seidman, LJ and Christensen, BK and Hamer, RM and Sharma, T and Sitskoorn, MM and Gur, RC and Tollefson, GD and Lieberman, JA}, Title = {Improved attention is associated with reductions in frontal lobe lactate levels in first episode psychosis}, Journal = {Biological Psychiatry}, Volume = {53}, Number = {8}, Pages = {156S-156S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2003}, Month = {April}, Key = {fds326768} } @article{fds273407, Author = {Keefe, RSE and Poe, MP and McEvoy, JP and Vaughan, A}, Title = {Source monitoring improvement in patients with schizophrenia receiving antipsychotic medications.}, Journal = {Psychopharmacology}, Volume = {169}, Number = {3-4}, Pages = {383-389}, Year = {2003}, Month = {September}, ISSN = {0033-3158}, url = {http://www.ncbi.nlm.nih.gov/pubmed/12759802}, Abstract = {RATIONALE: The absence of a relationship between cognitive deficit treatment response and positive symptom treatment response is often assumed, and few data have shed light on this issue. Most of these data have been collected using standard neuropsychological measures, which are ill-designed to assess the types of neurocognitive disturbances associated with psychotic symptoms. This study investigates the effect of treatment on source monitoring performance and its relation to the reduction of certain psychotic symptoms associated with the inability to identify self-generated mental events, known as "autonoetic agnosia". OBJECTIVES: To determine whether risperidone, olanzapine, and haloperidol were differentially effective in reducing autonoetic agnosia and whether changes in this aspect of cognition were related to reduction of specific symptoms of psychosis. METHODS: From a cohort of 49 patients diagnosed with schizophrenia by DSM-IV criteria and randomly assigned to double-blind treatment with risperidone, olanzapine, or haloperidol, 16 patients were identified with symptoms believed to reflect autonoetic agnosia ("target symptoms") as assessed with the Schneiderian Symptom Rating Scale, and then evaluated during a baseline period, and then at 1, 2, and 3 weeks. Autonoetic agnosia was assessed as the ability of a patient to distinguish self-generated words from both experimenter-generated words and pictorially presented words. RESULTS: Analysis of patients from all treatment groups found a significant reduction in the number of "target" Schneiderian symptoms. Discrimination for items from the self-generated and heard sources significantly improved with treatment, as did the number of self-generated items that patients remembered as coming from the heard source ("self-hear errors"). The correlation between improvement in recognition of self-generated items and reduction in target Schneiderian symptoms after 2 weeks of treatment suggested a modest relationship between symptom improvement and changes in autonoetic agnosia. CONCLUSIONS: While the differences between medications were not statistically significant, antipsychotic medication in general was associated with improvements in symptoms and cognitive deficits that may underlie autonoetic agnosia. Improvement of autonoetic agnosia was a weak predictor of positive symptom improvement in a limited sample.}, Doi = {10.1007/s00213-003-1476-0}, Key = {fds273407} } @article{fds354403, Author = {Perkins, D and Gu, HB and Zipursky, RB and Christensen, BK and Dixon, V and Keefe, RS}, Title = {Neurocognitive function in individuals "at-risk" for psychosis}, Journal = {Neuropsychopharmacology}, Volume = {29}, Pages = {S220-S220}, Year = {2004}, Key = {fds354403} } @article{fds354406, Author = {Keefe, RS and Eesley, CE and Poe, MP}, Title = {Defining a cognitive function decrement in schizophrenia}, Journal = {Biological Psychiatry}, Volume = {55}, Pages = {41S-41S}, Year = {2004}, Key = {fds354406} } @article{fds355041, Author = {Hawkins, KA and Addington, J and Keefe, RS and Christensen, B and Woods, SW and Miller, TJ and Trzaskoma, QN and Breier, A and Zipursky, RB and Perkins, DO}, Title = {Effect of olanzapine versus placebo on the neuropsychological status of prodromal subjects}, Journal = {Schizophrenia Research}, Volume = {67}, Number = {1}, Pages = {205-205}, Year = {2004}, Key = {fds355041} } @article{fds337109, Author = {Keefe, RSE and Goldberg, TE and Harvey, PD and Gold, JM and Poe, M and Coughenour, L}, Title = {The brief assessment of cognition in schizophrenia: Reliability, sensitivity, and comparison with a standard neurocognitive battery}, Journal = {Schizophrenia Research}, Volume = {67}, Number = {1}, Pages = {263-263}, Publisher = {ELSEVIER SCIENCE BV}, Year = {2004}, Month = {February}, Key = {fds337109} } @article{fds327091, Author = {Keefe, RSE and Seidman, LJ and Christensen, B and Hamer, RM and Yurgelun-Todd, D}, Title = {Neurocognitive effects of olanzapine and low-dose haloperidol: A two-year treatment study in first episode psychosis}, Journal = {Schizophrenia Research}, Volume = {67}, Number = {1}, Pages = {206-206}, Publisher = {ELSEVIER SCIENCE BV}, Year = {2004}, Month = {February}, Key = {fds327091} } @article{fds327092, Author = {Marquez, EM and Keefe, RSE and Purdon, SE and Rock, SL and Alaka, KJ and Ahmed, S and Mohs, RC}, Title = {Is cognitive improvement with antipsychotic treatment pseudospecific?}, Journal = {Schizophrenia Research}, Volume = {67}, Number = {1}, Pages = {207-207}, Publisher = {ELSEVIER SCIENCE BV}, Year = {2004}, Month = {February}, Key = {fds327092} } @article{fds327093, Author = {Mohs, RC and Alaka, KJ and Keefe, RSE and Purdon, SE and Rock, SL and Wei, H and Marquez, EM and Ahmed, S}, Title = {Functional outcomes and characteristics of olanzapine cognitive super-responders}, Journal = {Schizophrenia Research}, Volume = {67}, Number = {1}, Pages = {207-208}, Publisher = {ELSEVIER SCIENCE BV}, Year = {2004}, Month = {February}, Key = {fds327093} } @article{fds327094, Author = {Keefe, RSE}, Title = {The functional hurdle: Connecting through cognition}, Journal = {Schizophrenia Research}, Volume = {67}, Number = {1}, Pages = {277-277}, Publisher = {ELSEVIER SCIENCE BV}, Year = {2004}, Month = {February}, Key = {fds327094} } @article{fds273409, Author = {Harvey, PD and Green, MF and Keefe, RSE and Velligan, DI}, Title = {Cognitive functioning in schizophrenia: a consensus statement on its role in the definition and evaluation of effective treatments for the illness.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {65}, Number = {3}, Pages = {361-372}, Year = {2004}, Month = {March}, ISSN = {0160-6689}, url = {http://dx.doi.org/10.4088/JCP.v65n0312}, Abstract = {BACKGROUND: Truly effective treatments for schizophrenia require much more than clinical efficacy. Symptom improvement is all that is required to demonstrate clinical efficacy. However, for a treatment to be effective in a wide-ranging manner, improvement in various life domains, such as social functioning, independent living, and employment, should also be found. Thus, a much wider range of improvements, not widely produced by previous treatments, is required to take treatment for schizophrenia to a new level of effectiveness. CONSENSUS PROCESS: A teleconference consensus meeting was held with the bylined authors on December 10, 2002, to explore the factors that hinder the most effective treatments for schizophrenia. We argue that a possible unifying factor underlying these apparently disparate domains of effective treatment is cognitive functioning, which is impaired in people with schizophrenia. Treatment of cognitive dysfunction may have a central role in increasing the breadth of effective treatment for schizophrenia. CONCLUSIONS: Novel antipsychotics and specific cognitive-enhancing medications have preliminarily been shown to have cognitive benefits that might lead to broader effectiveness of treatments, eventually reflected in improvements in the daily lives of patients. These treatments may have their greatest impact when combined with focused psychological interventions. While the research to date does not provide a large number of successes, this area will be one of considerable research interest for the next decade, with developments likely to be very important to clinicians treating patients with schizophrenia.}, Doi = {10.4088/JCP.v65n0312}, Key = {fds273409} } @article{fds327090, Author = {Keefe, RSE}, Title = {Cognition and the concept of schizotaxia}, Journal = {European Psychiatry}, Volume = {19}, Pages = {114S-114S}, Publisher = {EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER}, Year = {2004}, Month = {April}, Key = {fds327090} } @article{fds273410, Author = {Hawkins, KA and Addington, J and Keefe, RSE and Christensen, B and Perkins, DO and Zipurksy, R and Woods, SW and Miller, TJ and Marquez, E and Breier, A and McGlashan, TH}, Title = {Neuropsychological status of subjects at high risk for a first episode of psychosis.}, Journal = {Schizophrenia Research}, Volume = {67}, Number = {2-3}, Pages = {115-122}, Year = {2004}, Month = {April}, url = {http://dx.doi.org/10.1016/j.schres.2003.08.007}, Abstract = {Thirty-six subjects aged 16 years or older judged at risk for a first episode of psychosis within a North American multi-site study of the schizophrenia prodrome [McGlashan et al., Schizophr. Res. (2003); Miller et al., Schizophr. Res. (2003)] performed at levels intermediate to population norms and data reported for schizophrenia samples on a comprehensive neuropsychological exam. In the context of normal intelligence, this intermediate status suggests that, as a group, these subjects are not fully normal in neuropsychological functioning. Conversely, the finding that they do not show the levels of impairment commonly observed in schizophrenia, including within the first episode, suggests that prodromal interventions might conceivably prevent, delay, or lessen the severity of declines associated with first psychotic episodes.}, Doi = {10.1016/j.schres.2003.08.007}, Key = {fds273410} } @article{fds327086, Author = {Sharma, T and Harvey, PD and Kumari, V and Keefe, RSE}, Title = {Cognitive enhancement in schizophrenia: Ending the therapeutic nihilism}, Journal = {Biological Psychiatry}, Volume = {55}, Pages = {151S-151S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2004}, Month = {April}, Key = {fds327086} } @article{fds327087, Author = {Hawkins, KA and Addington, J and Keefe, RSE and Christensen, BK and Woods, SW and Miller, TJ and Trzaskoma, QN and Breier, A and Zipursky, RB and Perkins, DO and McGlashan, TH}, Title = {Effect of olanzapine versus placebo on the neuropsychological status of prodromal subjects}, Journal = {Biological Psychiatry}, Volume = {55}, Pages = {27S-27S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2004}, Month = {April}, Key = {fds327087} } @article{fds327088, Author = {Marquez, E and Keefe, RSE and Purdon, SE and Rock, SL and Alaka, KJ and Ahmed, S and Mohs, RC}, Title = {The relationship of cognition changes and other symptoms following antipsychotic treatment}, Journal = {Biological Psychiatry}, Volume = {55}, Pages = {175S-175S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2004}, Month = {April}, Key = {fds327088} } @article{fds327089, Author = {Narendran, R and Frankle, WG and Keefe, RSE and Gil, RB and Martinez, D and Kegeles, LS and Talbot, PS and Huang, YY and Hwang, DR and Keilp, JG and Khenissi, L and Cooper, TB and Caton, C and Laruelle, M and Abi-Dargham, A}, Title = {PET imaging of prefrontal dopamine D1 receptors in chronic ketamine human abusers: A model for schizophrenia}, Journal = {Biological Psychiatry}, Volume = {55}, Pages = {19S-20S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2004}, Month = {April}, Key = {fds327089} } @article{fds327084, Author = {Keefe, RSE}, Title = {Treatment of cognitive deficits in first episode schizophrenia}, Journal = {The International Journal of Neuropsychopharmacology}, Volume = {7}, Pages = {S87-S87}, Publisher = {CAMBRIDGE UNIV PRESS}, Year = {2004}, Month = {June}, Key = {fds327084} } @article{fds327085, Author = {Keefe, RSE}, Title = {Cognition as a key to alliance, adherence, and functional outcomes}, Journal = {The International Journal of Neuropsychopharmacology}, Volume = {7}, Pages = {S106-S106}, Publisher = {CAMBRIDGE UNIV PRESS}, Year = {2004}, Month = {June}, Key = {fds327085} } @article{fds354404, Author = {Marquez, EM and Keefe, RS and Purdon, SE and Rock, SL and Alaka, K and Ahmed, S and Mohs, RC}, Title = {Is cognitive improvement with antipsychotic treatment pseudospecific?}, Journal = {The International Journal of Neuropsychopharmacology}, Volume = {7}, Pages = {S394-S394}, Publisher = {CAMBRIDGE UNIV PRESS}, Year = {2004}, Month = {June}, Key = {fds354404} } @article{fds354405, Author = {Sethuraman, G and Ahmed, S and Rock, SL and Young, CA and Marquez, EM and Purdon, SE and Keefe, RS}, Title = {Can the panss cognitive factor be a valid surrogate for neurocognition in schizophrenia?}, Journal = {The International Journal of Neuropsychopharmacology}, Volume = {7}, Pages = {S226-S226}, Publisher = {CAMBRIDGE UNIV PRESS}, Year = {2004}, Month = {June}, Key = {fds354405} } @article{fds273412, Author = {Keefe, RSE and Seidman, LJ and Christensen, BK and Hamer, RM and Sharma, T and Sitskoorn, MM and Lewine, RRJ and Yurgelun-Todd, DA and Gur, RC and Tohen, M and Tollefson, GD and Sanger, TM and Lieberman, JA}, Title = {Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol.}, Journal = {The American Journal of Psychiatry}, Volume = {161}, Number = {6}, Pages = {985-995}, Year = {2004}, Month = {June}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15169686}, Abstract = {OBJECTIVE: The effect of antipsychotic medication on neurocognitive function remains controversial, especially since most previous work has compared the effects of novel antipsychotic medications with those of high doses of conventional medications. This study compares the neurocognitive effects of olanzapine and low doses of haloperidol in patients with first-episode psychosis. METHOD: Patients with a first episode of schizophrenia, schizoaffective disorder, or schizophreniform disorder (N=167) were randomly assigned to double-blind treatment with olanzapine (mean modal dose= 9.63 mg/day) or haloperidol (mean modal dose=4.60 mg/day) for the 12-week acute phase of a 2-year study. The patients were assessed with a battery of neurocognitive tests at baseline and 12 weeks after beginning treatment. RESULTS: An unweighted neurocognitive composite score, composed of measures of verbal fluency, motor functions, working memory, verbal memory, and vigilance, improved significantly with both haloperidol and olanzapine treatment (effect sizes of 0.20 and 0.36, respectively, no significant difference between groups). A weighted composite score developed from a principal-component analysis of the same measures improved to a significantly greater degree with olanzapine, compared with haloperidol. Anticholinergic use, extrapyramidal symptoms, and estimated IQ had little effect on the statistical differentiation of the medications, although duration of illness had a modest effect. The correlations of cognitive improvement with changes in clinical characteristics and with side effects of treatment were significant for patients who received haloperidol but not for patients who received olanzapine. CONCLUSIONS: Olanzapine has a beneficial effect on neurocognitive function in patients with a first episode of psychosis. However, in a comparison of the effects of olanzapine and low doses of haloperidol, the difference in benefit is small.}, Doi = {10.1176/appi.ajp.161.6.985}, Key = {fds273412} } @article{fds273413, Author = {Keefe, RSE and Goldberg, TE and Harvey, PD and Gold, JM and Poe, MP and Coughenour, L}, Title = {The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery.}, Journal = {Schizophrenia Research}, Volume = {68}, Number = {2-3}, Pages = {283-297}, Year = {2004}, Month = {June}, url = {http://dx.doi.org/10.1016/j.schres.2003.09.011}, Abstract = {Studies of neurocognitive function in patients with schizophrenia use widely variable assessment techniques. Clinical trials assessing the cognitive enhancing effect of new medications have used neurocognitive assessment batteries that differed in content, length and administration procedures. The Brief Assessment of Cognition in Schizophrenia (BACS) is a newly developed instrument that assesses the aspects of cognition found to be most impaired and most strongly correlated with outcome in patients with schizophrenia. The BACS requires less than 35 min to complete in patients with schizophrenia, yields a high completion rate in these patients, and has high reliability. The BACS was found to be as sensitive to cognitive impairment in patients with schizophrenia as a standard battery of tests that required over 2 h to administer. Compared to healthy controls matched for age and parental education, patients with schizophrenia performed 1.49 standard deviations lower on a composite score calculated from the BACS and 1.61 standard deviations lower on a composite score calculated from the standard battery. The BACS composite scores were highly correlated with the standard battery composite scores in patients (r=0.76) and healthy controls (r=0.90). These psychometric properties make the BACS a promising tool for assessing cognition repeatedly in patients with schizophrenia, especially in clinical trials of cognitive enhancement.}, Doi = {10.1016/j.schres.2003.09.011}, Key = {fds273413} } @article{fds273411, Author = {Green, MF and Nuechterlein, KH and Gold, JM and Barch, DM and Cohen, J and Essock, S and Fenton, WS and Frese, F and Goldberg, TE and Heaton, RK and Keefe, RSE and Kern, RS and Kraemer, H and Stover, E and Weinberger, DR and Zalcman, S and Marder, SR}, Title = {Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria.}, Journal = {Biological Psychiatry}, Volume = {56}, Number = {5}, Pages = {301-307}, Year = {2004}, Month = {September}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/j.biopsych.2004.06.023}, Abstract = {To stimulate the development of new drugs for the cognitive deficits of schizophrenia, the National Institute of Mental Health (NIMH) established the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. This article presents an overview of decisions from the first MATRICS consensus conference. The goals of the meeting were to 1) identify the cognitive domains that should be represented in a consensus cognitive battery and 2) prioritize key criteria for selection of tests for the battery. Seven cognitive domains were selected based on a review of the literature and input from experts: working memory, attention/vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, speed of processing, and social cognition. Based on discussions at this meeting, five criteria were considered essential for test selection: good test-retest reliability, high utility as a repeated measure, relationship to functional outcome, potential response to pharmacologic agents, and practicality/tolerability. The results from this meeting constitute the initial steps for reaching a consensus cognitive battery for clinical trials in schizophrenia.}, Doi = {10.1016/j.biopsych.2004.06.023}, Key = {fds273411} } @article{fds327083, Author = {Sethuraman, G and Ahmed, S and Rock, SL and Young, CA and Marquez, EM and Purdon, SE and Keefe, RSE}, Title = {P.2.137 Can the PANSS cognitive factor be a validsurrogate for neurocognon in schizophrenia?}, Journal = {European Neuropsychopharmacology}, Volume = {14}, Pages = {S292-S293}, Publisher = {Elsevier BV}, Year = {2004}, Month = {October}, url = {http://dx.doi.org/10.1016/s0924-977x(04)80357-2}, Doi = {10.1016/s0924-977x(04)80357-2}, Key = {fds327083} } @article{fds354402, Author = {Lieberman, JA and Stroup, TS and McEvoy, JP and Swartz, MS and Rosenheck, RA and Perkins, DO and Keefe, RS and Davis, SM and Davis, CE and Lebowitz, B and Hsiao, J and Severe, J}, Title = {Effectiveness of antipsychotic drugs in patients with chronic schizophrenia: Primary efficacy and safety outcomes of the clinical antipsychotic trials of intervention effectiveness (CATIE) schizophrenia trial}, Journal = {Neuropsychopharmacology}, Volume = {30}, Pages = {S32-S32}, Year = {2005}, Key = {fds354402} } @article{fds273414, Author = {Buchanan, RW and Davis, M and Goff, D and Green, MF and Keefe, RSE and Leon, AC and Nuechterlein, KH and Laughren, T and Levin, R and Stover, E and Fenton, W and Marder, SR}, Title = {A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia.}, Journal = {Schizophrenia Bulletin}, Volume = {31}, Number = {1}, Pages = {5-19}, Year = {2005}, Month = {January}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbi020}, Abstract = {OBJECTIVE: On April 23, 2004, a joint meeting of the FDA, NIMH, MATRICS investigators, and experts from academia and the pharmaceutical industry was convened to develop guidelines for the design of clinical trials of cognitive-enhancing drugs for neurocognitive impairments in patients with schizophrenia. METHOD: Experts were asked to address specific questions relating to clinical trial design of adjunctive/co-treatment and broad spectrum agents. At the workshop, experts reviewed relevant evidence before offering the discussion panel proposed guidelines for a given subset of questions. The discussion panel, which consisted of presenters and representatives from FDA, NIMH, academia, and industry, deliberated to reach consensus on suggested guidelines. When evidence was insufficient, suggested guidelines represent the opinion of a cross-section of the presenters and discussion panel. RESULTS: Guidelines were developed for inclusion criteria, the use of co-primary outcome measures, and statistical approaches for study design. Consensus was achieved regarding diagnostic and concomitant medication inclusion criteria and on the use of cognitive screening measures. A key guideline was to limit the trial to patients in the residual phase of their illness, who have a predefined level of positive, negative, and affective symptoms. The most difficult issues were the feasibility of including a co-primary measure of functional improvement and the choice of comparator agent for a trial of a broad spectrum agent (with antipsychotic and cognitive-enhancing effects). CONCLUSIONS: The suggested guidelines represent reasonable starting points for trial design of cognitive-enhancing drugs, with the understanding that new data, subsequent findings, or other methodological considerations may lead to future modifications.}, Doi = {10.1093/schbul/sbi020}, Key = {fds273414} } @article{fds273415, Author = {Keefe, RSE and Eesley, CE and Poe, MP}, Title = {Defining a cognitive function decrement in schizophrenia.}, Journal = {Biological Psychiatry}, Volume = {57}, Number = {6}, Pages = {688-691}, Year = {2005}, Month = {March}, url = {http://dx.doi.org/10.1016/j.biopsych.2005.01.003}, Abstract = {BACKGROUND: Although cognitive impairment is described as a core component of the characterization of schizophrenia, a sizable percentage of patients are classified as unimpaired by traditional definitions of impairment. The purpose of this study was to determine the percentage of patients with schizophrenia meeting criteria for a "cognitive function decrement" defined as a current level of cognitive function that falls below the level predicted by premorbid estimates. METHODS: Linear regression analyses were performed on a healthy control population to determine a predicted composite cognitive score based on maternal education, paternal education, and reading score as indicators of premorbid intellectual function. The percentages of patients with current cognitive function above and below predicted values were calculated. RESULTS: When the Wide Range Achievement Test-3 (WRAT-3) score and maternal education are both used to predict current cognitive performance, as expected, about half (42%) of control subjects fall below expectations. However, 98.1 % of patients fall below expectations. CONCLUSIONS: When cognitive function decrement is defined as a failure to reach the expected level of cognitive functioning, almost all patients with schizophrenia meet this definition.}, Doi = {10.1016/j.biopsych.2005.01.003}, Key = {fds273415} } @article{fds273526, Author = {Lieberman, JA and Tollefson, GD and Charles, C and Zipursky, R and Sharma, T and Kahn, RS and Keefe, RSE and Green, AI and Gur, RE and McEvoy, J and Perkins, D and Hamer, RM and Gu, H and Tohen, M and HGDH Study Group}, Title = {Antipsychotic drug effects on brain morphology in first-episode psychosis.}, Journal = {Archives of General Psychiatry}, Volume = {62}, Number = {4}, Pages = {361-370}, Year = {2005}, Month = {April}, ISSN = {0003-990X}, url = {http://dx.doi.org/10.1001/archpsyc.62.4.361}, Abstract = {BACKGROUND: Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia. OBJECTIVE: To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition. DESIGN: Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes. SETTING: Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1). PARTICIPANTS: Patients with first-episode psychosis (DSM-IV) and healthy volunteers. INTERVENTIONS: Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d). MAIN OUTCOME MEASURES: Brain volume changes assessed by MRI. RESULTS: Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n = 58) examined contemporaneously showed no change in gray matter volume. CONCLUSIONS: Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.}, Doi = {10.1001/archpsyc.62.4.361}, Key = {fds273526} } @article{fds273556, Author = {Artiola I Fortuny and L and Garolera, M and Hermosillo Romo and D and Feldman, E and Fernández Barillas and H and Keefe, R and Lemaître, MJ and Ortiz Martín and A and Mirsky, A and Monguió, I and Morote, G and Parchment, S and Parchment, LJ and Da Pena and E and Politis, DG and Sedó, MA and Taussik, I and Valdivia, F and De Valdivia and LE and Verger Maestre, K}, Title = {Research with spanish-speaking populations in the United States: lost in the translation. A commentary and a plea.}, Journal = {Journal of Clinical and Experimental Neuropsychology}, Volume = {27}, Number = {5}, Pages = {555-564}, Year = {2005}, Month = {July}, url = {http://dx.doi.org/10.1080/13803390490918282}, Abstract = {Verbal material used to assess the cognitive abilities of Spanish-speakers in the the United States is frequently of linguistically unacceptable quality. The use of these materials in research settings is thought to pose a serious threat to test validity and hence to the validity of claimed results or conclusions. The authors explain how and why incorrect language finds its way into cognitive tests used in research and other settings and suggest solutions to this serious problem.}, Doi = {10.1080/13803390490918282}, Key = {fds273556} } @article{fds273416, Author = {Lieberman, JA and Stroup, TS and McEvoy, JP and Swartz, MS and Rosenheck, RA and Perkins, DO and Keefe, RSE and Davis, SM and Davis, CE and Lebowitz, BD and Severe, J and Hsiao, JK and Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators}, Title = {Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.}, Journal = {The New England Journal of Medicine}, Volume = {353}, Number = {12}, Pages = {1209-1223}, Year = {2005}, Month = {September}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16172203}, Abstract = {BACKGROUND: The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. METHODS: A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. RESULTS: Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. CONCLUSIONS: The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.}, Doi = {10.1056/NEJMoa051688}, Key = {fds273416} } @article{fds273527, Author = {Strakowski, SM and Johnson, JL and Delbello, MP and Hamer, RM and Green, AI and Tohen, M and Lieberman, JA and Glick, I and Patel, JK and HGDH Research Group}, Title = {Quality of life during treatment with haloperidol or olanzapine in the year following a first psychotic episode.}, Journal = {Schizophrenia Research}, Volume = {78}, Number = {2-3}, Pages = {161-169}, Year = {2005}, Month = {October}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2005.04.017}, Abstract = {OBJECTIVES: Schizophrenia causes significant impairments of quality of life. As treatment approaches have advanced, more attention has been given to re-integrating patients into their psychosocial environments, rather than simply monitoring psychotic symptoms. The development of the second-generation antipsychotics raised hope that these medications would provide better quality of life improvement than conventional antipsychotics. This improvement is particularly relevant early in the course of schizophrenia. METHODS: To address these considerations, improvements in measures of general health and social function (determined using the SF-36) were assessed in 195 patients with first-episode schizophrenia for up to one year following randomization to either olanzapine or haloperidol in a double blind clinical trial. We hypothesized that olanzapine would demonstrate better improvement on these measures than haloperidol. In order to test this hypothesis, we used a repeated measure model with SF-36 scores as the outcome, and treatment group, time, time2, time-by-treatment group interaction, and time2-by-treatment group interaction as fixed effects. RESULTS: Both treatments demonstrated similar changes on the SF-36. Independent of treatment, patients demonstrated significant improvements in most of the SF-36 subscales, which approached normative scores by the end of one year of treatment. Forty-six of 100 olanzapine-treated patients and 37 of 95 haloperidol-treated patients completed the one year of this study (p<.4). CONCLUSIONS: These results suggest an important initial treatment goal for patients with new onset schizophrenic disorders, namely that they can expect to recover significant quality of life and social function at least initially in treatment.}, Doi = {10.1016/j.schres.2005.04.017}, Key = {fds273527} } @article{fds273417, Author = {Miller, DD and McEvoy, JP and Davis, SM and Caroff, SN and Saltz, BL and Chakos, MH and Swartz, MS and Keefe, RSE and Rosenheck, RA and Stroup, TS and Lieberman, JA}, Title = {Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial.}, Journal = {Schizophrenia Research}, Volume = {80}, Number = {1}, Pages = {33-43}, Year = {2005}, Month = {December}, ISSN = {0920-9964}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16171976}, Abstract = {OBJECTIVE: To examine the clinical characteristics of individuals with schizophrenia that develop tardive dyskinesia (TD) associated with antipsychotic treatment. METHODS: Baseline data on 1460 patients with schizophrenia were collected as part of the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study. Subjects who met Schooler-Kane criteria for probable TD were compared to those without TD. Multiple regression analyses were used to examine the relationship between TD and clinical variables. RESULTS: 212 subjects met the Schooler-Kane criteria for probable TD and 1098 had no history or current evidence of TD. Subjects with TD were older, had a longer duration of receiving antipsychotic medication, and were more likely to have been receiving a conventional antipsychotic and an anticholinergic agent. After controlling for important baseline covariates, diabetes mellitus (DM) and hypertension did not predict TD, whereas substance abuse significantly predicted TD. Differences in cognitive functioning were not significantly different after controlling for baseline covariates. The TD subjects also had higher ratings of psychopathology, EPSE, and akathisia. CONCLUSION: Our results confirm the established relationships between the presence of TD and age, duration of treatment with antipsychotics, treatment with a conventional antipsychotic, treatment with anticholinergics, the presence of EPS and akathisia, and substance abuse. Subjects with TD had higher ratings of psychopathology as measured by the PANSS. We found no support for DM or hypertension increasing the risk of TD, or for TD being associated with cognitive impairment.}, Doi = {10.1016/j.schres.2005.07.034}, Key = {fds273417} } @article{fds273418, Author = {Meyer, JM and Nasrallah, HA and McEvoy, JP and Goff, DC and Davis, SM and Chakos, M and Patel, JK and Keefe, RSE and Stroup, TS and Lieberman, JA}, Title = {The Clinical Antipsychotic Trials Of Intervention Effectiveness (CATIE) Schizophrenia Trial: clinical comparison of subgroups with and without the metabolic syndrome.}, Journal = {Schizophrenia Research}, Volume = {80}, Number = {1}, Pages = {9-18}, Year = {2005}, Month = {December}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2005.07.015}, Abstract = {UNLABELLED: The metabolic syndrome (MS) is highly prevalent among patients with schizophrenia (current estimates 35-40%), yet no data exist on the correlation of this diagnosis with illness severity, neurocognitive or quality of life measures in this population. METHODS: Using baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assignment of MS status was performed using an updated definition derived from the National Cholesterol Education Program (NCEP) criteria. Those with and without MS were compared on the basis of primary and secondary variables of interest from baseline data encompassing psychiatric, neurocognitive and quality of life measures. RESULTS: Of 1460 subjects enrolled at baseline, MS status could be reliably assigned for 1231 subjects, with a prevalence of 35.8% using the NCEP derived criteria. After adjustment for age, gender, race, ethnicity and site variance, those with MS rated themselves significantly lower on physical health by SF-12 (p < .001), and scored higher on somatic preoccupation (PANSS item G1) (p = .03). There were no significant differences between the two cohorts on measures of symptom severity, depression, quality of life, neurocognition, or self-rated mental health. Neither years of antipsychotic exposure nor alcohol usage were significant predictors of MS status when adjusted for age, gender, race, and ethnicity. CONCLUSIONS: The metabolic syndrome is highly prevalent in this large cohort of schizophrenia patients and is strongly associated with a poor self-rating of physical health and increased somatic preoccupation. These results underscore the need for mental health practitioners to take an active role in the health monitoring of patients with schizophrenia to minimize the impact of medical comorbidity on long-term mortality and on daily functioning. Outcomes data from CATIE will provide important information on the metabolic and clinical impact of antipsychotic treatment for those subjects with MS and other medical comorbidities.}, Doi = {10.1016/j.schres.2005.07.015}, Key = {fds273418} } @article{fds273419, Author = {Stroup, S and Appelbaum, P and Swartz, M and Patel, M and Davis, S and Jeste, D and Kim, S and Keefe, R and Manschreck, T and McEvoy, J and Lieberman, J}, Title = {Decision-making capacity for research participation among individuals in the CATIE schizophrenia trial.}, Journal = {Schizophrenia Research}, Volume = {80}, Number = {1}, Pages = {1-8}, Year = {2005}, Month = {December}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2005.08.007}, Abstract = {OBJECTIVE: Uncertainty regarding the degree to which persons with schizophrenia may lack decision-making capacity, and what the predictors of capacity may be led us to examine the relationship between psychopathology, neurocognitive functioning, and decision-making capacity in a large sample of persons with schizophrenia at entry into a clinical trial. METHOD: In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, a clinical trial sponsored by the National Institute of Mental Health designed to compare the effectiveness of antipsychotic drugs, subjects were administered the MacArthur Competence Assessment Tool-Clinical Research (MacCAT-CR) and had to demonstrate adequate decision-making capacity before randomization. The MacCAT-CR, the Positive and Negative Syndrome Scale (PANSS), and an extensive neurocognitive battery were completed for 1447 study participants. RESULTS: The neurocognitive composite score and all 5 neurocognitive subscores (verbal memory, vigilance, processing speed, reasoning, and working memory) were positive correlates of the MacCAT-CR understanding, appreciation, and reasoning scales at baseline. Higher levels of negative symptoms, but not positive symptoms, were inversely correlated with these three MacCAT-CR scales. Linear regression models of all three MacCAT-CR scales identified working memory as a predictor; negative symptoms made a small contribution to the understanding and appreciation scores. CONCLUSIONS: Negative symptoms and aspects of neurocognitive functioning were correlated with decision-making capacity in this large sample of moderately ill subjects with schizophrenia. In multiple regression models predicting performance on the MacCAT-CR scales, working memory was the only consistent predictor of the components of decision-making capacity. Individuals with schizophrenia who have prominent cognitive dysfunction, especially memory impairment, may warrant particular attention when participating in research.}, Doi = {10.1016/j.schres.2005.08.007}, Key = {fds273419} } @article{fds273420, Author = {Rosenheck, R and Stroup, S and Keefe, RSE and McEvoy, J and Swartz, M and Perkins, D and Hsiao, J and Shumway, M and Lieberman, J}, Title = {Measuring outcome priorities and preferences in people with schizophrenia.}, Journal = {The British Journal of Psychiatry : the Journal of Mental Science}, Volume = {187}, Number = {DEC.}, Pages = {529-536}, Year = {2005}, Month = {December}, ISSN = {0007-1250}, url = {http://dx.doi.org/10.1192/bjp.187.6.529}, Abstract = {BACKGROUND: Measures have not taken account of the relative importance patients place on various outcomes. AIMS: To construct and evaluate a multidimensional, preference-weighted mental health index. METHOD: Each of over 1200 patients identified the relative importance of improvement in six domains: social life, energy, work, symptoms, confusion and side-effects. A mental health index was created in which measures of well-being in these six domains were weighted for their personal importance. RESULTS: The strongest preference was placed on reducing confusion and the least on reducing side-effects. There was no significant difference between the unweighted and preference-weighted mental health status measures and they had similar correlations with global health status measures. Patients with greater preference for functional activities such as work had less preference for medical model goals such as reducing symptoms and had less symptoms. CONCLUSIONS: A preference-weighted mental health index demonstrated no advantage over an unweighted index.}, Doi = {10.1192/bjp.187.6.529}, Key = {fds273420} } @article{fds273557, Author = {Narendran, R and Frankle, WG and Keefe, R and Gil, R and Martinez, D and Slifstein, M and Kegeles, LS and Talbot, PS and Huang, Y and Hwang, D-R and Khenissi, L and Cooper, TB and Laruelle, M and Abi-Dargham, A}, Title = {Altered prefrontal dopaminergic function in chronic recreational ketamine users.}, Journal = {The American Journal of Psychiatry}, Volume = {162}, Number = {12}, Pages = {2352-2359}, Year = {2005}, Month = {December}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.162.12.2352}, Abstract = {OBJECTIVE: Ketamine is a noncompetitive antagonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor that is used in human and animal medicine as an injectable anesthetic. The illegal use of ketamine as a recreational drug is rapidly growing. Very little is currently known about the consequences of repeated ketamine exposure in the human brain. Animal studies indicate that the prefrontal dopaminergic system is particularly vulnerable to the toxic effects of repeated administration of NMDA antagonists. In this study, dopamine D1 receptor availability was assessed by using positron emission tomography and the selective D1 receptor radioligand [11C]NNC 112 in a group of 14 recreational chronic ketamine users and matched healthy subjects. METHOD: History of ketamine abuse was confirmed in subjects by hair analysis. [11C]NNC 112 binding potential was measured with kinetic analysis using the arterial input function. RESULTS: Dorsolateral prefrontal cortex D1 receptor availability was significantly up-regulated in chronic ketamine users ([11C]NNC 112 binding potential: mean=1.68 ml/g, SD=0.40) relative to comparison subjects (mean=1.35 ml/g, SD=0.35). No significant differences were noted in other cortical, limbic, or striatal regions. In the chronic ketamine user group, dorsolateral prefrontal cortex [11C]NNC 112 binding potential up-regulation was significantly correlated with the number of vials of ketamine (with a vial representing approximately 200-300 mg of ketamine) used per week. CONCLUSIONS: Chronic ketamine users exhibited a regionally selective up-regulation of D1 receptor availability in the dorsolateral prefrontal cortex, a phenomenon observed following chronic dopamine depletion in animal studies. These data suggest that the repeated use of ketamine for recreational purposes affects prefrontal dopaminergic transmission, a system critically involved in working memory and executive function.}, Doi = {10.1176/appi.ajp.162.12.2352}, Key = {fds273557} } @article{fds371784, Author = {Lieberman, J and Stroup, S and Fleischhacker, WW and Lewis, S and Swartz, M and Keefe, R and Essock, S}, Title = {Comparative effectiveness of antipsychotic drugs: Complete results of the CATIE study}, Journal = {Neuropsychopharmacology}, Volume = {31}, Pages = {S12-S12}, Year = {2006}, Key = {fds371784} } @article{fds327082, Author = {Keefe, RSE and Gu, H and Perkins, D and Hamer, RM and Lieberman, JA}, Title = {The effects of olanzapine, quetiapine, and risperidone on neurocognitive function in first-episode psychosis: A double-blind, 52-week comparison}, Journal = {Schizophrenia Research}, Volume = {81}, Pages = {54-54}, Publisher = {ELSEVIER SCIENCE BV}, Year = {2006}, Month = {January}, Key = {fds327082} } @article{fds273558, Author = {Keefe, RSE and Young, CA and Rock, SL and Purdon, SE and Gold, JM and Breier, A and HGGN Study Group}, Title = {One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {81}, Number = {1}, Pages = {1-15}, Year = {2006}, Month = {January}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2005.07.038}, Abstract = {Neurocognitive deficits in schizophrenia can reach 1 to 2 standard deviations below healthy controls. The comparative effect of typical and atypical antipsychotic medications on neurocognition is controversial, and based primarily on studies with small samples and large doses of typical comparator medications. The present study assessed neurocognitive efficacy. It was hypothesized that olanzapine treatment would improve neurocognitive deficits to a greater degree than either risperidone or haloperidol treatment. This was a double-blind, randomized, controlled, parallel study with neurocognition assessed at baseline, and 8, 24, and 52 weeks. Per protocol, the haloperidol arm was discontinued. Four hundred and fourteen inpatients or outpatients with schizophrenia and schizoaffective disorder were treated with oral olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Individual domains (executive function, learning and memory, processing speed, attention/vigilance, verbal working memory, verbal fluency, motor function, and visuospatial ability) were transformed into composite scores and compared between treatment groups. At the 52-week endpoint, neurocognition significantly improved in each group (p < 0.01 for olanzapine and risperidone, p = 0.04 for haloperidol), with no significant differences between groups. Olanzapine- and risperidone-treated patients significantly (p < 0.05) improved on domains of executive function, learning/memory, processing speed, attention/vigilance, verbal working memory, and motor functions. Additionally, risperidone-treated patients improved on domains of visuospatial memory. Haloperidol-treated patients improved only on domains of learning/memory. However, patients able to remain in treatment for the entire 52 weeks benefited more from olanzapine or risperidone treatment than haloperidol treatment.}, Doi = {10.1016/j.schres.2005.07.038}, Key = {fds273558} } @article{fds273559, Author = {Keefe, RSE and Seidman, LJ and Christensen, BK and Hamer, RM and Sharma, T and Sitskoorn, MM and Rock, SL and Woolson, S and Tohen, M and Tollefson, GD and Sanger, TM and Lieberman, JA and HGDH Research Group}, Title = {Long-term neurocognitive effects of olanzapine or low-dose haloperidol in first-episode psychosis.}, Journal = {Biological Psychiatry}, Volume = {59}, Number = {2}, Pages = {97-105}, Year = {2006}, Month = {January}, ISSN = {0006-3223}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16140282}, Abstract = {BACKGROUND: Neurocognitive deficits are severe in first-episode psychosis. METHODS: Patients (N = 263) with first-episode psychosis (schizophrenia, schizoaffective, or schizophreniform disorders) were randomly assigned to double-blind treatment with olanzapine (mean 11.30 mg/day) or haloperidol (mean 4.87 mg/day) for 104 weeks. A neurocognitive battery was administered at baseline (n = 246) and 12 (n = 167), 24 (n = 126), 52 (n = 89), and 104 (n = 46) weeks during treatment. Weighted principal component and unweighted composite scores were derived from individual tests. RESULTS: Both treatment groups demonstrated significant improvement on both composite scores. On the basis of the weighted composite score, olanzapine had greater improvement than haloperidol only at 12 (p = .014) and 24 (p = .029) weeks. For the unweighted composite, olanzapine had significantly better improvement compared with haloperidol only at week 12 (p = .044). At week 12 only, olanzapine improved performance on the Digit Symbol and Continuous Performance Test significantly more than haloperidol. CONCLUSIONS: Both antipsychotic agents appeared to improve neurocognitive functioning among first-episode psychosis patients with schizophrenia. A significantly greater benefit in terms of neurocognitive improvement was found with olanzapine than with haloperidol at weeks 12 and 24.}, Doi = {10.1016/j.biopsych.2005.06.022}, Key = {fds273559} } @article{fds273560, Author = {Keefe, RSE and Poe, M and Walker, TM and Harvey, PD}, Title = {The relationship of the Brief Assessment of Cognition in Schizophrenia (BACS) to functional capacity and real-world functional outcome.}, Journal = {Journal of Clinical and Experimental Neuropsychology}, Volume = {28}, Number = {2}, Pages = {260-269}, Year = {2006}, Month = {February}, ISSN = {1380-3395}, url = {http://dx.doi.org/10.1080/13803390500360539}, Abstract = {The Brief Assessment of Cognition in Schizophrenia (BACS) assesses five different domains of cognitive function with six tests, and takes about 30-35 minutes to complete in patients with schizophrenia. Previous work has demonstrated the reliability of this measure, and its sensitivity to the deficits of schizophrenia. However, the relationship of this brief cognitive measure to functional outcome has not been determined. Further, future registration trials for potentially cognitive enhancing compounds may not only assess efficacy with cognitive performance measures, but with assessments of real-world functional outcome and functional capacity. The purpose of this study was to determine the relationship between the BACS and a potential co-primary measure for treatment studies of cognition in schizophrenia, and to determine if such a measure accounts for significant variance in functioning beyond that provided by cognitive function. The current study assessed 60 patients with schizophrenia over the course of six months. Cognitive functions were measured with the BACS. Functional capacity was measured with the UCSD Performance-based Skills Assessment (UPSA). Real-world functional outcome was measured with the Independent Living Skills Inventory (ILSI). BACS composite scores were significantly correlated with functional capacity as measured by the UPSA (r = .65, df = 55, p < .001), and real-world functional outcome as assessed by the ILSI (r = .37, df = 56, p = .005). In multiple regression analyses, UPSA scores did not account for additional variance in real-world functioning beyond that accounted for by the BACS. These data suggest that brief cognitive assessments such as the BACS are able to assess aspects of cognition that are related to important functional measures in clinical trials of cognitive enhancement. They also suggest that the measures being considered as potential co-primary indicators of cognitive function for registration trials are significantly correlated with cognition as assessed by brief cognitive assessments.}, Doi = {10.1080/13803390500360539}, Key = {fds273560} } @article{fds273421, Author = {Perkins, DO and Johnson, JL and Hamer, RM and Zipursky, RB and Keefe, RS and Centorrhino, F and Green, AI and Glick, IB and Kahn, RS and Sharma, T and Tohen, M and McEvoy, JP and Weiden, PJ and Lieberman, JA and HGDH Research Group}, Title = {Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode.}, Journal = {Schizophrenia Research}, Volume = {83}, Number = {1}, Pages = {53-63}, Year = {2006}, Month = {March}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2005.10.016}, Abstract = {BACKGROUND: Many patients recovering from a first psychotic episode will discontinue medication against medical advice, even before a 1-year treatment course is completed. Factors associated with treatment adherence in patients with chronic schizophrenia include beliefs about severity of illness and need for treatment, treatment with typical versus atypical antipsychotic and medication side effects. METHOD: In this 2-year prospective study of 254 patients recovering from a first episode of schizophrenia, schizophreniform, or schizoaffective disorder we examined the relationship between antipsychotic medication non-adherence and patient beliefs about: need for treatment, antipsychotic medication benefits, and negative aspects of antipsychotic medication treatment. We also examined the relationship between medication non-adherence and treatment with either haloperidol or olanzapine, and objective measures of symptom response and side effects. RESULTS: The likelihood of becoming medication non-adherent for 1 week or longer was greater in subjects whose belief in need for treatment was less (HR=1.75, 95% CI 1.16, 2.65, p=0.0077) or who believed medications were of low benefit (HR=2.88, 95 CI 1.79-4.65, p<0.0001). Subjects randomized to haloperidol were more likely to become medication non-adherent for >or=1 week than subjects randomized to olanzapine (HR-1.51, 95% CI 1.01, 2.27, p=0.045). CONCLUSION: Beliefs about need for treatment and the benefits of antipsychotic medication may be intervention targets to improve likelihood of long-term medication adherence in patients recovering from a first episode of schizophrenia, schizoaffective, or schizophreniform disorder.}, Doi = {10.1016/j.schres.2005.10.016}, Key = {fds273421} } @article{fds273422, Author = {Rosenheck, R and Leslie, D and Keefe, R and McEvoy, J and Swartz, M and Perkins, D and Stroup, S and Hsiao, JK and Lieberman, J and CATIE Study Investigators Group}, Title = {Barriers to employment for people with schizophrenia.}, Journal = {The American Journal of Psychiatry}, Volume = {163}, Number = {3}, Pages = {411-417}, Year = {2006}, Month = {March}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.163.3.411}, Abstract = {OBJECTIVE: There is growing interest in identifying and surmounting barriers to employment for people with schizophrenia. The authors examined factors associated with participation in competitive employment or other vocational activities in a large group of patients with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, a multisite clinical trial comparing the effects of first- and second-generation antipsychotics. METHOD: Baseline data on more than 1,400 patients with a diagnosis of schizophrenia were collected before their entry into the CATIE study. Multinomial logistic regression was used to examine the relationship between participation in either competitive employment or other vocational activities and sociodemographic characteristics, schizophrenia symptoms, neurocognitive functioning, intrapsychic functioning, availability of psychosocial rehabilitation services, and local unemployment rates. RESULTS: Altogether, 14.5% of the patients reported participating in competitive employment in the month before the baseline assessment, 12.6% reported other (noncompetitive) employment activity, and 72.9% reported no employment activity. Participation in either competitive or noncompetitive employment was associated with having less severe symptoms, better neurocognitive functioning, and higher scores on a measure of intrapsychic functioning that encompassed motivation, empathy, and other psychological characteristics. Competitive employment, in contrast to other employment or no employment, was negatively associated with receipt of disability payments as well as with being black. Greater access to rehabilitation services was associated with greater participation in both competitive and noncompetitive employment. CONCLUSIONS: Overall employment of persons with schizophrenia seems to be impeded by clinical problems, including symptoms of schizophrenia and poorer neurocognitive and intrapsychic functioning. However, participation in competitive employment may be specifically impeded by the potentially adverse incentives of disability payments and by race and may be promoted by the availability of rehabilitation services.}, Doi = {10.1176/appi.ajp.163.3.411}, Key = {fds273422} } @article{fds273423, Author = {Lieberman, JA and Stroup, TS and McEvoy, JP and Swartz, MS and Rosenheck, RA and Perkins, DO and Keefe, RSE and Davis, SM and Davis, CE and Hsiao, J and Severe, J and Lebowitz, BD}, Title = {Dr. Lieberman and Colleagues reply [17]}, Journal = {The American Journal of Psychiatry}, Volume = {163}, Number = {3}, Pages = {555-556}, Year = {2006}, Month = {March}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.163.3.555-a}, Doi = {10.1176/appi.ajp.163.3.555-a}, Key = {fds273423} } @article{fds273561, Author = {Keefe, RSE and Poe, M and Walker, TM and Kang, JW and Harvey, PD}, Title = {The Schizophrenia Cognition Rating Scale: an interview-based assessment and its relationship to cognition, real-world functioning, and functional capacity.}, Journal = {The American Journal of Psychiatry}, Volume = {163}, Number = {3}, Pages = {426-432}, Year = {2006}, Month = {March}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.163.3.426}, Abstract = {OBJECTIVE: Interview-based measures of cognition may serve as potential coprimary measures in clinical trials of cognitive-enhancing drugs for schizophrenia. However, there is no such valid scale available. Interviews of patients and their clinicians are not valid in that they are unrelated to patients' levels of cognitive impairment as assessed by cognitive performance tests. This study describes the reliability and validity of a new interview-based assessment of cognition, the Schizophrenia Cognition Rating Scale (SCoRS), that involves interviews with patients and informants. METHOD: Sixty patients with schizophrenia were assessed with the SCoRS and three potential validators of an interview-based measure of cognition: cognitive performance, as measured by the Brief Assessment of Cognition in Schizophrenia (BACS); real-world functioning, as measured by the Independent Living Skills Inventory; and functional capacity, as measured by the University of California, San Diego, Performance-Based Skills Assessment (UPSA). RESULTS: The SCoRS global ratings were significantly correlated with composite scores of cognitive performance and functional capacity and with ratings of real-world functioning. Multiple regression analyses suggested that SCoRS global ratings predicted unique variance in real-world functioning beyond that predicted by the performance measures. CONCLUSIONS: An interview-based measure of cognition that included informant reports was related to cognitive performance as well as real-world functioning. Interview-based measures of cognition, such as the SCoRS, may be valid coprimary measures for clinical trials assessing cognitive change and may also aid clinicians desiring to assess patients' level of cognitive impairment.}, Doi = {10.1176/appi.ajp.163.3.426}, Key = {fds273561} } @article{fds336083, Author = {LIEBERMAN, JA and STROUP, TS and McEVOY, JP and SWARTZ, MS and ROSENHECK, RA and PERKINS, DO and KEEFE, RSE and DAVIS, SM and DAVIS, CE and HSIAO, J and SEVERE, J and LEBOWITZ, BD and the CATIE Investigators}, Title = {Dr. Lieberman and Colleagues Reply}, Journal = {The American Journal of Psychiatry}, Volume = {163}, Number = {3}, Pages = {555-556}, Publisher = {American Psychiatric Association Publishing}, Year = {2006}, Month = {March}, url = {http://dx.doi.org/10.1176/appi.ajp.163.3.555-a}, Doi = {10.1176/appi.ajp.163.3.555-a}, Key = {fds336083} } @article{fds273424, Author = {McEvoy, JP and Lieberman, JA and Stroup, TS and Davis, SM and Meltzer, HY and Rosenheck, RA and Swartz, MS and Perkins, DO and Keefe, RSE and Davis, CE and Severe, J and Hsiao, JK and CATIE Investigators}, Title = {Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment.}, Journal = {The American Journal of Psychiatry}, Volume = {163}, Number = {4}, Pages = {600-610}, Year = {2006}, Month = {April}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16585434}, Abstract = {OBJECTIVE: When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation. METHOD: Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]). RESULTS: Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median=3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation. CONCLUSIONS: For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine's serious side effects.}, Doi = {10.1176/ajp.2006.163.4.600}, Key = {fds273424} } @article{fds273427, Author = {Stroup, TS and Lieberman, JA and McEvoy, JP and Swartz, MS and Davis, SM and Rosenheck, RA and Perkins, DO and Keefe, RSE and Davis, CE and Severe, J and Hsiao, JK and CATIE Investigators}, Title = {Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic.}, Journal = {The American Journal of Psychiatry}, Volume = {163}, Number = {4}, Pages = {611-622}, Year = {2006}, Month = {April}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16585435}, Abstract = {BACKGROUND: In the treatment of schizophrenia, changing antipsychotics is common when one treatment is suboptimally effective, but the relative effectiveness of drugs used in this strategy is unknown. This randomized, double-blind study compared olanzapine, quetiapine, risperidone, and ziprasidone in patients who had just discontinued a different atypical antipsychotic. METHOD: Subjects with schizophrenia (N=444) who had discontinued the atypical antipsychotic randomly assigned during phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) investigation were randomly reassigned to double-blind treatment with a different antipsychotic (olanzapine, 7.5-30 mg/day [N=66]; quetiapine, 200-800 mg/day [N=63]; risperidone, 1.5-6.0 mg/day [N=69]; or ziprasidone, 40-160 mg/day [N=135]). The primary aim was to determine if there were differences between these four treatments in effectiveness measured by time until discontinuation for any reason. RESULTS: The time to treatment discontinuation was longer for patients treated with risperidone (median: 7.0 months) and olanzapine (6.3 months) than with quetiapine (4.0 months) and ziprasidone (2.8 months). Among patients who discontinued their previous antipsychotic because of inefficacy (N=184), olanzapine was more effective than quetiapine and ziprasidone, and risperidone was more effective than quetiapine. There were no significant differences between antipsychotics among those who discontinued their previous treatment because of intolerability (N=168). CONCLUSIONS: Among this group of patients with chronic schizophrenia who had just discontinued treatment with an atypical antipsychotic, risperidone and olanzapine were more effective than quetiapine and ziprasidone as reflected by longer time until discontinuation for any reason.}, Doi = {10.1176/ajp.2006.163.4.611}, Key = {fds273427} } @article{fds354401, Author = {Chwastiak, LA and Rosenheck, RA and McEvoy, JP and Keefe, RS and Swartz, MS and Lieberman, JA}, Title = {Interrelationships of psychiatric symptom severity, medical comorbidity and functional status in patients with schizophrenia}, Journal = {Journal of General Internal Medicine}, Volume = {21}, Pages = {76-76}, Publisher = {SPRINGER}, Year = {2006}, Month = {April}, Key = {fds354401} } @article{fds327081, Author = {Keefe, RSE and Hongbin, GU and Sweeney, JA and Perkins, DO and McEvoy, JP and Hamer, RM and Lieberman, JA}, Title = {The effects of olanzapine, quetiapine, and risperidone on neurocognitive function in first-episode psychosis: A double-blind, 52-week comparison}, Journal = {Biological Psychiatry}, Volume = {59}, Number = {8}, Pages = {231S-232S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2006}, Month = {April}, Key = {fds327081} } @article{fds327080, Author = {Keefe, RSE}, Title = {Measures of cognitive change in schizophrenia clinical trials}, Journal = {The International Journal of Neuropsychopharmacology}, Volume = {9}, Pages = {S48-S48}, Publisher = {CAMBRIDGE UNIV PRESS}, Year = {2006}, Month = {July}, Key = {fds327080} } @article{fds273425, Author = {Woodward, TS and Menon, M and Hu, X and Keefe, RSE}, Title = {Optimization of a multinomial model for investigating hallucinations and delusions with source monitoring.}, Journal = {Schizophrenia Research}, Volume = {85}, Number = {1-3}, Pages = {106-112}, Year = {2006}, Month = {July}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2006.03.008}, Abstract = {Studies of source monitoring have played an important role in cognitive investigations of the inner/outer confusions that characterize hallucinations and delusions in schizophrenia, and multinomial modelling is a statistical/cognitive modelling technique that provides a powerful method for analyzing source monitoring data. The purpose of the current work is to describe how multinomial models can be optimized to answer direct questions about hallucinations and delusions in schizophrenia research. To demonstrate this, we present a reanalysis of previously published source monitoring data, comparing a group of patients with schneiderian first rank symptoms to a group without schneiderian first rank symptoms. The main findings of this analysis were (1) impaired recognition of self-generated items and (2) evidence that impaired source discrimination of perceived items is accompanied by an internalization bias in the target symptom group. Statistical and cognitive interpretations of the findings are discussed.}, Doi = {10.1016/j.schres.2006.03.008}, Key = {fds273425} } @article{fds327079, Author = {Keefe, RSE}, Title = {Missing the sweet spot disengagement in schizophrenia.}, Journal = {Psychiatry (Edgmont (Pa. : Township))}, Volume = {3}, Number = {7}, Pages = {36-41}, Year = {2006}, Month = {July}, Abstract = {The extent to which an individual engages in a cognitive task is associated with performance in laboratory settings(1) and a variety of domains of functioning, such as athletic activity and artistic expression.(2) The neural circuitry associated with task engagement is in the process of being elucidated by cognitive neuroscience investigations. These newly acquired data provide an opportunity to understand the cognitive, social, and functional disabilities that lie at the core of dysfunction in patients with schizophrenia. This article describes the importance of task engagement in human functioning, its impairment in schizophrenia, and the possibility that disengagement during late adolescence may herald future development of schizophrenia.(3,4) Since treatment studies suggest that improvement in this aspect of cognitive functioning has the potential to improve the functioning of patients with schizophrenia in various domains, it is possible that these improvements may be mediated by improved engagement with external processes, including social processes and patient-clinician relationships, leading to improved therapeutic alliance and increased treatment adherence.}, Key = {fds327079} } @article{fds273426, Author = {Chakos, MH and Glick, ID and Miller, AL and Hamner, MB and Miller, DD and Patel, JK and Tapp, A and Keefe, RSE and Rosenheck, RA}, Title = {Baseline use of concomitant psychotropic medications to treat schizophrenia in the CATIE trial.}, Journal = {Psychiatric Services (Washington, D.C.)}, Volume = {57}, Number = {8}, Pages = {1094-1101}, Year = {2006}, Month = {August}, ISSN = {1075-2730}, url = {http://dx.doi.org/10.1176/ps.2006.57.8.1094}, Abstract = {OBJECTIVE: This study examined the prevalence and correlates of concomitant psychotropic medications and use of anticholinergic drugs to treat schizophrenia. METHODS: Concomitant medication use was studied at baseline for participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial. RESULTS: Of the 1,380 patients with baseline medication data, 82 percent were taking psychotropic medications. Of this group, 6 percent were taking two antipsychotics (one first generation and one second generation); 38 percent, antidepressants; 22 percent, anxiolytics; 4 percent, lithium, and 15 percent, other mood stabilizers. The strongest predictors of taking several medications were having anxiety or depression, being female, and taking second-generation antipsychotics. Conversely, African Americans and those with better neurocognitive functioning were less likely to be taking several concomitant psychotropic medications. In some cases symptoms that were likely targets of polypharmacy, such as depression, remained prominent, suggesting only partial response. CONCLUSIONS: Concomitant use of psychotropic medications to treat people with schizophrenia is common. Empirical data demonstrating the effectiveness of many of these agents for this population are lacking.}, Doi = {10.1176/ps.2006.57.8.1094}, Key = {fds273426} } @article{fds273429, Author = {Chwastiak, LA and Rosenheck, RA and McEvoy, JP and Keefe, RS and Swartz, MS and Lieberman, JA}, Title = {Interrelationships of psychiatric symptom severity, medical comorbidity, and functioning in schizophrenia.}, Journal = {Psychiatric Services (Washington, D.C.)}, Volume = {57}, Number = {8}, Pages = {1102-1109}, Year = {2006}, Month = {August}, ISSN = {1075-2730}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16870960}, Abstract = {OBJECTIVE: This cross-sectional study aimed to evaluate the interrelationships of psychiatric symptom severity, medical comorbidity, and psychosocial functioning in a sample of patients with schizophrenia by utilizing the baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). METHODS: This study utilized baseline data from a multisite trial of antipsychotic pharmacotherapy, which collected data from 1,460 patients with schizophrenia at more than 50 sites in the United States between 2001 and 2003. Bivariate correlations were used to evaluate associations between schizophrenia symptoms and medical comorbidity, and multivariate regression models were used to determine the independent association between medical comorbidity and psychosocial functioning. RESULTS: Of the 1,424 participants in the study sample, 58 percent had at least one medical condition: 20 percent had hypertension, 11 percent had diabetes mellitus, and 9 percent had four or more medical conditions. Medical comorbidity was associated with poorer neurocognitive functioning and greater depressive symptoms. The number of medical conditions was not associated with more severe schizophrenia symptoms. Both the number of medical conditions and physical health status were only weak correlates of psychosocial functioning. CONCLUSIONS: In this sample of persons with schizophrenia, medical comorbidity was associated with depression and neurocognitive impairment but was a weaker correlate of psychosocial functioning or employment status than psychotic symptoms, depression, and neurocognitive impairment.}, Doi = {10.1176/ps.2006.57.8.1102}, Key = {fds273429} } @article{fds273428, Author = {Keefe, RSE and Bilder, RM and Harvey, PD and Davis, SM and Palmer, BW and Gold, JM and Meltzer, HY and Green, MF and Miller, DD and Canive, JM and Adler, LW and Manschreck, TC and Swartz, M and Rosenheck, R and Perkins, DO and Walker, TM and Stroup, TS and McEvoy, JP and Lieberman, JA}, Title = {Baseline neurocognitive deficits in the CATIE schizophrenia trial.}, Journal = {Neuropsychopharmacology}, Volume = {31}, Number = {9}, Pages = {2033-2046}, Year = {2006}, Month = {September}, ISSN = {0893-133X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16641947}, Abstract = {Neurocognition is moderately to severely impaired in patients with schizophrenia. However, the factor structure of the various neurocognitive deficits, the relationship with symptoms and other variables, and the minimum amount of testing required to determine an adequate composite score has not been determined in typical patients with schizophrenia. An 'all-comer' approach to cognition is needed, as provided by the baseline assessment of an unprecedented number of patients in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial. From academic sites and treatment providers representative of the community, 1493 patients with chronic schizophrenia were entered into the study, including those with medical comorbidity and substance abuse. Eleven neurocognitive tests were administered, resulting in 24 individual scores reduced to nine neurocognitive outcome measures, five domain scores and a composite score. Despite minimal screening procedures, 91.2% of patients provided meaningful neurocognitive data. Exploratory principal components analysis yielded one factor accounting for 45% of the test variance. Confirmatory factor analysis showed that a single-factor model comprised of five domain scores was the best fit. The correlations among the factors were medium to high, and scores on individual factors were very highly correlated with the single composite score. Neurocognitive deficits were modestly correlated with negative symptom severity (r=0.13-0.27), but correlations with positive symptom severity were near zero (r<0.08). Even in an 'all-comer' clinical trial, neurocognitive deficits can be assessed in the overwhelming majority of patients, and the severity of impairment is similar to meta-analytic estimates. Multiple analyses suggested that a broad cognitive deficit characterizes this sample. These deficits are modestly related to negative symptoms and essentially independent of positive symptom severity.}, Doi = {10.1038/sj.npp.1301072}, Key = {fds273428} } @article{fds273430, Author = {McEvoy, JP and Johnson, J and Perkins, D and Lieberman, JA and Hamer, RM and Keefe, RSE and Tohen, M and Glick, ID and Sharma, T}, Title = {Insight in first-episode psychosis.}, Journal = {Psychological Medicine}, Volume = {36}, Number = {10}, Pages = {1385-1393}, Year = {2006}, Month = {October}, ISSN = {0033-2917}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16740175}, Abstract = {BACKGROUND: We report here a study examining the relationships between insight and psychopathology, cognitive performance, brain volume and co-morbid depression in 251 patients experiencing a first episode of psychosis, who were then randomly assigned to 2 years of double-blind treatment with either olanzapine or haloperidol. METHOD: Repeated measures of insight were obtained at baseline and 12, 24, 52 and 104 weeks by the Insight and Treatment Attitudes Questionnaire (ITAQ). RESULTS: Older age, female gender and white ethnicity were associated with more insight. Higher total, positive, negative and general psychopathology scores on the Positive and Negative Syndromes Scale (PANSS) were associated with less insight. Higher depression scores were associated with more insight. Better neurocognitive function and large brain volumes were associated with more insight. More insight throughout the study was associated with longer time to medication non-adherence. However, baseline insight was not significantly related to the probability of discontinuing the study before 2 years. Insight improved significantly over the course of the study, but the improvement in insight was not significantly different between the two antipsychotic treatment groups. CONCLUSIONS: Multiple factors contribute to insight. Patients experiencing a first episode of psychosis who have little insight are at increased risk of discontinuing their medication.}, Doi = {10.1017/S0033291706007793}, Key = {fds273430} } @article{fds354400, Author = {Keefe, R and Bilder, RM and Davis, SM and Harvey, PD and Palmer, BW and Gold, JM and Meltzer, HY and Green, MF and Capuano, G and Stroup, TS and McEvoy, JP and Swartz, MS and Rosenheck, RA and Perkins, DO and Davis, CE and Hsiao, JK and Lieberman, JA}, Title = {Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial}, Journal = {Neuropsychopharmacology}, Volume = {31}, Pages = {S244-S245}, Publisher = {NATURE PUBLISHING GROUP}, Year = {2006}, Month = {December}, Key = {fds354400} } @article{fds371819, Author = {Wilson, WH and McEvoy, J and Keefe, R and Byerly, M and Masand, P}, Title = {Effects of risperidone microspheres on polypharmacy and cognitive function}, Journal = {Neuropsychopharmacology}, Volume = {31}, Pages = {S178-S178}, Publisher = {NATURE PUBLISHING GROUP}, Year = {2006}, Month = {December}, Key = {fds371819} } @article{fds273431, Author = {Keefe, RSE and Perkins, DO and Gu, H and Zipursky, RB and Christensen, BK and Lieberman, JA}, Title = {A longitudinal study of neurocognitive function in individuals at-risk for psychosis.}, Journal = {Schizophrenia Research}, Volume = {88}, Number = {1-3}, Pages = {26-35}, Year = {2006}, Month = {December}, ISSN = {0920-9964}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16930949}, Abstract = {INTRODUCTION: Clinically defined prodromal diagnostic criteria identify at-risk individuals with a 35-40% likelihood of developing a psychotic disorder within a year. The time course and predictive value of cognitive deficits in the development of psychosis has not been established. METHODS: A comprehensive neurocognitive battery and clinical assessments were administered to 37 subjects meeting Criteria of Prodromal States (COPS) criteria for being at risk for psychosis, and two comparison groups: 59 first episode and 47 healthy subjects. Subjects were also evaluated at 6-month and 1-year follow-up periods. Primary analyses used a neurocognitive composite score derived from individual neurocognitive measures, including measures of vigilance, verbal memory, working memory, and processing speed. RESULTS: At-risk subjects performed more poorly than healthy subjects (t=2.93, P=0.01), but better than first episode subjects (t=4.72, p<0.0001). At-risk subjects were particularly impaired on measures of vigilance and processing speed. Cognitive composite scores were significantly lower in at-risk subjects who progressed to psychosis (N=11; z=-1.2), while those at-risk subjects who did not progress to psychosis (N=17) performed better (z=-0.5), and not significantly different from controls. Poor CPT performance combined with better WAIS-R digit symbol performance predicted progression to psychosis. Severity of neurocognitive deficits was not related to duration of prodrome or to time to development of psychosis and neurocognitive function improved in all subjects except those who progressed to psychosis. CONCLUSION: Neurocognitive impairment emerges early in the course of psychotic illness. Performance on tests of neurocognition may prove to be an early risk predictor for subsequent development of psychotic disorders.}, Doi = {10.1016/j.schres.2006.06.041}, Key = {fds273431} } @article{fds273432, Author = {Rosenheck, RA and Leslie, DL and Sindelar, J and Miller, EA and Lin, H and Stroup, TS and McEvoy, J and Davis, SM and Keefe, RSE and Swartz, M and Perkins, DO and Hsiao, JK and Lieberman, J and CATIE Study Investigators}, Title = {Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia.}, Journal = {The American Journal of Psychiatry}, Volume = {163}, Number = {12}, Pages = {2080-2089}, Year = {2006}, Month = {December}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/ajp.2006.163.12.2080}, Abstract = {BACKGROUND: Second-generation antipsychotics have largely replaced first-generation antipsychotics for the treatment of schizophrenia, but a large-scale cost/effectiveness analysis has not been attempted. METHOD: Patients with schizophrenia (N=1,493) were assigned to treatment with a first-generation antipsychotic (perphenazine) or one of four second-generation drugs (olanzapine, quetia-pine, risperidone, or ziprasidone) and followed for up to 18 months. Patients with tardive dyskinesia were prohibited from assignment to perphenazine. Patients could be reassigned at any time to another second-generation drug, including clozapine, but not to perphenazine. The cost analysis included medications plus health services use. Quality-adjusted life year (QALY) ratings were assessed on the basis of Positive and Negative Syndrome Scale (PANSS) subscale scores and side effects. An intention-to-treat analysis included all available observations, classified by initial drug assignment, and costs of reassignment of most patients to another second-generation drug. The analysis was repeated considering only treatment on initially assigned medications. RESULTS: Although QALY ratings, PANSS scores, and other quality of life measures indicated modest improvement over 18 months, there were no significant differences between perphenazine and any second-generation medication. Average total monthly health care costs were 300 dollars-600 dollars (20%-30%) lower for perphenazine than for second-generation antipsychotics because of lower drug cost. Differences in costs remained when maximally discounted drug prices were used for all patients and when only observations during treatment with the first medication were included. CONCLUSIONS: Treatment with perphenazine was less costly than treatment with second-generation antipsychotics with no significant differences in measures of effectiveness. However, the trial was limited by a high dropout rate, and longer-term neurological and metabolic side effects require further study.}, Doi = {10.1176/ajp.2006.163.12.2080}, Key = {fds273432} } @article{fds354398, Author = {Bratti, I and Marder, SR and Keefe, RS and Bilder, RM}, Title = {A brief cognitive assessment tool for schizophrenia (B-CATS): Scale construction}, Journal = {Schizophrenia Bulletin}, Volume = {33}, Number = {2}, Pages = {584-584}, Year = {2007}, Key = {fds354398} } @article{fds354399, Author = {Hill, SK and Sweeney, JA and Hamer, RM and Keefe, RS and Perkins, DO and Gu, H and Koch, G and McEvoy, JP and Lieberman, JA}, Title = {Efficiency of the BACS and CATIE neuropsychological batteries in assessing cognition and antipsychotic treatment related change in cognition during the CAFE clinical trial}, Journal = {Schizophrenia Bulletin}, Volume = {33}, Number = {2}, Pages = {561-561}, Year = {2007}, Key = {fds354399} } @article{fds371783, Author = {Lipkovich, I and Kollack-Walker, S and Kinon, BJ and Stauffer, V and Ascher-Svanum, H and Keefe, R}, Title = {Cognitive status of patients with schizophrenia as modulator or mediator of functional outcome}, Journal = {Biological Psychiatry}, Volume = {61}, Number = {8}, Pages = {246S-246S}, Year = {2007}, Key = {fds371783} } @article{fds273433, Author = {Keefe, RSE}, Title = {Cognitive deficits in patients with schizophrenia: effects and treatment.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {68 Suppl 14}, Number = {SUPPL. 14}, Pages = {8-13}, Year = {2007}, ISSN = {0160-6689}, Abstract = {The average patient with schizophrenia performs on cognitive tests at the lowest 5% to 10% of the general population. Cognitive impairments impact patients on virtually every aspect of functioning, interfere with patients' ability to engage in real-world tasks, and affect long-term outcome. Therefore, cognitive deficits should be included in the diagnostic criteria for schizophrenia. Clinicians need to focus treatment options on helping patients to regain premorbid levels of cognitive functioning.}, Key = {fds273433} } @article{fds354396, Author = {Salgado, JV and Carvalhaes, CFR and Pires, ADM and Neves, MDCLD and Cruz, BF and Cardoso, CS and Lauar, H and Teixeira, AL and Keefe, RSE}, Title = {Sensitivity and applicability of the Brazilian version of the Brief Assessment of Cognition in Schizophrenia (BACS).}, Journal = {Dementia & Neuropsychologia}, Volume = {1}, Number = {3}, Pages = {260-265}, Year = {2007}, url = {http://dx.doi.org/10.1590/S1980-57642008DN10300007}, Abstract = {UNLABELLED: Cognitive assessment in schizophrenia has traditionally used batteries that are long and complex or differ widely in their content. The Brief Assessment of Cognition in Schizophrenia (BACS) has been developed to cover the main cognitive deficits of schizophrenia as well as to be easily and briefly administered, portable, sensitive and reliable. OBJECTIVES: To investigate the applicability and sensitivity of the Brazilian Version of the BACS (Brazilian-BACS). METHODS: Performance of 20 stable patients with schizophrenia on the Brazilian-BACS was compared to 20 matched healthy controls. RESULTS: Applying the Brazilian-BACS required 43.4±8.4minutes for patients and 40.5±5.7 minutes for controls (p=0.17). All tests demonstrated significant differences between controls and patients (P<0.01). Pearson's correlation analysis and Cronbach's a evidenced a high internal consistency for patient performance. The cognitive deficit in the patients was approximately 1.5 standard deviations below controls. These results were consistent with those reported in the validation of the original version and in meta-analyses of similar studies. CONCLUSIONS: The Brazilian-BACS displayed good applicability and sensitivity in assessing the major cognitive constructs that are impaired in schizophrenia. Thus, the Brazilian-BACS seems to be a promising tool for assessing cognition in patients with schizophrenia in Brazil.}, Doi = {10.1590/S1980-57642008DN10300007}, Key = {fds354396} } @article{fds273438, Author = {Rosenheck, R and Stroup, TS and Swartz, M and McEvoy, J and Davis, SM and Keefe, RSE and Hsiao, JK and Lieberman, J}, Title = {Dr. Rosenheck and colleagues reply [2]}, Journal = {The American Journal of Psychiatry}, Volume = {164}, Number = {4}, Pages = {678-680}, Publisher = {American Psychiatric Publishing}, Year = {2007}, Month = {January}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/ajp.2007.164.4.678a}, Doi = {10.1176/ajp.2007.164.4.678a}, Key = {fds273438} } @article{fds273434, Author = {Pinheiro, AP and Keefe, RSE and Skelly, T and Olarte, M and Leviel, K and Lange, LA and Lange, EM and Stroup, TS and Lieberman, J and Sullivan, PF}, Title = {AKT1 and neurocognition in schizophrenia.}, Journal = {The Australian and New Zealand Journal of Psychiatry}, Volume = {41}, Number = {2}, Pages = {169-177}, Year = {2007}, Month = {February}, ISSN = {0004-8674}, url = {http://dx.doi.org/10.1080/00048670601109956}, Abstract = {OBJECTIVE: Previous research has shown conflicting results for the significance of five v-akt murine thymoma viral oncogene homolog 1 (AKT1) single-nucleotide polymorphisms (SNPs) to the aetiology of schizophrenia. Neurocognition is a plausible endophenotype for schizophrenia and it was reasoned that the lack of agreement might be due to variability in neurocognition across studies. Therefore, the association of genetic variation in AKT1 with neurocognition was investigated in patients with schizophrenia. METHODS: The same five SNPs used in previous studies of the etiology of schizophrenia (rs2494732, rs2498799, rs3730358, rs1130214, [corrected] and rs3803300) were genotyped in 641 individuals with schizophrenia who had participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project. The primary dependent variable was a neurocognitive composite score and exploratory analyses investigated five domain scores (processing speed, reasoning, verbal memory, working memory, and vigilance). RESULTS: There were no significant asymptotic or empirical associations between any SNP and the neurocognitive composite score. The authors also investigated the association of five-SNP haplotypes with the neurocognitive composite score. A marginally significant association was observed for the neurocognitive composite score with one of the five-SNP haplotypes (global score statistic 19.51, df = 9, permutation p = 0.02). Exploratory analyses of five domain scores (processing speed, reasoning, verbal memory, working memory, and vigilance) were non-significant for all five SNPs. CONCLUSION: Results published to date for an association between genetic variation in AKT1 with schizophrenia are inconsistent. The results suggest that the AKT1 markers studied are not associated with neurocognition in schizophrenia, and do not support unassessed variation in neurocognitive scores as a reason for this discrepancy.}, Doi = {10.1080/00048670601109956}, Key = {fds273434} } @article{fds273435, Author = {Stroup, TS and Lieberman, JA and McEvoy, JP and Swartz, MS and Davis, SM and Capuano, GA and Rosenheck, RA and Keefe, RSE and Miller, AL and Belz, I and Hsiao, JK and CATIE Investigators}, Title = {Effectiveness of olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia after discontinuing perphenazine: a CATIE study.}, Journal = {The American Journal of Psychiatry}, Volume = {164}, Number = {3}, Pages = {415-427}, Year = {2007}, Month = {March}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17329466}, Abstract = {OBJECTIVE: The relative effectiveness of newly started antipsychotic drugs for individuals with schizophrenia may depend on multiple factors, including each patient's previous treatment response and the reason for a new medication trial. This randomized, double-blind study compared olanzapine, quetiapine, and risperidone in patients who had just discontinued the older antipsychotic perphenazine. METHOD: Subjects with schizophrenia (N=114) who had been randomly assigned to and then discontinued perphenazine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study were reassigned randomly to double-blinded treatment with olanzapine, 7.5-30.0 mg/day (N=38); quetiapine, 200-800 mg/day (N=38); or risperidone, 1.5-6.0 mg/day (N=38). The primary aim was to determine whether there were differences among these three treatments in effectiveness, as measured by time to treatment discontinuation for any reason. Secondary outcomes included reasons for treatment discontinuation and measures of drug tolerability. RESULTS: The time to treatment discontinuation was longer for patients treated with quetiapine (median, 9.9 months) and olanzapine (7.1 months) than with risperidone (3.6 months). There were no significant differences between treatments on discontinuation due to inefficacy, intolerability, or patient decision. CONCLUSIONS: Among this group of patients with chronic schizophrenia who had just discontinued the older antipsychotic perphenazine, quetiapine and olanzapine were more effective than risperidone, as reflected by longer time to discontinuation for any reason. In the context of other results from the CATIE study, the effectiveness and acceptability of antipsychotic drugs appears to vary considerably according to clinical circumstances.}, Doi = {10.1176/ajp.2007.164.3.415}, Key = {fds273435} } @article{fds273436, Author = {Swartz, MS and Perkins, DO and Stroup, TS and Davis, SM and Capuano, G and Rosenheck, RA and Reimherr, F and McGee, MF and Keefe, RSE and McEvoy, JP and Hsiao, JK and Lieberman, JA and CATIE Investigators}, Title = {Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study.}, Journal = {The American Journal of Psychiatry}, Volume = {164}, Number = {3}, Pages = {428-436}, Year = {2007}, Month = {March}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17329467}, Abstract = {OBJECTIVE: This study examined the relative effects of the second-generation antipsychotic drugs and an older representative agent on psychosocial functioning in patients with chronic schizophrenia. METHOD: Consenting patients were enrolled in the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project. In phase 1, patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months. Clozapine was included for patients who chose this pathway after discontinuing phase 1 due to inefficacy; all other patients received another second-generation antipsychotic. Psychosocial functioning was assessed using the Quality of Life Scale. RESULTS: Psychosocial functioning modestly improved for the one-third of phase 1 patients who reached the primary Quality of Life Scale analysis endpoint of 12 months (average effect size 0.19 SD units). Although for several of the drugs individually there were significant changes from baseline, overall there were no significant differences between the different agents. Results were similar at 6 and 18 months. There were no significant differences among the treatment groups in the amount of change in the Quality of Life Scale total score or subscale scores at 6, 12, or 18 months. Patients treated with clozapine in the efficacy pathway made comparable gains. Early treatment discontinuations, especially among patients most impaired at baseline, limited the ability to achieve more substantial functional gains. CONCLUSIONS: All antipsychotic treatment groups in all phases made modest improvements in psychosocial functioning. There were no differences among them after 6, 12, or 18 months. More substantial improvements would likely require more intensive adjunctive psychosocial rehabilitation interventions.}, Doi = {10.1176/ajp.2007.164.3.428}, Key = {fds273436} } @article{fds273437, Author = {Sullivan, PF and Keefe, RSE and Lange, LA and Lange, EM and Stroup, TS and Lieberman, J and Maness, PF}, Title = {NCAM1 and neurocognition in schizophrenia.}, Journal = {Biological Psychiatry}, Volume = {61}, Number = {7}, Pages = {902-910}, Year = {2007}, Month = {April}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/j.biopsych.2006.07.036}, Abstract = {BACKGROUND: Alterations in neurocognition may be fundamental to schizophrenia and may be endophenotypes. Neural cell adhesion molecule 1 (NCAM1, aliases NCAM and CD56) may be a candidate gene for schizophrenia or for neurocognition in schizophrenia as supported by linkage and functional findings. METHODS: Subjects were 641 patients with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) clinical trial. Neurocognition was assessed at study baseline. Nine NCAM1 single nucleotide polymorphisms (SNPs) were blindly genotyped. Analysis of covariance was used to test for single SNP associations and haplotype regression for multilocus associations. RESULTS: As there were suggestions of population stratification, all analyses were conducted stratified by inferred ancestry. In the "Europe only" stratum, there were nominally significant associations with five contiguous SNPs (rs1943620, rs1836796, rs1821693, rs686050, rs584427) with the strongest association at rs1836796 (p = .007). Via permutation testing, the probability of obtaining five consecutive statistically significant SNPs with p-values <or= .05 was p = .0044. These results were robust to examination of model assumptions. Haplotype analyses did not identify significant haplotype associations. CONCLUSIONS: Although it is essential to see if these findings replicate in additional samples, we suggest that NCAM1 deserves further scrutiny for its relevance to clinical and etiological aspects of schizophrenia.}, Doi = {10.1016/j.biopsych.2006.07.036}, Key = {fds273437} } @article{fds273441, Author = {Rosenheck, R and Swartz, M and McEvoy, J and Stroup, TS and Davis, S and Keefe, RS and Hsiao, J and Lieberman, J}, Title = {Second-generation antipsychotics: reviewing the cost-effectiveness component of the CATIE trial.}, Journal = {Expert Rev Pharmacoecon Outcomes Res}, Volume = {7}, Number = {2}, Pages = {103-111}, Year = {2007}, Month = {April}, ISSN = {1473-7167}, url = {http://dx.doi.org/10.1586/14737167.7.2.103}, Abstract = {The cost-effectiveness component of the 18-month CATIE trial of schizophrenia pharmacotherapy (n = 1460) showed that the first-generation antipsychotic perphenazine was US$300-600 per month less expensive than each of four second-generation antipsychotics, and no less effective across multiple measures. We consider whether or not each of eight potential methodological limitations could weaken this conclusion: follow-up rates, study duration, sample characteristics, the choice of outcome measures, exclusion of patients with tardive dyskinesia from assignment to perphenazine, choice of study drugs and doses, reliance on intention-to-treat analysis, and differences in prestudy treatment. We conclude that results of CATIE are robust to these limitations. Perphenazine seems to have been a more representative choice for first-generation antipsychotic comparison treatment than haloperidol.}, Doi = {10.1586/14737167.7.2.103}, Key = {fds273441} } @article{fds336082, Author = {ROSENHECK, R and STROUP, TS and SWARTZ, M and McEVOY, J and DAVIS, SM and KEEFE, RSE and HSIAO, JK and LIEBERMAN, J}, Title = {Dr. Rosenheck and Colleagues Reply}, Journal = {The American Journal of Psychiatry}, Volume = {164}, Number = {4}, Pages = {678-680}, Publisher = {American Psychiatric Association Publishing}, Year = {2007}, Month = {April}, url = {http://dx.doi.org/10.1176/appi.ajp.164.4.678-a}, Doi = {10.1176/appi.ajp.164.4.678-a}, Key = {fds336082} } @article{fds327078, Author = {Nasrallah, HA and Keefe, RSE and Davis, S and Mcevoy, J and Goff, D and Meyer, J and Stroup, TS and Lieberman, JA}, Title = {Cognitive improvement correlates with weight gain in schizophrenia subjects receiving quetiapine but not other antipsychotics: Data from the CATIE trial}, Journal = {Biological Psychiatry}, Volume = {61}, Number = {8}, Pages = {247S-248S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2007}, Month = {April}, Key = {fds327078} } @article{fds354397, Author = {Marx, CE and Keefe, RS and Leimone, LA and Hamer, RM and Bradford, DW and Dunn, L and Payne, VM and Naylor, JC and Savitz, AJ and Strauss, JL and Lieberman, JA and Shampine, LJ}, Title = {Proof-of-concept trial with the neurosterold pregnenolone targeting neurocognitive and negative symptoms in schizophrenia}, Journal = {Biological Psychiatry}, Volume = {61}, Number = {8}, Pages = {13S-13S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2007}, Month = {April}, Key = {fds354397} } @article{fds327077, Author = {Keefe, RSE and Harvey, PD and Goldberg, TE and Gold, JM and Walker, TM}, Title = {General and specific cognitive deficits in bipolar depression: the Brief Assessment of Cognition in Affective Disorders (BAC-A)}, Journal = {Bipolar Disorders}, Volume = {9}, Pages = {9-9}, Publisher = {BLACKWELL PUBLISHING}, Year = {2007}, Month = {June}, Key = {fds327077} } @article{fds273439, Author = {Keefe, RSE and Bilder, RM and Davis, SM and Harvey, PD and Palmer, BW and Gold, JM and Meltzer, HY and Green, MF and Capuano, G and Stroup, TS and McEvoy, JP and Swartz, MS and Rosenheck, RA and Perkins, DO and Davis, CE and Hsiao, JK and Lieberman, JA and CATIE Investigators, and Neurocognitive Working Group}, Title = {Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial.}, Journal = {Archives of General Psychiatry}, Volume = {64}, Number = {6}, Pages = {633-647}, Year = {2007}, Month = {June}, ISSN = {0003-990X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17548746}, Abstract = {CONTEXT: Neurocognitive impairment in schizophrenia is severe and is an important predictor of functional outcome. The relative effect of the second-generation (atypical) antipsychotic drugs and older agents on neurocognition has not been comprehensively determined. OBJECTIVE: To compare the neurocognitive effects of several second-generation antipsychotics and a first-generation antipsychotic, perphenazine. DESIGN: Randomized, double-blind study of patients with schizophrenia assigned to receive treatment with olanzapine, perphenazine, quetiapine fumarate, or risperidone for up to 18 months as reported previously by Lieberman et al. Ziprasidone hydrochloride was included after its approval by the Food and Drug Administration. SETTING: Fifty-seven sites participated, including academic sites and treatment mental health facilities representative of the community. PATIENTS: From a cohort of 1460 patients in the treatment study, 817 completed neurocognitive testing immediately prior to randomization and then after 2 months of treatment. MAIN OUTCOME MEASURES: The primary outcome was change in a neurocognitive composite score after 2 months of treatment. Secondary outcomes included neurocognitive composite score change at 6 months and 18 months after continued treatment and changes in neurocognitive domains. RESULTS: At 2 months, treatment resulted in small neurocognitive improvements of z = 0.13 for olanzapine (P<.002), 0.25 for perphenazine (P<.001), 0.18 for quetiapine (P<.001), 0.26 for risperidone (P<.001), and 0.12 for ziprasidone (P<.06), with no significant differences between groups. Results at 6 months were similar. After 18 months of treatment, neurocognitive improvement was greater in the perphenazine group than in the olanzapine and risperidone groups. Neurocognitive improvement predicted longer time to treatment discontinuation, independently from symptom improvement, in patients treated with quetiapine or ziprasidone. CONCLUSIONS: After 2 months of antipsychotic treatment, all groups had a small but significant improvement in neurocognition. There were no differences between any pair of agents, including the typical drug perphenazine. These results differ from the majority of previous studies, and the possible reasons are discussed.}, Doi = {10.1001/archpsyc.64.6.633}, Key = {fds273439} } @article{fds273440, Author = {Keefe, RSE and Fenton, WS}, Title = {How should DSM-V criteria for schizophrenia include cognitive impairment?}, Journal = {Schizophrenia Bulletin}, Volume = {33}, Number = {4}, Pages = {912-920}, Year = {2007}, Month = {July}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbm046}, Abstract = {Neurocognitive impairment is considered a core component of schizophrenia and is increasingly under investigation as a potential treatment target. On average, cognitive impairment is severe to moderately severe compared with healthy controls, and almost all patients with schizophrenia demonstrate cognitive decrements compared with their expected level if they had not developed the illness. Compared with patients with affective disorders, cognitive impairment in schizophrenia appears earlier, is more severe, and tends to be more independent of clinical symptoms. While the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, description of schizophrenia includes several references to cognitive impairment, neither the diagnostic criteria nor the subtypology of schizophrenia include a requirement of cognitive impairment. We forward for consideration a proposal that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria include a specific criterion of "a level of cognitive functioning suggesting a consistent severe impairment and/or a significant decline from premorbid levels considering the patient's educational, familial, and socioeconomic background." The inclusion of this criterion may increase the "point of rarity" with affective psychoses and may increase clinicians' awareness of cognitive impairment, potentially leading to more accurate prognosis and better treatment outcomes. Future research will need to address the validity of these possibilities. The reliable determination of cognitive impairment as part of a standard diagnostic evaluation may present challenges to diagnosticians with limited resources or insufficient expertise. Various cognitive assessment methods for clinicians, including brief assessments and interview-based assessments, are discussed. Given the current emphasis on the development of cognitive treatments, the evaluation of cognition in schizophrenia is an essential component of mental health education.}, Doi = {10.1093/schbul/sbm046}, Key = {fds273440} } @article{fds273443, Author = {Keefe, RSE and Sweeney, JA and Gu, H and Hamer, RM and Perkins, DO and McEvoy, JP and Lieberman, JA}, Title = {Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison.}, Journal = {The American Journal of Psychiatry}, Volume = {164}, Number = {7}, Pages = {1061-1071}, Year = {2007}, Month = {July}, ISSN = {0002-953X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17606658}, Abstract = {OBJECTIVE: The authors sought to compare the effects of olanzapine, quetiapine, and risperidone on neurocognitive function in patients with early psychosis. METHOD: In a 52-week double-blind, multicenter study, 400 patients early in the course of psychotic illness (<5 years) were randomly assigned to treatment with olanzapine (2.5-20 mg/day), quetiapine (100-800 mg/day), or risperidone (0.5-4 mg/day). The mean modal daily dose was 11.7 mg (SD=5.3) for olanzapine, 506 mg (SD=215) for quetiapine, and 2.4 mg (SD=1.0) for risperidone. A total of 224 patients completed neurocognitive assessments at baseline and at 12 weeks, and 81 patients also completed them at 52 weeks. Neurocognitive composite scores were calculated from the neurocognitive battery used in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and from the Brief Assessment of Cognition in Schizophrenia. RESULTS: At week 12, there was significant improvement in neurocognition for each treatment (p<0.01), but no significant overall difference between treatments. Composite z score improvements on the CATIE neurocognitive battery were 0.17 for olanzapine, 0.33 for quetiapine, and 0.32 for risperidone. Composite z score improvements on the Brief Assessment of Cognition in Schizophrenia were 0.19 for olanzapine, 0.34 for quetiapine, and 0.22 for risperidone. Statistically significant relationships between improvements in neurocognition and functional outcome were observed at weeks 12 and 52. CONCLUSIONS: Olanzapine, quetiapine, and risperidone all produced significant improvements in neurocognition in early-psychosis patients. Although cognitive improvements were modest, their clinical importance was suggested by relationships with improvements in functional outcome.}, Doi = {10.1176/ajp.2007.164.7.1061}, Key = {fds273443} } @article{fds273442, Author = {Pandina, GJ and Bilder, R and Harvey, PD and Keefe, RSE and Aman, MG and Gharabawi, G}, Title = {Risperidone and cognitive function in children with disruptive behavior disorders.}, Journal = {Biological Psychiatry}, Volume = {62}, Number = {3}, Pages = {226-234}, Year = {2007}, Month = {August}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/j.biopsych.2006.09.036}, Abstract = {BACKGROUND: Effects of risperidone on cognitive function in children with disruptive behavior disorders (DBDs) and subaverage intelligence quotient (IQ) were assessed. METHODS: Data from two 6-week, double-blind, placebo-controlled studies (n = 228) were combined, as were three 1-year, open-label studies (n = 688). Patients with DBDs and subaverage IQ, 5 to14 years, received placebo or risperidone .02 to .06 mg/kg/day. Cognitive measures included the Continuous Performance Task (CPT) and Verbal Learning Test for Children (VLT-C). Efficacy was assessed using the Nisonger Child Behavior Rating Form (NCBRF). Adverse events were collected via spontaneous report; sedation was assessed using visual analog scale. RESULTS: Improvements on the NCBRF Conduct Problem subscale were significantly greater for risperidone- versus placebo-treated patients (-15.8 vs. -6.4, p < .0001) in short-term studies; significant reductions were observed in long-term studies (-16.3, p < .0001). No overall decline and some significant improvement in attention (CPT) and memory (VLT-C) were noted regardless of treatment in short-term studies. VLT-C improved significantly (p < .0001) for both groups, with no difference between treatment groups. Improvements in memory (VLT-C) and attention (CPT) were noted in long-term studies. Somnolence/sedation did not affect cognitive function. CONCLUSIONS: Cognitive function was not altered by risperidone in short-term studies and was maintained or improved with one year of treatment in children with DBDs and subaverage IQ, potentially representing age-appropriate gains.}, Doi = {10.1016/j.biopsych.2006.09.036}, Key = {fds273442} } @article{fds273445, Author = {Kraus, MS and Keefe, RSE}, Title = {Cognition as an outcome measure in schizophrenia.}, Journal = {The British Journal of Psychiatry. Supplement}, Volume = {50}, Number = {SUPPL. 50}, Pages = {s46-s51}, Year = {2007}, Month = {August}, ISSN = {0007-1250}, url = {http://dx.doi.org/10.1192/bjp.191.50.s46}, Abstract = {BACKGROUND: Cognitive deficits are a core feature of schizophrenia. These deficits are not caused by medication or symptoms, and have a dramatic negative effect on real-world functioning. AIMS: To critically examine a selection of the most common batteries used to assess cognition in schizophrenia. METHOD: Literature review of cognitive assessment batteries for use in schizophrenia. RESULTS: A wide variety of neurocognitive test batteries have been developed or adapted to assess cognition in schizophrenia. These differ in time requirements, repeatability, ease of administration, degree of face validity, availability of co-normative data and degree to which results can be parsed into separate domains of cognitive functioning. The most appropriate depends on the setting and the question being addressed. CONCLUSIONS: Cognitive outcome measures have reshaped our understanding of schizophrenia and will be essential tools for unravelling the aetiology ofthe disease and designing more effective interventions.}, Doi = {10.1192/bjp.191.50.s46}, Key = {fds273445} } @article{fds273444, Author = {Bralet, M-C and Falissard, B and Neveu, X and Lucas-Ross, M and Eskenazi, A-M and Keefe, RSE}, Title = {Validation of the French version of the BACS (the brief assessment of cognition in schizophrenia) among 50 French schizophrenic patients.}, Journal = {European Psychiatry}, Volume = {22}, Number = {6}, Pages = {365-370}, Year = {2007}, Month = {September}, ISSN = {0924-9338}, url = {http://dx.doi.org/10.1016/j.eurpsy.2007.02.001}, Abstract = {Schizophrenic patients demonstrate impairments in several key dimensions of cognition. These impairments are correlated with important aspects of functional outcome. While assessment of these cognition disorders is increasingly becoming a part of clinical and research practice in schizophrenia, there is no standard and easily administered test battery. The BACS (Brief Assessment of Cognition in Schizophrenia) has been validated in English language [Keefe RSE, Golberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: reliability, sensibility, and comparison with a standard neurocognitive battery. Schizophr. Res 2004;68:283-97], and was found to be as sensitive to cognitive dysfunction as a standard battery of tests, with the advantage of requiring less than 35 min to complete. We developed a French adaptation of the BACS and this study tested its ease of administration and concurrent validity. Correlation analyses between the BACS (version A) and a standard battery were performed. A sample of 50 stable schizophrenic patients received the French Version A of the BACS in a first session, and in a second session a standard battery. All the patients completed each of the subtests of the French BACS . The mean duration of completion for the BACS French version was 36 min (S.D.=5.56). A correlation analysis between the BACS (version A) global score and the standard battery global score showed a significant result (r=0.81, p<0.0001). The correlation analysis between the BACS (version A) sub-scores and the standard battery sub-scores showed significant results for verbal memory, working memory, verbal fluency, attention and speed of information processing and executive functions (p<0.001) and for motor speed (p<0.05). The French Version of the BACS is easier to use in French schizophrenic patients compared to a standard battery (administration shorter and completion rate better) and its good psychometric properties suggest that the French Version of the BACS may be a useful tool for assessing cognition in schizophrenic patients with French as their primary language.}, Doi = {10.1016/j.eurpsy.2007.02.001}, Key = {fds273444} } @article{fds273446, Author = {Kaneda, Y and Sumiyoshi, T and Keefe, R and Ishimoto, Y and Numata, S and Ohmori, T}, Title = {Brief assessment of cognition in schizophrenia: validation of the Japanese version.}, Journal = {Psychiatry and Clinical Neurosciences}, Volume = {61}, Number = {6}, Pages = {602-609}, Year = {2007}, Month = {December}, ISSN = {1323-1316}, url = {http://dx.doi.org/10.1111/j.1440-1819.2007.01725.x}, Abstract = {This preliminary study was performed to test the reliability and validity of the Brief Assessment of Cognition in Schizophrenia (BACS) as an assessment tool in a Japanese-language version (BACS-J). The subjects for the present study were 30 outpatients with chronic schizophrenia. Each subject gave written informed consent to participate in the research. Cronbach's alpha for the BACS-J was 0.77. The BACS-J composite score was significantly correlated with all primary measures of BACS-J (verbal memory, working memory, motor speed, verbal fluency, attention, and executive function). All BACS-J primary measures and the composite score were significantly correlated between two assessments. The mean score of the Digit Sequencing Task and composite score on the second assessment were significantly larger than those on the first assessment. All BACS-J primary measures except the Symbol Coding Task were significantly correlated with relevant standard neurocognitive tests. Also, the BACS-J composite score was significantly correlated with all standard neurocognitive tests except the Continuous Performance Test. A principal components analysis with varimax rotation resulted in a three-factor solution (executive function and memory; motor speed and general cognitive functions; and working memory). This preliminary study indicates that the BACS-J is a reliable and practical scale to evaluate cognitive function.}, Doi = {10.1111/j.1440-1819.2007.01725.x}, Key = {fds273446} } @article{fds273447, Author = {Keefe, RSE and Sweeney, JA and Gu, H and Hamer, RM and Perkins, DO and McEvoy, JP and Lieberman, JA}, Title = {Dr. Keefe and colleagues reply}, Journal = {The American Journal of Psychiatry}, Volume = {164}, Number = {12}, Pages = {1911-1912}, Publisher = {American Psychiatric Publishing}, Year = {2007}, Month = {December}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.2007.07071086r}, Doi = {10.1176/appi.ajp.2007.07071086r}, Key = {fds273447} } @article{fds273448, Author = {Goff, DC and Keefe, R and Citrome, L and Davy, K and Krystal, JH and Large, C and Thompson, TR and Volavka, J and Webster, EL}, Title = {Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials.}, Journal = {Journal of Clinical Psychopharmacology}, Volume = {27}, Number = {6}, Pages = {582-589}, Year = {2007}, Month = {December}, ISSN = {0271-0749}, url = {http://dx.doi.org/10.1097/jcp.0b013e31815abf34}, Abstract = {OBJECTIVE: : Lamotrigine previously was found to attenuate ketamine-induced behavioral changes and, in 2 placebo-controlled trials, to improve psychosis when added to antipsychotic medication. We sought to evaluate the potential role of lamotrigine augmentation in schizophrenia patients resistant to atypical antipsychotic medication. METHODS: : Two multicenter, randomized, double-blind, 12-week, parallel-group trials were conducted to compare flexibly dosed lamotrigine (100-400 mg/d) with placebo as add-on treatment in schizophrenia patients with stable, residual psychotic symptoms. The primary end point was changed in Positive and Negative Syndrome Scale total score at week 12. RESULTS: : Two hundred seventeen patients were enrolled in study 1 and 212 in study 2; completion rates in the intent-to-treat samples were 71% and 74%, respectively, and did not differ between treatment groups. Overall, mean Positive and Negative Syndrome Scale total scores improved in both studies and did not differ between treatment groups. In study 1, the Scale for Assessment of Negative Symptoms total score and Clinical Global Impression improved more with placebo than with lamotrigine; in study 2, the cognitive composite score improved more with lamotrigine than with placebo. CONCLUSIONS: : Results from these 2 studies do not support the use of lamotrigine as an adjunct to atypical antipsychotics in patients with refractory psychosis. It is unclear why positive results from previous lamotrigine trials were not replicated. The positive effect of lamotrigine on cognition in one trial, while of uncertain significance, may merit further study.}, Doi = {10.1097/jcp.0b013e31815abf34}, Key = {fds273448} } @article{fds273449, Author = {Nuechterlein, KH and Green, MF and Kern, RS and Baade, LE and Barch, DM and Cohen, JD and Essock, S and Fenton, WS and Frese, FJ and Gold, JM and Goldberg, T and Heaton, RK and Keefe, RSE and Kraemer, H and Mesholam-Gately, R and Seidman, LJ and Stover, E and Weinberger, DR and Young, AS and Zalcman, S and Marder, SR}, Title = {The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity.}, Journal = {The American Journal of Psychiatry}, Volume = {165}, Number = {2}, Pages = {203-213}, Year = {2008}, Month = {February}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.2007.07010042}, Abstract = {OBJECTIVE: The lack of an accepted standard for measuring cognitive change in schizophrenia has been a major obstacle to regulatory approval of cognition-enhancing treatments. A primary mandate of the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was to develop a consensus cognitive battery for clinical trials of cognition-enhancing treatments for schizophrenia through a broadly based scientific evaluation of measures. METHOD: The MATRICS Neurocognition Committee evaluated more than 90 tests in seven cognitive domains to identify the 36 most promising measures. A separate expert panel evaluated the degree to which each test met specific selection criteria. Twenty tests were selected as a beta battery. The beta battery was administered to 176 individuals with schizophrenia and readministered to 167 of them 4 weeks later so that the 20 tests could be compared directly. RESULTS: The expert panel ratings are presented for the initially selected 36 tests. For the beta battery tests, data on test-retest reliability, practice effects, relationships to functional status, practicality, and tolerability are presented. Based on these data, 10 tests were selected to represent seven cognitive domains in the MATRICS Consensus Cognitive Battery. CONCLUSIONS: The structured consensus method was a feasible and fair mechanism for choosing candidate tests, and direct comparison of beta battery tests in a common sample allowed selection of a final consensus battery. The MATRICS Consensus Cognitive Battery is expected to be the standard tool for assessing cognitive change in clinical trials of cognition-enhancing drugs for schizophrenia. It may also aid evaluation of cognitive remediation strategies.}, Doi = {10.1176/appi.ajp.2007.07010042}, Key = {fds273449} } @article{fds273450, Author = {Keefe, RSE}, Title = {Should cognitive impairment be included in the diagnostic criteria for schizophrenia?}, Journal = {World Psychiatry : Official Journal of the World Psychiatric Association (Wpa)}, Volume = {7}, Number = {1}, Pages = {22-28}, Year = {2008}, Month = {February}, ISSN = {1723-8617}, url = {http://dx.doi.org/10.1002/j.2051-5545.2008.tb00142.x}, Abstract = {Neurocognitive impairment is considered a core component of schizophrenia, and is increasingly under investigation as a potential treatment target. On average, cognitive impairment is severe to moderately severe compared to healthy controls, and almost all patients with schizophrenia demonstrate cognitive decrements compared to their expected level if they had not developed the illness. Compared to patients with affective disorders, cognitive impairment in schizophrenia appears earlier, is more severe, and is more independent of clinical symptoms. Although the DSM-IV-TR and ICD-10 descriptions of schizophrenia include several references to cognitive impairment, neither the diagnostic criteria nor the subtypology of schizophrenia include a requirement of cognitive impairment. This paper forwards for consideration a proposal that the diagnostic criteria include a specific criterion of "a level of cognitive functioning suggesting a consistent severe impairment and/or a significant decline from premorbid levels considering the patient's educational, familial, and socioeconomic background". The inclusion of this criterion may increase the "point of rarity" with affective psychoses and may increase clinicians' awareness of cognitive impairment, potentially leading to more accurate prognosis, better treatment outcomes, and a clearer diagnostic signal for genetic and biological studies. Future research will need to address the validity of these possibilities. The reliable determination of cognitive impairment as part of a standard diagnostic evaluation will present challenges to diagnosticians with limited resources or insufficient expertise. Cognitive assessment methods for clinicians, including brief assessments and interview-based assessments, are discussed. Given the current emphasis on the development of cognitive treatments, the evaluation of cognition in schizophrenia is an essential component of mental health education.}, Doi = {10.1002/j.2051-5545.2008.tb00142.x}, Key = {fds273450} } @article{fds273451, Author = {Green, MF and Nuechterlein, KH and Kern, RS and Baade, LE and Fenton, WS and Gold, JM and Keefe, RSE and Mesholam-Gately, R and Seidman, LJ and Stover, E and Marder, SR}, Title = {Functional co-primary measures for clinical trials in schizophrenia: results from the MATRICS Psychometric and Standardization Study.}, Journal = {The American Journal of Psychiatry}, Volume = {165}, Number = {2}, Pages = {221-228}, Year = {2008}, Month = {February}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.2007.07010089}, Abstract = {OBJECTIVE: During the consensus meetings of the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) Initiative, the U.S. Food and Drug Administration took the position that a drug for this purpose should show changes on 1) an accepted consensus cognitive performance measure and 2) an additional measure (i.e., a co-primary) that is considered functionally meaningful. The goal of the current study was to describe steps to evaluate four potential co-primary measures for psychometric properties and validity. METHOD: As part of the five-site MATRICS Psychometric and Standardization Study (PASS), two measures of functional capacity and two interview-based measures of cognition were evaluated in 176 patients with schizophrenia (167 of these patients were retested 4 weeks later). RESULTS: Data are presented for each co-primary measure for test-retest reliability, utility as a repeated measure, relationship to cognitive performance, relationship to functioning, tolerability/practicality, and number of missing data. CONCLUSIONS: Psychometric properties of all of the measures were considered acceptable, and the measures were generally comparable across the various criteria, except that the functional capacity measures had stronger relationships to cognitive performance and fewer missing data. The development and evaluation of potential co-primary measures is still at an early stage, and it was decided not to endorse a single measure for clinical trials at this point. The current findings offer the initial steps to identify functionally meaningful co-primary measures in this area and will help to guide further evaluation of such measures.}, Doi = {10.1176/appi.ajp.2007.07010089}, Key = {fds273451} } @article{fds273452, Author = {Kern, RS and Nuechterlein, KH and Green, MF and Baade, LE and Fenton, WS and Gold, JM and Keefe, RSE and Mesholam-Gately, R and Mintz, J and Seidman, LJ and Stover, E and Marder, SR}, Title = {The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization.}, Journal = {The American Journal of Psychiatry}, Volume = {165}, Number = {2}, Pages = {214-220}, Year = {2008}, Month = {February}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.2007.07010043}, Abstract = {OBJECTIVE: The consensus cognitive battery developed by the National Institute of Mental Health's (NIMH's) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative includes 10 independently developed tests that are recommended as the standard battery for clinical trials of cognition-enhancing interventions for schizophrenia. To facilitate interpretation of results from the MATRICS Consensus Cognitive Battery using a common scaling across tests, normative data were obtained from a single representative U.S. community sample with the battery administered as a unit. METHOD: The MATRICS Consensus Cognitive Battery was administered to 300 individuals from the general community at five sites in differing geographic regions. For each site, recruitment was stratified by age, gender, and education. A scientific survey sampling method was used to help avoid sampling bias. The battery was administered in a standard order to each participant in a single session lasting approximately 60 minutes. Descriptive data were generated, and age, gender, and education effects on performance were examined. RESULTS: Prominent age and education effects were observed across tests. The results for gender differed by measure, suggesting the need for age and gender corrections in clinical trials. The MATRICS Consensus Cognitive Battery components were co-normed, with allowance for demographic corrections. CONCLUSIONS: Co-norming a battery such as the MATRICS Consensus Cognitive Battery, comprising tests from independent test developers each with their own set of norms, facilitates valid interpretation of test scores and communication of findings across studies. These normative data will aid in estimating the magnitude of change during clinical trials of cognition-enhancing agents and make it possible to derive more directly interpretable composite scores.}, Doi = {10.1176/appi.ajp.2007.07010043}, Key = {fds273452} } @article{fds273453, Author = {Hill, SK and Sweeney, JA and Hamer, RM and Keefe, RSE and Perkins, DO and Gu, H and McEvoy, JP and Lieberman, JA}, Title = {Efficiency of the CATIE and BACS neuropsychological batteries in assessing cognitive effects of antipsychotic treatments in schizophrenia.}, Journal = {J Int Neuropsychol Soc}, Volume = {14}, Number = {2}, Pages = {209-221}, Year = {2008}, Month = {March}, ISSN = {1355-6177}, url = {http://dx.doi.org/10.1017/S1355617708080570}, Abstract = {Efficient and reliable assessments of cognitive treatment effects are essential for the comparative evaluation of procognitive effects of pharmacologic therapies. Yet, no studies have addressed the sensitivity and efficiency with which neurocognitive batteries evaluate cognitive abilities before and after treatment. Participants were primarily first episode schizophrenia patients who completed baseline (n = 367) and 12-week (n = 219) assessments with the BACS (Brief Assessment of Cognition in Schizophrenia) and CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) neuropsychological batteries in a clinical trial comparing olanzapine, quetiapine, and risperidone. Exploratory factor analysis revealed that performance on both batteries was characterized by a single factor of generalized cognitive deficit for both baseline performance and cognitive change after treatment. Both batteries estimated similar levels of change following treatment, although the BACS battery required half the administration time. Because a unitary factor characterized baseline cognitive abilities in early psychosis as well as cognitive change after treatment with atypical antipsychotic medications, short batteries such as the BACS may efficiently provide sufficient assessment of procognitive treatment effects with antipsychotic medications. Assessment of cognitive effects of adjunctive therapies targeting specific cognitive domains or impairments may require more extensive testing of the domains targeted to maximize sensitivity for detecting specific predicted cognitive outcomes.}, Doi = {10.1017/S1355617708080570}, Key = {fds273453} } @article{fds370978, Author = {Keefe, R and Kraus, M and Dixon, V and Kennel, C and Perkins, D}, Title = {Olfactory and cognitive function in subjects at ultra-high risk for psychosis}, Journal = {Biological Psychiatry}, Volume = {63}, Number = {7}, Pages = {120S-120S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2008}, Month = {April}, Key = {fds370978} } @article{fds273455, Author = {Resnick, SG and Rosenheck, RA and Canive, JM and De Souza and C and Stroup, TS and McEvoy, J and Davis, S and Keefe, RSE and Swartz, M and Lieberman, J}, Title = {Employment outcomes in a randomized trial of second-generation antipsychotics and perphenazine in the treatment of individuals with schizophrenia.}, Journal = {J Behav Health Serv Res}, Volume = {35}, Number = {2}, Pages = {215-225}, Year = {2008}, Month = {April}, ISSN = {1094-3412}, url = {http://dx.doi.org/10.1007/s11414-007-9101-3}, Abstract = {Employment has been increasingly recognized as an important goal for individuals with schizophrenia. Previous research has shown mixed results on the relationship of specific antipsychotic medications to employment outcomes, with some studies finding greater benefits for second-generation antipsychotic medications (SGAs) over first-generation antipsychotic medication (FGAs). A randomized controlled trial (CATIE) examined medication assignment and both employment outcomes and participation in psychosocial rehabilitation (PSR) among 1,121 individuals with a diagnosis of schizophrenia randomized to SGAs (olanzapine, quetiapine, risperidone, ziprasidone) or one FGA (perphenazine). Service use and employment were assessed at quarterly interviews. There were no differences between medication groups on employment outcomes or participation in PSR. Consistent with other CATIE results, there were no differences in employment or participation in PSR among these five medications, including the FGA perphenazine.}, Doi = {10.1007/s11414-007-9101-3}, Key = {fds273455} } @article{fds273454, Author = {Keefe, RSE and Malhotra, AK and Meltzer, HY and Kane, JM and Buchanan, RW and Murthy, A and Sovel, M and Li, C and Goldman, R}, Title = {Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: significant placebo/practice effects in a 12-week, randomized, double-blind, placebo-controlled trial.}, Journal = {Neuropsychopharmacology}, Volume = {33}, Number = {6}, Pages = {1217-1228}, Year = {2008}, Month = {May}, ISSN = {0893-133X}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17625502}, Abstract = {Altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions may contribute to the cognitive impairment exhibited in patients with schizophrenia. Increasing cholinergic activity through the use of a cholinesterase inhibitor (ChEI) therefore represents a possible strategy for cognitive augmentation in schizophrenia. We examined the efficacy and safety of the ChEI donepezil as cotreatment for mild to moderate cognitive impairment in schizophrenia or schizoaffective disorder in a prospective, 12-week, placebo-controlled, double-blind, parallel-group study. In total, 250 patients (18-55 years) with schizophrenia or schizoaffective disorder who were clinically stabilized on risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole, alone or in combination, were enrolled at 38 outpatient psychiatric clinics in the United States. Patients were randomized to donepezil 5 mg q.d. for 6 weeks then 10 mg q.d. for 6 weeks, or placebo administered as oral tablets. The primary outcome measure was the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) neurocognitive battery composite score. In the intent-to-treat sample (donepezil, n=121; placebo, n=124), both treatments showed improvement in the composite score from baseline to week 12. At week 12, cognitive improvement with donepezil was similar to that with placebo (last-observation-carried-forward effect size, 0.277 vs 0.411; p=0.1182) and statistically significantly inferior for the observed-cases analysis (0.257 vs 0.450; p=0.044). There was statistically significant improvement in the Positive and Negative Syndrome Assessment Scale negative symptoms score for placebo compared with donepezil, while total and positive symptom scores were similar between both treatments. Statistically significant improvements in positive symptoms score and Clinical Global Impression-Improvement for donepezil compared with placebo were noted at Week 6. Treatment-emergent adverse events (AEs) were observed for 54.5% of donepezil- and 61.3% of placebo-treated patients; most AEs were rated as mild to moderate in severity. Donepezil was safe and well-tolerated but was not effective compared with placebo as a cotreatment for the improvement of cognitive impairment in this patient population. A significant and surprisingly large placebo/practice effect was observed among placebo-treated patients, and is a serious consideration in future clinical trial study designs for potential cognitive enhancing compounds in schizophrenia.}, Doi = {10.1038/sj.npp.1301499}, Key = {fds273454} } @article{fds273456, Author = {Swartz, MS and Stroup, TS and McEvoy, JP and Davis, SM and Rosenheck, RA and Keefe, RSE and Hsiao, JK and Lieberman, JA}, Title = {What CATIE found: results from the schizophrenia trial.}, Journal = {Psychiatric Services (Washington, D.C.)}, Volume = {59}, Number = {5}, Pages = {500-506}, Year = {2008}, Month = {May}, ISSN = {1075-2730}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18451005}, Abstract = {The authors provide an overview of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) sponsored by the National Institute of Mental Health. CATIE was designed to compare a proxy first-generation antipsychotic, perphenazine, to several newer drugs. In phase 1 of the trial, consenting patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months on a double-blind basis. Patients with tardive dyskinesia were excluded from being randomly assigned to perphenazine and were assigned to one of the four second-generation antipsychotics in phase 1A. Clozapine was included in phase 2 of the study. Overall, olanzapine had the longest time to discontinuation in phase 1, but it was associated with significant weight and metabolic concerns. Perphenazine was not significantly different in overall effectiveness, compared with quetiapine, risperidone, and ziprasidone. Also, perphenazine was found to be the most cost-effective drug. Clozapine was confirmed as the most effective drug for individuals with a poor symptom response to previous antipsychotic drug trials, although clozapine was also associated with troublesome adverse effects. There were no differences in neurocognitive or psychosocial functioning in response to medications. Subsequent randomizations suggest that a poor response to an initial medication may mean that a different medication will be more effective or better tolerated. Although the CATIE results are controversial, they are broadly consistent with most previous antipsychotic drug trials and meta-analyses; however, the results may not generalize well to patients at high risk of tardive dyskinesia. Patient characteristics and clinical circumstances affected drug effectiveness; these patient factors are important in making treatment choices.}, Doi = {10.1176/ps.2008.59.5.500}, Key = {fds273456} } @article{fds273457, Author = {Lieberman, JA and Drake, RE and Sederer, LI and Belger, A and Keefe, R and Perkins, D and Stroup, S}, Title = {Science and recovery in schizophrenia.}, Journal = {Psychiatric Services (Washington, D.C.)}, Volume = {59}, Number = {5}, Pages = {487-496}, Year = {2008}, Month = {May}, ISSN = {1075-2730}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18451003}, Abstract = {Mental health advocates and policy makers are increasingly attuned to the importance of the recovery concept, and psychiatrists and neuroscientists increasingly emphasize the medical model and neurobiological mechanisms in relation to schizophrenia. Studies have shown that people with schizophrenia are tremendously heterogeneous in each domain of recovery, and the various domains of recovery are themselves relatively independent from one another. Studies have also shown that current interventions are effective for specific dimensions of the illness and functions, are usually ameliorative rather than curative, and are effective only for a proportion of patients. Hence, the authors suggest defining recovery in terms of improvements in specific domains rather than globally -- for example, "recovery of cognitive functioning" or "recovery of vocational functioning" -- to signify improvements in specific areas. This definition realistically emphasizes states of relative and partial recovery that patients can achieve in response to treatment. The emphasis on a range of improvements in specific areas should allow clinicians to communicate more clearly regarding the current findings and goals of treatment. The article also examines current research on various aspects of recovery, including the effects of treatment on pathophysiology, symptoms, cognitive impairments, quality of life, and self-agency. An operational definition of recovery allows for bridging hope and recovery with important advances in the science of the brain. Future clinical and neuroscience research and service development should emphasize measures of recovery as outcomes for people with schizophrenia.}, Doi = {10.1176/ps.2008.59.5.487}, Key = {fds273457} } @article{fds273458, Author = {Keefe, RSE and Harvey, PD and Goldberg, TE and Gold, JM and Walker, TM and Kennel, C and Hawkins, K}, Title = {Norms and standardization of the Brief Assessment of Cognition in Schizophrenia (BACS).}, Journal = {Schizophrenia Research}, Volume = {102}, Number = {1-3}, Pages = {108-115}, Year = {2008}, Month = {July}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2008.03.024}, Abstract = {According to the recommendations of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Neurocognition Committee, one of the desired characteristics of a cognitive battery for assessing cognition in schizophrenia studies and clinical trials is the availability of normative data. This report describes normative data collected on the Brief Assessment of Cognition in Schizophrenia (BACS) from 404 healthy controls with demographic characteristics matching the 2005 United States Census of English-speakers. The six test measures demonstrated the expected pattern of correlations with age, gender, and education. Individual test scores were converted into standardized (T and z) scores and composite scores that were corrected for age and gender. An education-correction factor was calculated and recommended only for non-schizophrenia patients. Eight different verbal memory tests were found to have equivalent levels of difficulty.}, Doi = {10.1016/j.schres.2008.03.024}, Key = {fds273458} } @article{fds273459, Author = {Keefe, RSE and Harvey, PD}, Title = {Implementation considerations for multisite clinical trials with cognitive neuroscience tasks.}, Journal = {Schizophrenia Bulletin}, Volume = {34}, Number = {4}, Pages = {656-663}, Year = {2008}, Month = {July}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbn042}, Abstract = {Multisite clinical trials aimed at cognitive enhancement across various neuropsychiatric conditions have employed standard neuropsychological tests as outcome measures. While these tests have enjoyed wide clinical use and have proven reliable and predictive of functional disability, a number of implementation challenges have arisen when these tests are used in clinical trials. These issues are likely to be magnified in future studies when cognitive neuroscience (CN) procedures are explored in these trials, because in their current forms CN procedures are less standardized and more difficult to teach and monitor. For multisite trials, we anticipate that the most challenging issues will include assuring tester competence, monitoring tester performance, specific challenges with complex assessment methods, and having resources available for adequate monitoring of data quality. Suggestions for overcoming these implementation challenges are offered.}, Doi = {10.1093/schbul/sbn042}, Key = {fds273459} } @article{fds273460, Author = {Mohamed, S and Rosenheck, R and Swartz, M and Stroup, S and Lieberman, JA and Keefe, RSE}, Title = {Relationship of cognition and psychopathology to functional impairment in schizophrenia.}, Journal = {American Journal of Psychiatry}, Volume = {165}, Number = {8}, Pages = {978-987}, Year = {2008}, Month = {August}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.2008.07111713}, Abstract = {OBJECTIVE: This study evaluated the association of neurocognition and symptoms with measures of social and occupational functioning in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). METHOD: CATIE was an 18-month study of individuals with schizophrenia. Symptoms of 1,386 patients were measured with the positive syndrome scale of the Positive and Negative Syndrome Scale (PANSS) and a PANSS negative symptom scale that eliminated items that most overlap with measures of community functioning or neurocognition. The Heinrichs-Carpenter Quality of Life Scale, which a rater completes on the basis of the patient's self-report, and recent employment were used to assess community functioning. Hierarchical regression analyses and mixed models tested the association of neurocognition and symptoms with social/occupational functioning as well as changes in these measures during treatment. RESULTS: Both symptoms and neurocognition were associated with quality of life in bivariate correlation analyses. Symptoms contributed more to the incremental explained variance in quality of life than did neurocognitive functioning, but both kinds of measures were significantly related to quality of life. In an analysis including only the positive syndrome scale, the increased explained variance in quality of life was about equal to that associated with neurocognition. Neurocognition and both symptom measures were independently associated with quality of life in the cross-sectional mixed-model analysis. Changes in neurocognition and both symptom measures during treatment were also significantly associated with change in the quality of life. CONCLUSIONS: Both psychotic symptoms and neurocognitive deficits appear to contribute independently to decreased quality of life in schizophrenia.}, Doi = {10.1176/appi.ajp.2008.07111713}, Key = {fds273460} } @article{fds273461, Author = {Hawkins, KA and Keefe, RSE and Christensen, BK and Addington, J and Woods, SW and Callahan, J and Zipursky, RB and Perkins, DO and Tohen, M and Breier, A and McGlashan, TH}, Title = {Neuropsychological course in the prodrome and first episode of psychosis: findings from the PRIME North America Double Blind Treatment Study.}, Journal = {Schizophrenia Research}, Volume = {105}, Number = {1-3}, Pages = {1-9}, Year = {2008}, Month = {October}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2008.07.008}, Abstract = {OBJECTIVE: There is uncertainty regarding the onset timing of the cognitive deficiencies of schizophrenia. We investigated whether conversion to psychosis and/or olanzapine altered the neuropsychological course of subjects within the first-ever double blind medication study of the putative schizophrenia first episode prodrome. METHOD: Sixty participants in a double blind trial of olanzapine as a treatment for putative prodromal states were assessed at entry (pre-randomization), and again at 6 and 12 months (if they remained non-psychotic), or at any of these points prior to psychosis followed by post-psychosis and 6 months post-psychosis assessments. RESULTS: Participants who converted to psychosis did not differ from placebo non-converters in pre-randomization global neuropsychological status. Early converters did not differ from later converters in entry neuropsychological status. Subjects who converted after 6 months did not show neuropsychological declines during the initial, pre-psychosis, 6 months. Neuropsychological course did not differ between converters to psychosis and non-converters, or between olanzapine and placebo-assigned subjects. CONCLUSIONS: Neither the onset of frank psychosis nor olanzapine treatment of the prodrome significantly alters neuropsychological course in persons considered to be at high risk at their initial (pre-psychosis) assessment. These findings suggest that the neuropsychological deficiencies associated with psychotic conditions largely pre-exist the first frank psychotic episode.}, Doi = {10.1016/j.schres.2008.07.008}, Key = {fds273461} } @article{fds273462, Author = {Miller, DD and Caroff, SN and Davis, SM and Rosenheck, RA and McEvoy, JP and Saltz, BL and Riggio, S and Chakos, MH and Swartz, MS and Keefe, RSE and Stroup, TS and Lieberman, JA and Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators}, Title = {Extrapyramidal side-effects of antipsychotics in a randomised trial.}, Journal = {Br J Psychiatry}, Volume = {193}, Number = {4}, Pages = {279-288}, Year = {2008}, Month = {October}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18827289}, Abstract = {BACKGROUND: There are claims that second-generation antipsychotics produce fewer extrapyramidal side-effects (EPS) compared with first-generation drugs. AIMS: To compare the incidence of treatment-emergent EPS between second-generation antipsychotics and perphenazine in people with schizophrenia. METHOD: Incidence analyses integrated data from standardised rating scales and documented use of concomitant medication or treatment discontinuation for EPS events. Mixed model analyses of change in rating scales from baseline were also conducted. RESULTS: There were no significant differences in incidence or change in rating scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when comparing second-generation antipsychotics with perphenazine or comparing between second-generation antipsychotics. Secondary analyses revealed greater rates of concomitant antiparkinsonism medication among individuals on risperidone and lower rates among individuals on quetiapine, and lower rates of discontinuation because of parkinsonism among people on quetiapine and ziprasidone. There was a trend for a greater likelihood of concomitant medication for akathisia among individuals on risperidone and perphenazine. CONCLUSIONS: The incidence of treatment-emergent EPS and change in EPS ratings indicated that there are no significant differences between second-generation antipsychotics and perphenazine or between second-generation antipsychotics in people with schizophrenia.}, Doi = {10.1192/bjp.bp.108.050088}, Key = {fds273462} } @article{fds273463, Author = {Crowley, JJ and Keefe, RSE and Perkins, DO and Stroup, TS and Lieberman, JA and Sullivan, PF}, Title = {The neuregulin 1 promoter polymorphism rs6994992 is not associated with chronic schizophrenia or neurocognition.}, Journal = {Am J Med Genet B Neuropsychiatr Genet}, Volume = {147B}, Number = {7}, Pages = {1298-1300}, Year = {2008}, Month = {October}, ISSN = {1552-4841}, url = {http://dx.doi.org/10.1002/ajmg.b.30727}, Abstract = {The neuregulin 1 (NRG1) promoter single nucleotide polymorphism (SNP) rs6994992 has shown association with decreased activation of frontal and temporal lobe regions, increased risk of psychosis, and decreased premorbid IQ. This SNP is part of a putative schizophrenia risk-associated haplotype and was associated with increased expression of the type IV transcript in postmortem tissue. We tested for association between rs6994992 and chronic schizophrenia by genotyping 738 cases from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and 733 matched controls. We further tested for associations with age at onset and baseline neurocognition in cases with schizophrenia reasoning that these phenotypes might yield results similar to those seen for premorbid IQ. Affection status was weakly associated with rs6994992 genotypes and trended towards association under a recessive model. This association did not survive correction for multiple comparisons and was in the opposite direction than has been reported. There was no association between rs6994992 and age at onset, an estimate of premorbid IQ, or neurocognition at study baseline. We were unable to replicate previous associations of rs6994992 with schizophrenia and, moreover, did not find significant associations with age of onset, an estimate of pre-morbid IQ, or neurocognition.}, Doi = {10.1002/ajmg.b.30727}, Key = {fds273463} } @article{fds327076, Author = {Targum, SD and Keefe, RSE}, Title = {Cognition and schizophrenia: is there a role for cognitive assessments in diagnosis and treatment?}, Journal = {Psychiatry (Edgmont (Pa. : Township))}, Volume = {5}, Number = {12}, Pages = {55-59}, Year = {2008}, Month = {December}, Key = {fds327076} } @article{fds354395, Author = {Ventura, J and Bilder, RM and Reise, SR and Keefe, RS}, Title = {DEVELOPMENT OF AN INTERVIEW-BASED "CO-PRIMARY'' MEASURE OF COGNITION}, Journal = {Schizophrenia Bulletin}, Volume = {35}, Pages = {21-22}, Year = {2009}, Key = {fds354395} } @article{fds354394, Author = {Javitt, DC and Buchanan, RW and Lieberman, JA and Keefe, RS and Marder, SR}, Title = {EVALUATION OF THE EFFECTS OF AL-108 ON NEUROCOGNITION IN SCHIZOPHRENIA: INITIAL TURNS STUDY RESULTS}, Journal = {Schizophrenia Bulletin}, Volume = {35}, Pages = {365-366}, Year = {2009}, Key = {fds354394} } @article{fds370743, Author = {Schneider, LS and Vigen, CL and Mack, WJ and Dagerman, KS and Keefe, R and Sano, M and Sultzer, D and Stroup, S and Hsiao, J and Lebowitz, B and Lyketsos, CG and Tariot, PN and Zheng, L}, Title = {Cognitive Effects of Atypical Antipsychotics in Patients with Alzheimer's Disease: Outcomes from CATIE-AD}, Journal = {American Journal of Geriatric Psychiatry}, Volume = {17}, Number = {3}, Pages = {A76-A76}, Year = {2009}, Key = {fds370743} } @article{fds370744, Author = {Harvey, PD and Ogasa, M and Cucchiaro, J and Loebel, A and Keefe, R}, Title = {PERFORMANCE AND INTERVIEW-BASED ASSESSMENTS OF COGNITIVE CHANGE IN A RANDOMIZED, DOUBLE-BLIND COMPARISON OF LURASIDONE VS. ZIPRASIDONE}, Journal = {Schizophrenia Bulletin}, Volume = {35}, Pages = {357-357}, Year = {2009}, Key = {fds370744} } @article{fds370745, Author = {Kern, RS and Gold, J and Dickinson, D and Green, M and Nuechterlein, K and Baade, L and Keefe, R and Mesholam-Gately, R and Seidman, L and Marder, S}, Title = {PATTERNS OF COGNITIVE DYSFUNCTION IN SCHIZOPHRENIA: RESULTS FROM THE MATRICS PSYCHOMETRIC AND STANDARDIZATION STUDY (PASS)}, Journal = {Schizophrenia Bulletin}, Volume = {35}, Pages = {283-283}, Year = {2009}, Key = {fds370745} } @article{fds371782, Author = {Segarra, N and Bernardo, M and Justicia, A and Fernadez-Egea, E and Gutierrez, F and Allas, M and Contreras, F and Safont, G and Gascon, J and Menchon, J and Keefe, R}, Title = {COGNITIVE ASSESSMENT IN PATIENTS WITH FIRST EPISODE PSYCHOSIS USING SPANISH BACS (BRIEF ASSESSMENT IN COGNITION IN SCHIZOPHRENIA)}, Journal = {Schizophrenia Bulletin}, Volume = {35}, Pages = {286-287}, Year = {2009}, Key = {fds371782} } @article{fds327075, Author = {Keefe, RSE}, Title = {Increasing sensitivity of early detection of psychosis with cognitive measures}, Journal = {International Journal of Psychiatry in Clinical Practice}, Volume = {13}, Pages = {7-7}, Publisher = {TAYLOR & FRANCIS AS}, Year = {2009}, Month = {January}, Key = {fds327075} } @article{fds273464, Author = {Stroup, TS and Lieberman, JA and McEvoy, JP and Davis, SM and Swartz, MS and Keefe, RSE and Miller, AL and Rosenheck, RA and Hsiao, JK and CATIE Investigators}, Title = {Results of phase 3 of the CATIE schizophrenia trial.}, Journal = {Schizophrenia Research}, Volume = {107}, Number = {1}, Pages = {1-12}, Year = {2009}, Month = {January}, ISSN = {0920-9964}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19027269}, Abstract = {OBJECTIVE: The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study examined the comparative effectiveness of antipsychotic treatments for individuals with chronic schizophrenia. Patients who had discontinued antipsychotic treatment in phases 1 and 2 were eligible for phase 3, in which they selected one of nine antipsychotic regimens with the help of their study doctor. We describe the characteristics of the patients who selected each treatment option and their outcomes. METHOD: Two hundred and seventy patients entered phase 3. The open-label treatment options were monotherapy with oral aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone, long-acting injectable fluphenazine decanoate, or a combination of any two of these treatments. RESULTS: Few patients selected fluphenazine decanoate (n=9) or perphenazine (n=4). Similar numbers selected each of the other options (range 33-41). Of the seven common choices, those who selected clozapine and combination antipsychotic treatment were the most symptomatic, and those who selected aripiprazole and ziprasidone had the highest body mass index. Symptoms improved for all groups, although the improvements were modest for the groups starting with relatively mild levels of symptoms. Side effect profiles of the medications varied considerably but medication discontinuations due to intolerability were rare (7% overall). CONCLUSIONS: Patients and their doctors made treatment selections based on clinical factors, including severity of symptoms, response to prior treatments, and physical health status. Fluphenazine decanoate was rarely used among those with evidence of treatment non-adherence and clozapine was underutilized for those with poor previous response. Combination antipsychotic treatment warrants further study.}, Doi = {10.1016/j.schres.2008.10.011}, Key = {fds273464} } @article{fds336081, Author = {Pinheiro, AP and Keefe, RSE and Skelly, T and Olarte, M and Leviel, K and Lange, LA and Lange, EM and Stroup, TS and Lieberman, J and Sullivan, PF}, Title = {AKT1 and neurocognition in schizophrenia (vol 41, pg 169, 2007)}, Journal = {The Australian and New Zealand Journal of Psychiatry}, Volume = {43}, Number = {10}, Pages = {983-983}, Publisher = {INFORMA HEALTHCARE}, Year = {2009}, Month = {January}, Key = {fds336081} } @article{fds273468, Author = {Kern, RS and Green, MF and Nuechterlein, KH and Keefe, RSE}, Title = {CMINDS does not have identical tests to the CATIE and MATRICS batteries. Commentary on O'Halloran et al.}, Journal = {Schizophrenia Research}, Volume = {107}, Number = {2-3}, Pages = {327-329}, Year = {2009}, Month = {February}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2008.10.015}, Doi = {10.1016/j.schres.2008.10.015}, Key = {fds273468} } @article{fds273469, Author = {Kleinman, L and Lieberman, J and Dube, S and Mohs, R and Zhao, Y and Kinon, B and Carpenter, W and Harvey, PD and Green, MF and Keefe, RSE and Frank, L and Bowman, L and Revicki, DA}, Title = {Development and psychometric performance of the schizophrenia objective functioning instrument: an interviewer administered measure of function.}, Journal = {Schizophrenia Research}, Volume = {107}, Number = {2-3}, Pages = {275-285}, Year = {2009}, Month = {February}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2008.10.002}, Abstract = {Existing measures for functional assessment do not adequately address the relationship between cognitive impairment and function. The Schizophrenia Outcomes Functioning Interview (SOFI) was developed to measure community functioning related to cognitive impairment and psychopathology. Following review of existing measures and discussion with experts, caregivers, and patients, content was generated for four domains: 1) living situation; 2) IADLs; 3) productive activities; and 4) social functioning. The final SOFI was constructed with items informing domain scores, and an interviewer-completed global rating for each domain. Psychometric characteristics of the SOFI were evaluated in a sample of 104 community residing patients with schizophrenia and their informants. Test-retest reliability was evaluated in a sub-sample of patient-informant dyads using ICC; all values were >0.70 for both patient-interviews (SOFI-P) and informant-interviews (SOFI-I). Inter-rater reliability ICCs ranged from 0.50 to 0.79 on a different sub-sample. The SOFI demonstrated adequate construct validity based on correlations with the PSP (range 0.58 to 0.76; p<0.0001) and the QLS (p<0.001). Some correlations between SOFI and PETiT scores were low to moderate (p<0.05). Discriminant validity was supported based on SOFI score comparisons for patient groups based on PANSS and BACS scores (p<0.05); SOFI scores differed between borderline and moderately ill patients as measured by the CGI-S (p<0.05). The SOFI expands on existing measures and more comprehensively captures functioning of patients in the real world than other performance-based (proxy) measures. The SOFI has good evidence supporting reliability and construct validity, and may be a useful measure of functional outcomes in schizophrenia.}, Doi = {10.1016/j.schres.2008.10.002}, Key = {fds273469} } @article{fds273525, Author = {Need, AC and Ge, D and Weale, ME and Maia, J and Feng, S and Heinzen, EL and Shianna, KV and Yoon, W and Kasperaviciūte, D and Gennarelli, M and Strittmatter, WJ and Bonvicini, C and Rossi, G and Jayathilake, K and Cola, PA and McEvoy, JP and Keefe, RSE and Fisher, EMC and St Jean and PL and Giegling, I and Hartmann, AM and Möller, H-J and Ruppert, A and Fraser, G and Crombie, C and Middleton, LT and St Clair and D and Roses, AD and Muglia, P and Francks, C and Rujescu, D and Meltzer, HY and Goldstein, DB}, Title = {A genome-wide investigation of SNPs and CNVs in schizophrenia.}, Journal = {Plos Genet}, Volume = {5}, Number = {2}, Pages = {e1000373}, Year = {2009}, Month = {February}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19197363}, Abstract = {We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.}, Doi = {10.1371/journal.pgen.1000373}, Key = {fds273525} } @article{fds370563, Author = {Keefe, R and Mohamed, S and Siu, C and Rosenheck, R and Fox, K and Lowe, DA and Garibaldi, G and Santarelli, L and Murray, S}, Title = {GLOBAL COGNITIVE MEASURES AS PRIMARY OUTCOMES IN TREATMENT TRIALS}, Journal = {Schizophrenia Bulletin}, Volume = {35}, Pages = {249-250}, Publisher = {OXFORD UNIV PRESS}, Year = {2009}, Month = {March}, Key = {fds370563} } @article{fds370564, Author = {Keefe, R and Siu, C and Fox, K and Lowe, DA and Garibaldi, G and Santarelli, L and Murray, S}, Title = {TEST-RETEST CHARACTERISTICS OF THE MATRICS CONSENSUS COGNITIVE BATTERY IN A 20-SITE SCHIZOPHRENIA CLINICAL TRIAL OF R3487/MEM3454 VERSUS PLACEBO}, Journal = {Schizophrenia Bulletin}, Volume = {35}, Pages = {358-359}, Publisher = {OXFORD UNIV PRESS}, Year = {2009}, Month = {March}, Key = {fds370564} } @article{fds370755, Author = {Keefe, R and Hurley, K and Kraus, M and Leech, D and Harvey, P and Walker, T and Loebel, AD and Krishnan, R and Roscigno, R and Pietrobon, R}, Title = {FUNCTIONAL CAPACITY ASSESSMENTS FOR SCHIZOPHRENIA CLINICAL TRIALS}, Journal = {Schizophrenia Bulletin}, Volume = {35}, Pages = {316-316}, Publisher = {OXFORD UNIV PRESS}, Year = {2009}, Month = {March}, Key = {fds370755} } @article{fds354392, Author = {Marx, CE and Keefe, RS and Payne, VM and Kilts, JD and Strauss, JL and Naylor, JC and Hamer, RM and Buchanan, RW and Lieberman, JA and Shampine, LJ and Massing, MW}, Title = {NEUROSTEROIDS AS NOVEL THERAPEUTIC AGENTS IN SCHIZOPHRENIA AND PTSD}, Journal = {Schizophrenia Bulletin}, Volume = {35}, Pages = {368-368}, Publisher = {OXFORD UNIV PRESS}, Year = {2009}, Month = {March}, Key = {fds354392} } @article{fds354393, Author = {Kane, JM and D'Souza, DC and Patkar, AA and Youakim, JM and Tiller, J and Yang, R and Keefe, RS}, Title = {EFFICACY AND TOLERABILITY OF ADJUNCTIVE ARMODAFINIL IN PATIENTS WITH SCHIZOPHRENIA}, Journal = {Schizophrenia Bulletin}, Volume = {35}, Pages = {356-357}, Publisher = {OXFORD UNIV PRESS}, Year = {2009}, Month = {March}, Key = {fds354393} } @article{fds326767, Author = {Tiller, J and D'Souza, DC and Keefe, RSE and Kane, JM and Patkar, AA and Youakim, JM}, Title = {Effects of Adjunctive Armodafinil on Patients with Schizophrenia}, Journal = {Neurology}, Volume = {72}, Number = {11}, Pages = {A336-A336}, Publisher = {LIPPINCOTT WILLIAMS & WILKINS}, Year = {2009}, Month = {March}, Key = {fds326767} } @article{fds273471, Author = {Keefe, RSE and Kraus, MS}, Title = {Measuring memory-prediction errors and their consequences in youth at risk for schizophrenia.}, Journal = {Ann Acad Med Singap}, Volume = {38}, Number = {5}, Pages = {414-416}, Year = {2009}, Month = {May}, ISSN = {0304-4602}, Abstract = {The largely consistent columnar circuitry observed throughout the cortex may serve to continuously predict bottom-up activation based on invariant memories. This "memory-prediction" function is essential to efficient and accurate perception. Many of the defined cognitive deficits associated with schizophrenia suggest a breakdown of memory-prediction function. As deficits in memory-prediction function are proposed to lie more proximal to the biological causes of schizophrenia than deficits in standard cognitive constructs, tests that more directly probe memory-prediction function may be especially sensitive predictors of conversion in individuals at high-risk for schizophrenia. In this article, we review the conceptual basis for this hypothesis, and outline how it may be tested with specific cognitive paradigms. The accurate identification of cognitive processes that precede the onset of psychosis will not only be useful for clinicians to predict which young people are at greatest risk for schizophrenia, but will also help determine the neurobiology of psychosis onset, thus leading to new and effective treatments for preventing schizophrenia and other psychoses.}, Key = {fds273471} } @article{fds273472, Author = {Lim, C and Chong, SA and Keefe, RSE}, Title = {Psychosocial factors in the neurobiology of schizophrenia: a selective review.}, Journal = {Ann Acad Med Singap}, Volume = {38}, Number = {5}, Pages = {402-406}, Year = {2009}, Month = {May}, ISSN = {0304-4602}, Abstract = {AIM: Various forms of social adversity have been implicated in the development and emergence of psychosis. However, how and when these events exert their influences are not clear. In this paper, we attempt to examine these putative psychosocial factors and place them in a temporal context and propose a neurobiological mechanism linking these factors. METHODS: Medline databases were searched between 1966 and 2007 followed by the cross-checking of references using the following keywords: psychosocial, stress, stressors, life events, psychological, combined with psychosis and schizophrenia. RESULTS: While some findings are conflicting, there are a number of positive studies which suggest that factors like prenatal stress, urban birth and childhood trauma accentuate the vulnerability for schizophrenia and other psychoses while other factors like life events, migration particularly being a minority group, and high expressed emotions, which occur later in the vulnerable individual may move the individual towards the tipping point for psychosis. CONCLUSION: Overall, there is evidence to implicate psychosocial factors in the pathophysiology of schizophrenia. These factors may act via a common pathway, which involves stress-induced dysregulation of the HPA axis and the dopaminergic systems. To establish the causal relationship of the various factors would require prospective studies that are adequately powered.}, Key = {fds273472} } @article{fds273474, Author = {Harvey, PD and Keefe, RSE and Patterson, TL and Heaton, RK and Bowie, CR}, Title = {Abbreviated neuropsychological assessment in schizophrenia: prediction of different aspects of outcome.}, Journal = {J Clin Exp Neuropsychol}, Volume = {31}, Number = {4}, Pages = {462-471}, Year = {2009}, Month = {May}, ISSN = {1380-3395}, url = {http://dx.doi.org/10.1080/13803390802251386}, Abstract = {The aim of this study was to identify the best subset of neuropsychological tests for prediction of several different aspects of functioning in a large (n = 236) sample of older people with schizophrenia. While the validity of abbreviated assessment methods has been examined before, there has never been a comparative study of the prediction of different elements of cognitive impairment, real-world outcomes, and performance-based measures of functional capacity. Scores on 10 different tests from a neuropsychological assessment battery were used to predict global neuropsychological (NP) performance (indexed with averaged scores or calculated general deficit scores), performance-based indices of everyday-living skills and social competence, and case-manager ratings of real-world functioning. Forward entry stepwise regression analyses were used to identify the best predictors for each of the outcomes measures. Then, the analyses were adjusted for estimated premorbid IQ, which reduced the magnitude, but not the structure, of the correlations. Substantial amounts (over 70%) of the variance in overall NP performance were accounted for by a limited number of NP tests. Considerable variance in measures of functional capacity was also accounted for by a limited number of tests. Different tests constituted the best predictor set for each outcome measure. A substantial proportion of the variance in several different NP and functional outcomes can be accounted for by a small number of NP tests that can be completed in a few minutes, although there is considerable unexplained variance. However, the abbreviated assessments that best predict different outcomes vary across outcomes. Future studies should determine whether responses to pharmacological and remediation treatments can be captured with brief assessments as well.}, Doi = {10.1080/13803390802251386}, Key = {fds273474} } @article{fds273475, Author = {Sim, K and Yang, GL and Loh, D and Poon, LY and Sitoh, YY and Verma, S and Keefe, R and Collinson, S and Chong, SA and Heckers, S and Nowinski, W and Pantelis, C}, Title = {White matter abnormalities and neurocognitive deficits associated with the passivity phenomenon in schizophrenia: a diffusion tensor imaging study.}, Journal = {Psychiatry Research}, Volume = {172}, Number = {2}, Pages = {121-127}, Year = {2009}, Month = {May}, ISSN = {0925-4927}, url = {http://dx.doi.org/10.1016/j.pscychresns.2009.02.003}, Abstract = {The passivity phenomenon is a distressing Schneiderian first rank symptom in patients with schizophrenia. Based on extant data of functional and structural cerebral changes underlying passivity, we sought to examine cerebral white matter integrity in our subjects. We hypothesised that the passivity phenomenon would be associated with white matter changes in specific cortical (frontal, parietal cortices, and cingulate gyrus) and subcortical regions (thalamus and basal ganglia) and correlated with relevant neurocognitive deficits, compared with characteristics in those without the passivity phenomenon. Thirty-six subjects (11 with passivity and 25 without passivity) with schizophrenia were compared with 32 age-, gender- and handedness-matched healthy controls using diffusion tensor imaging. Neuropsychological testing was administered. Patients with passivity were associated with increased fractional anisotropy within the frontal cortex, cingulate gyrus, and basal ganglia and decreased fractional anisotropy within the thalamus when compared with patients without passivity. Within patients with passivity, fractional anisotropy in the frontal cortex correlated with the age of onset of illness and neurocognitive deficits related to attention and executive functioning. The findings suggest distributed involvement of cortical and subcortical regions underlying passivity and support the notion of neural network models underlying specific psychiatric symptoms such as passivity.}, Doi = {10.1016/j.pscychresns.2009.02.003}, Key = {fds273475} } @article{fds273473, Author = {Krishnan, RR and Keefe, R and Kraus, M}, Title = {Schizophrenia is a disorder of higher order hierarchical processing.}, Journal = {Med Hypotheses}, Volume = {72}, Number = {6}, Pages = {740-744}, Year = {2009}, Month = {June}, ISSN = {0306-9877}, url = {http://dx.doi.org/10.1016/j.mehy.2008.12.039}, Abstract = {Schizophrenia is a mental disorder in which the patient manifests with auditory hallucinations, paranoid or bizarre delusions, and disorganized speech and thinking. It is associated with significant social dysfunction. There are many hypotheses regarding schizophrenia. Most of these focus on schizophrenia as a manifestation of abnormalities from genetic [Mulle JG. Genomic structural variation and schizophrenia. Curr Psychiatry Rep 2008;10(2):171-7], viral [Fruntes V, Limosin F. Schizophrenia and viral infection during neurodevelopment: a pathogenesis model? Med Sci Monit 2008;14(6):RA71-7], neurochemical [e.g. dopamine (Lewis DA, Akil M. Cortical dopamine in schizophrenia: strategies for postmortem studies. J Psychiatr Res 1997;31(2):175-95) or interactions between neurotransmitters (Duncan GE, Sheitman BB, Lieberman JA. An integrated view of pathophysiological models of schizophrenia. Brain Res Brain Res Rev 1999;29(2):250-64)] or brain structural [Kotrla KJ, Weinberger DR. Brain imaging in schizophrenia. Annu Rev Med 1995;46:113-22] origins. Most of these hypotheses do not account for how or why these presumed causes lead to the manifestations of schizophrenia. We argue that brain structure and function is compatible with a hierarchical processing structure that forms the basis for perception and thought in healthy humans. We propose that perturbations of the types listed above lead to disruption of higher levels of perception and hierarchical temporal processing by the brain and that this constitutes the core deficit in schizophrenia. We present evidence that this model explains many of the features of schizophrenia and we make a series of predictions about schizophrenia.}, Doi = {10.1016/j.mehy.2008.12.039}, Key = {fds273473} } @article{fds273476, Author = {Davidson, M and Galderisi, S and Weiser, M and Werbeloff, N and Fleischhacker, WW and Keefe, RS and Boter, H and Keet, IPM and Prelipceanu, D and Rybakowski, JK and Libiger, J and Hummer, M and Dollfus, S and López-Ibor, JJ and Hranov, LG and Gaebel, W and Peuskens, J and Lindefors, N and Riecher-Rössler, A and Kahn, RS}, Title = {Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: a randomized, open-label clinical trial (EUFEST).}, Journal = {American Journal of Psychiatry}, Volume = {166}, Number = {6}, Pages = {675-682}, Year = {2009}, Month = {June}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.2008.08060806}, Abstract = {OBJECTIVE: Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. METHODS: Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation. RESULTS: Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. CONCLUSION: Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change.}, Doi = {10.1176/appi.ajp.2008.08060806}, Key = {fds273476} } @article{fds273524, Author = {Need, AC and Keefe, RSE and Ge, D and Grossman, I and Dickson, S and McEvoy, JP and Goldstein, DB}, Title = {Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis.}, Journal = {European Journal of Human Genetics : Ejhg}, Volume = {17}, Number = {7}, Pages = {946-957}, Year = {2009}, Month = {July}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19156168}, Abstract = {The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. Although trials such as CATIE present important opportunities for pharmacogenetics research, the very richness of the clinical data presents challenges for statistical interpretation, and in particular the risk that data mining will lead to false-positive discoveries. For this reason, it is both misleading and unhelpful to perpetuate the current practice of reporting association results for these trials one gene at a time, ignoring the fact that multiple gene-by-phenotype tests are being carried out on the same data set. On the other hand, suggestive associations in such trials may lead to new hypotheses that can be tested through both replication efforts and biological experimentation. The appropriate handling of these forms of data therefore requires dissemination of association statistics without undue emphasis on select findings. Here we attempt to illustrate this approach by presenting association statistics for 2769 polymorphisms in 118 candidate genes evaluated for 21 pharmacogenetic phenotypes. On current evidence it is impossible to know which of these associations may be real, although in total they form a valuable resource that is immediately available to the scientific community.}, Doi = {10.1038/ejhg.2008.264}, Key = {fds273524} } @article{fds273530, Author = {Marx, CE and Keefe, RSE and Buchanan, RW and Hamer, RM and Kilts, JD and Bradford, DW and Strauss, JL and Naylor, JC and Payne, VM and Lieberman, JA and Savitz, AJ and Leimone, LA and Dunn, L and Porcu, P and Morrow, AL and Shampine, LJ}, Title = {Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia.}, Journal = {Neuropsychopharmacology}, Volume = {34}, Number = {8}, Pages = {1885-1903}, Year = {2009}, Month = {July}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19339966}, Abstract = {The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (r(s)=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (r(s)=0.74, p=0.046). In addition, baseline pregnenolone (r(s)=-0.76, p=0.037), pregnenolone sulfate (r(s)=-0.83, p=0.015), and allopregnanolone levels (r(s)=-0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (r(s)=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.}, Doi = {10.1038/npp.2009.26}, Key = {fds273530} } @article{fds273477, Author = {Lipkovich, IA and Deberdt, W and Csernansky, JG and Sabbe, B and Keefe, RS and Kollack-Walker, S}, Title = {Relationships among neurocognition, symptoms and functioning in patients with schizophrenia: a path-analytic approach for associations at baseline and following 24 weeks of antipsychotic drug therapy.}, Journal = {Bmc Psychiatry}, Volume = {9}, Pages = {44}, Year = {2009}, Month = {July}, ISSN = {1471-244X}, url = {http://dx.doi.org/10.1186/1471-244X-9-44}, Abstract = {BACKGROUND: Neurocognitive impairment and psychiatric symptoms have been associated with deficits in psychosocial and occupational functioning in patients with schizophrenia. This post-hoc analysis evaluates the relationships among cognition, psychopathology, and psychosocial functioning in patients with schizophrenia at baseline and following sustained treatment with antipsychotic drugs. METHODS: Data were obtained from a clinical trial assessing the cognitive effects of selected antipsychotic drugs in patients with schizophrenia. Patients were randomly assigned to 24 weeks of treatment with olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Psychosocial functioning was assessed with the Heinrichs-Carpenter Quality of Life Scale [QLS], cognition with a standard battery of neurocognitive tests; and psychiatric symptoms with the Positive and Negative Syndrome Scale [PANSS]. A path-analytic approach was used to evaluate the effects of changes in cognitive functioning on subdomains of quality of life, and to determine whether such effects were direct or mediated via changes in psychiatric symptoms. RESULTS: At baseline, processing speed affected functioning mainly indirectly via negative symptoms. Positive symptoms also affected functioning at baseline although independent of cognition. At 24 weeks, changes in processing speed affected changes in functioning both directly and indirectly via PANSS negative subscale scores. Positive symptoms no longer contributed to the path-analytic models. Although a consistent relationship was observed between processing speed and the 3 functional domains, variation existed as to whether the paths were direct and/or indirect. Working memory and verbal memory did not significantly contribute to any of the path-analytic models studied. CONCLUSION: Processing speed demonstrated direct and indirect effects via negative symptoms on three domains of functioning as measured by the QLS at baseline and following 24 weeks of antipsychotic treatment.}, Doi = {10.1186/1471-244X-9-44}, Key = {fds273477} } @article{fds273466, Author = {Kraus, MS and Keefe, RSE and Krishnan, RKR}, Title = {Memory-prediction errors and their consequences in schizophrenia.}, Journal = {Neuropsychol Rev}, Volume = {19}, Number = {3}, Pages = {336-352}, Year = {2009}, Month = {September}, ISSN = {1040-7308}, url = {http://dx.doi.org/10.1007/s11065-009-9106-1}, Abstract = {Cognitive deficits play a central role in the onset of schizophrenia. Cognitive impairment precedes the onset of psychosis in at least a subgroup of patients, and accounts for considerable dysfunction. Yet cognitive deficits as currently measured are not significantly related to hallucinations and delusions. Part of this counterintuitive absence of a relationship may be caused by the lack of an organizing principle of cognitive impairment in schizophrenia research. We review literature suggesting that a system of memory-based prediction is central to human perception, thought and action , and forward the notion that many of the symptoms of schizophrenia are a result of a failure of this system.}, Doi = {10.1007/s11065-009-9106-1}, Key = {fds273466} } @article{fds273467, Author = {Keefe, RSE and Seidman, LJ and Christensen, BK and Hamer, RM and Sharma, T and Sitskoorn, MM and Lewine, RRJ and Yurgelun-Todd, DA and Gur, RC and Tohen, M and Tollefson, GD and Sanger, TM and Lieberman, JA}, Title = {Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: A randomized, double-blind trial of olanzapine versus low doses of haloperidol (American Journal of Psychiatry (2004) 161, (985-995))}, Journal = {The American Journal of Psychiatry}, Volume = {166}, Number = {8}, Pages = {942}, Year = {2009}, Month = {September}, ISSN = {0002-953X}, Key = {fds273467} } @article{fds273478, Author = {Penn, DL and Keefe, RSE and Davis, SM and Meyer, PS and Perkins, DO and Losardo, D and Lieberman, JA}, Title = {The effects of antipsychotic medications on emotion perception in patients with chronic schizophrenia in the CATIE trial.}, Journal = {Schizophrenia Research}, Volume = {115}, Number = {1}, Pages = {17-23}, Year = {2009}, Month = {November}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2009.08.016}, Abstract = {Few pharmacological intervention studies have examined the impact of medication on social cognition, particularly emotion perception. The goal of this randomized, double-blind study is to compare the effects of several second generation antipsychotics and a first generation antipsychotic, perphenazine, on emotion perception in individuals with schizophrenia. Patients were assigned to receive treatment with olanzapine, queitapine fumarate, risperidone, ziprasidone or perphenazine for up to 18 months. Eight hundred and seventy three patients completed an emotion perception test immediately prior to randomization and after 2 months of treatment. We also examined baseline predictors of emotion perception change. Most treatments were associated with a small, non-statistically significant improvement in emotion perception at two months, although they did not differ from one another. Greater improvement in emotion perception at 2 months was significantly predicted by lower baseline emotion perception and higher baseline neurocognitive functioning, and marginally predicted by less time on an antipsychotic.}, Doi = {10.1016/j.schres.2009.08.016}, Key = {fds273478} } @article{fds273479, Author = {Pinheiro, AP and Keefe, RSE and Skelly, T and Olarte, M and Leviel, K and Lange, LA and Lange, EM and Stroup, TS and Lieberman, J and Sullivan, PF}, Title = {Erratum: Rates of depressive and anxiety disorders in a residential mother-infant unit for unsettled infants (Australian and New Zealand Journal of Psychiatry (2007) 41 (836-842))}, Journal = {The Australian and New Zealand Journal of Psychiatry}, Volume = {43}, Number = {11}, Pages = {1087}, Publisher = {SAGE Publications}, Year = {2009}, Month = {November}, ISSN = {0004-8674}, url = {http://dx.doi.org/10.1080/00048670903270266}, Doi = {10.1080/00048670903270266}, Key = {fds273479} } @article{fds273480, Author = {Fox, KH and Burdick, KE and Lombardo, I and Keefe, RSE}, Title = {Cognitive impairment in patients with bipolar disorder}, Journal = {Psychiatric Times}, Volume = {26}, Number = {12}, Pages = {66-68}, Year = {2009}, Month = {December}, ISSN = {0893-2905}, Key = {fds273480} } @article{fds273465, Author = {Pinheiro, AP and Keefe, RSE and Skelly, T and Olarte, M and Leviel, K and Lange, LA and Lange, EM and Stroup, TS and Lieberman, J and Sullivan, PF}, Title = {Erratum: AKT1 and neurocognition in schizophrenia (Australian and New Zealand Journal of Psychiatry (2007) 41 (169-177))}, Journal = {The Australian and New Zealand Journal of Psychiatry}, Volume = {43}, Number = {10}, Pages = {983}, Publisher = {SAGE Publications}, Year = {2009}, Month = {December}, ISSN = {0004-8674}, url = {http://dx.doi.org/10.1080/00048670903228991}, Doi = {10.1080/00048670903228991}, Key = {fds273465} } @article{fds273380, Author = {Lamonica, HM and Keefe, RSE and Harvey, PD and Gold, JM and Goldberg, TE}, Title = {Differential effects of emotional information on interference task performance across the life span.}, Journal = {Frontiers in Aging Neuroscience}, Volume = {2}, Year = {2010}, ISSN = {1663-4365}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000208561300001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Abstract = {While functioning in multiple domains declines with age, emotional regulation appears to remain preserved in older adults. The Emotion Inhibition (Emotional Stroop) Test requires participants to name the ink color in which neutrally and emotionally valenced words are printed. It was employed in the current investigation as a measure of affective regulation in the context of an interference task in relation to age. Results demonstrated that while participants ranging from 20 to 50 years of age performed significantly worse on the emotion Stroop Inhibition relative to the neutral Stroop Inhibition condition, subjects over 60 years of age displayed the converse of this pattern, performing better on the emotion than the neutral condition, suggesting that they are less affected by the emotional impact of the positive and negative words used in the former condition. This pattern of age-related change in the ability to manage emotion may be related to blunting of affective signaling in limbic structures or, at the psychological level, focusing on emotional regulation.}, Doi = {10.3389/fnagi.2010.00141}, Key = {fds273380} } @article{fds327074, Author = {Keefe, RSE and Fenton, WS}, Title = {HOW SHOULD DSM-V CRITERIA FOR SCHIZOPHRENIA INCLUDE COGNITIVE IMPAIRMENT?}, Journal = {DECONSTRUCTING PSYCHOSIS: REFINING THE RESEARCH AGENDA FOR DSM-V}, Pages = {83-98}, Publisher = {AMER PSYCHIATRIC PRESS, INC}, Editor = {Tamminga, CA and Sirovatka, PJ and Regier, DA and VanOs, J}, Year = {2010}, Month = {January}, Key = {fds327074} } @article{fds273298, Author = {Keefe, RSE}, Title = {Neurocognition}, Pages = {97-119}, Publisher = {Cambridge University Press}, Year = {2010}, Month = {January}, url = {http://dx.doi.org/10.1017/CBO9780511712265.007}, Abstract = {Neurocognition is commonly impaired in patients with schizophrenia in all stages of the illness and varying levels of severity. While these impairments may appear prior to the onset of psychosis, their severity in chronic schizophrenia patients is about 1.5 to 2.0 standard deviations below the healthy population. Neurocognitive impairment is a central clinical feature of schizophrenia, as it is associated with pre-morbid history, concurrent brain functioning, and functional outcomes, and is under consideration as a possible component of the diagnosis for schizophrenia in DSM-V and ICD-11. Despite the centrality of cognition in schizophrenia, there are no proven pharmacologic treatments currently available. Spurred by the NIMH Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, a pathway for FDA approval of compounds to improve cognition is being established including an approved battery of tests, the MATRICS Consensus Cognitive Battery (MCCB), and numerous clinical trials are underway to identify new treatments. While these studies utilize newly established methods primarily developed to assess cognition in stable patients with schizophrenia, the methods for assessing cognition in patients who require a change in antipsychotic may differ. Most published studies of cognition have used samples of convenience that have included groups of patients who can complete extensive research protocols due to their chronic institutionalization or who are available because they have entered a clinical trial or other specialized research study, and have thus been carefully screened with extensive exclusion criteria, such as the absence of substance abuse and medical co-morbidities.}, Doi = {10.1017/CBO9780511712265.007}, Key = {fds273298} } @article{fds273481, Author = {Barch, DM and Keefe, RSE}, Title = {Anticipating DSM-V: opportunities and challenges for cognition and psychosis.}, Journal = {Schizophrenia Bulletin}, Volume = {36}, Number = {1}, Pages = {43-47}, Year = {2010}, Month = {January}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbp139}, Abstract = {The current debate regarding the role that cognitive function should play in the diagnostic criteria for schizophrenia in the DSM-V has been a healthy one that has engendered much useful discussion and potentially interesting pathways for future research. At this point, there is little support for the idea that cognition should be included as a criterion A-type symptom that would differentiate those individuals with schizophrenia from individuals with other psychiatric illnesses. However, there continues to be much interest in including assessments of cognition in the DSM-V as a means of highlighting the importance of cognitive function for understanding functional status and outcome and to facilitate attention to cognitive function in treatment planning. However, as discussed here and in the Bora commentary, these suggestions do raise important theoretical and practical challenges as to how to best accomplish these goals and to provide a means of assessment of cognition that is viable across a wide range of contexts. In order to accomplish these goals, the structure of DSM-V will need to be modified to facilitate the inclusion of treatment-relevant domains that may not be part of the diagnostic criteria such as including assessments of one more domains for all disorders (eg, suicidality and perhaps even cognition) or assessments of domains that may be specific to certain classes of disorders (eg, cognition for psychotic and mood disorders). Bora et al suggest either using specifiers to indicate which individuals with schizophrenia have cognitive impairment or using a dimensional assessment of cognition. We tend to favor a dimensional approach as one that preserves the most information and does not necessitate placing what may be arbitrary thresholds on the level of cognitive dysfunction that would be sufficient to warrant a specifier of cognitive impairment. Furthermore, it is becoming increasingly apparent from the work of Bora and others that cognition may also deserve attention in the assessment of individuals with affective as well as nonaffective psychosis, and thus, whatever approach is adopted in the DSM-V for assessing cognition in schizophrenia may also need to be applicable to individuals with other disorders as well. These are solvable challenges and well worth the effort in terms of their potential payoff for enhancing the quality of life of people with mental illnesses and reducing demands on public health resources.}, Doi = {10.1093/schbul/sbp139}, Key = {fds273481} } @article{fds273528, Author = {Reichenberg, A and Caspi, A and Harrington, H and Houts, R and Keefe, RSE and Murray, RM and Poulton, R and Moffitt, TE}, Title = {Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: a 30-year study.}, Journal = {American Journal of Psychiatry}, Volume = {167}, Number = {2}, Pages = {160-169}, Year = {2010}, Month = {February}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20048021}, Abstract = {OBJECTIVE: Premorbid cognitive deficits in schizophrenia are well documented and have been interpreted as supporting a neurodevelopmental etiological model. The authors investigated the following three unresolved questions about premorbid cognitive deficits: What is their developmental course? Do all premorbid cognitive deficits follow the same course? Are premorbid cognitive deficits specific to schizophrenia or shared by other psychiatric disorders? METHOD: Participants were members of a representative cohort of 1,037 males and females born between 1972 and 1973 in Dunedin, New Zealand. Cohort members underwent follow-up evaluations at specific intervals from age 3 to 32 years, with a 96% retention rate. Cognitive development was analyzed and compared in children who later developed schizophrenia or recurrent depression as well as in healthy comparison subjects. RESULTS: Children who developed adult schizophrenia exhibited developmental deficits (i.e., static cognitive impairments that emerge early and remain stable) on tests indexing verbal and visual knowledge acquisition, reasoning, and conceptualization. In addition, these children exhibited developmental lags (i.e., growth that is slower relative to healthy comparison subjects) on tests indexing processing speed, attention, visual-spatial problem solving ability, and working memory. These two premorbid cognitive patterns were not observed in children who later developed recurrent depression. CONCLUSIONS: These findings suggest that the origins of schizophrenia include two interrelated developmental processes evident from childhood to early adolescence (ages 7-13 years). Children who will grow up to develop adult schizophrenia enter primary school struggling with verbal reasoning and lag further behind their peers in working memory, attention, and processing speed as they get older.}, Doi = {10.1176/appi.ajp.2009.09040574}, Key = {fds273528} } @article{fds327073, Author = {Kern, RS and Gold, JM and Dickinson, D and Green, MF and Nuechterlein, KH and Keefe, RSE and Marder, SR and Sugar, CA}, Title = {COGNITIVE DYSFUNCTION AND COMMUNITY FUNCTIONING IN SCHIZOPHRENIA: RESULTS FROM THE MATRICS PSYCHOMETRIC AND STANDARDIZATION STUDY (PASS)}, Journal = {Schizophrenia Research}, Volume = {117}, Number = {2-3}, Pages = {323-324}, Publisher = {Elsevier BV}, Year = {2010}, Month = {April}, url = {http://dx.doi.org/10.1016/j.schres.2010.02.551}, Doi = {10.1016/j.schres.2010.02.551}, Key = {fds327073} } @article{fds354391, Author = {Reichenberg, A and Caspi, A and Harrington, H and Houts, R and Keefe, R and Murray, R and Poulton, R and Moffitt, T}, Title = {STATIC AND DYNAMIC COGNITIVE DEFICITS IN CHILDHOOD PRECEDE ADULT SCHIZOPHRENIA: A 30-YEAR STUDY}, Journal = {Schizophrenia Research}, Volume = {117}, Number = {2-3}, Pages = {175-175}, Publisher = {Elsevier BV}, Year = {2010}, Month = {April}, url = {http://dx.doi.org/10.1016/j.schres.2010.02.207}, Doi = {10.1016/j.schres.2010.02.207}, Key = {fds354391} } @article{fds370552, Author = {Geffen, Y and Anand, R and Keefe, R and Davidson, M}, Title = {RESULTS OF PHASE 2B EAGLE TRIAL; A DOUBLE BLIND PLACEBO CONTROL STUDY EVALUATING THE EFFICACY AND SAFETY OF BL-1020, A GABA ENHANCED ANTIPSYCHOTIC FOR THE TREATMENT OF SCHIZOPHRENIA}, Journal = {Schizophrenia Research}, Volume = {117}, Number = {2-3}, Pages = {212-212}, Publisher = {Elsevier BV}, Year = {2010}, Month = {April}, url = {http://dx.doi.org/10.1016/j.schres.2010.02.296}, Doi = {10.1016/j.schres.2010.02.296}, Key = {fds370552} } @article{fds370560, Author = {Volovyk, SV and Keefe, RS}, Title = {UNIQUE OPPORTUNITY FOR COHERENT INSIGHTS INTO THE NATURE OF EARTH/SPACE NATURAL RADIATION EFFECTS ON MAN'S BRAIN DISORDERS}, Journal = {Schizophrenia Research}, Volume = {117}, Number = {2-3}, Pages = {530-531}, Publisher = {Elsevier BV}, Year = {2010}, Month = {April}, url = {http://dx.doi.org/10.1016/j.schres.2010.02.1024}, Doi = {10.1016/j.schres.2010.02.1024}, Key = {fds370560} } @article{fds370754, Author = {Keefe, R and Vinogradov, S and Medalia, A and Buckley, P and Caroff, S and D'Souza, D and Harvey, P and Graham, K and Marder, S and Miller, D and Olson, S and Patel, J and Velligan, D and Walker, T and Haim, A and Stroup, S}, Title = {FEASIBILITY STUDY OF MULTI-SITE COGNITIVE REMEDIATION IN THE SCHIZOPHRENIA TRIALS NETWORK (CRSTN)}, Journal = {Schizophrenia Research}, Volume = {117}, Number = {2-3}, Pages = {394-394}, Publisher = {Elsevier BV}, Year = {2010}, Month = {April}, url = {http://dx.doi.org/10.1016/j.schres.2010.02.712}, Doi = {10.1016/j.schres.2010.02.712}, Key = {fds370754} } @article{fds370579, Author = {Carpenter, W and Hofer, A and Keefe, R and Mueser, K and Naber, D and Chen, E}, Title = {DSM-V: NEW PARADIGMS AND OTHER CONTROVERSIES}, Journal = {Schizophrenia Research}, Volume = {117}, Number = {2-3}, Pages = {110-110}, Publisher = {Elsevier BV}, Year = {2010}, Month = {April}, url = {http://dx.doi.org/10.1016/j.schres.2010.02.025}, Doi = {10.1016/j.schres.2010.02.025}, Key = {fds370579} } @article{fds371781, Author = {Buchanan, RW and Barch, D and Csernansky, J and Goff, D and Gold, J and Jarskog, F and Javitt, D and Keefe, R and Lieberman, J and McEvoy, J and McMahon, R and Marder, S}, Title = {MK-0777 FOR THE TREATMENT OF COGNITIVE IMPAIRMENTS IN PEOPLE WITH SCHIZOPHRENIA}, Journal = {Schizophrenia Research}, Volume = {117}, Number = {2-3}, Pages = {119-119}, Publisher = {Elsevier BV}, Year = {2010}, Month = {April}, url = {http://dx.doi.org/10.1016/j.schres.2010.02.053}, Doi = {10.1016/j.schres.2010.02.053}, Key = {fds371781} } @article{fds273482, Author = {Goldberg, TE and Keefe, RSE and Goldman, RS and Robinson, DG and Harvey, PD}, Title = {Circumstances under which practice does not make perfect: a review of the practice effect literature in schizophrenia and its relevance to clinical treatment studies.}, Journal = {Neuropsychopharmacology}, Volume = {35}, Number = {5}, Pages = {1053-1062}, Year = {2010}, Month = {April}, ISSN = {0893-133X}, url = {http://dx.doi.org/10.1038/npp.2009.211}, Abstract = {In this article, we review the literature on practice effects in schizophrenia, an underappreciated confound in interpreting cognitive improvement in clinical trials. We first examine claims regarding first- and second-generation antipsychotic medications as cognitive enhancers, and follow it with a discussion of recent studies demonstrating how practice or placebo effects may drive 'positive' findings. Thus, this review suggests that many previous findings can be reinterpreted in this light. Critically, we also make several suggestions about test construction, study design, and statistical analyses that the field might use to overcome this potential confound. Our suggestions may also have implications for drug discovery and regulatory approval of cognitive-enhancing adjunctive agents, in terms of study design and/or test psychometric characteristics, including the development of tests that are relatively insensitive to practice-related changes. Such advances might be important for improving the methodology involved in the assessment of cognitive change in treatment studies.}, Doi = {10.1038/npp.2009.211}, Key = {fds273482} } @article{fds273529, Author = {Polanczyk, G and Moffitt, TE and Arseneault, L and Cannon, M and Ambler, A and Keefe, RSE and Houts, R and Odgers, CL and Caspi, A}, Title = {Etiological and clinical features of childhood psychotic symptoms: results from a birth cohort.}, Journal = {Arch Gen Psychiatry}, Volume = {67}, Number = {4}, Pages = {328-338}, Year = {2010}, Month = {April}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20368509}, Abstract = {CONTEXT: It has been reported that childhood psychotic symptoms are common in the general population and may signal neurodevelopmental processes that lead to schizophrenia. However, it is not clear whether these symptoms are associated with the same extensive risk factors established for adult schizophrenia. OBJECTIVE: To examine the construct validity of children's self-reported psychotic symptoms by testing whether these symptoms share the risk factors and clinical features of adult schizophrenia. DESIGN: Prospective, longitudinal cohort study of a nationally representative birth cohort in Great Britain. PARTICIPANTS: A total of 2232 twelve-year-old children followed up since age 5 years (retention, 96%). Main Outcome Measure Children's self-reported hallucinations and delusions. RESULTS: Children's psychotic symptoms are familial and heritable and are associated with social risk factors (eg, urbanicity); cognitive impairments at age 5; home-rearing risk factors (eg, maternal expressed emotion); behavioral, emotional, and educational problems at age 5; and comorbid conditions, including self-harm. CONCLUSIONS: The results provide a comprehensive picture of the construct validity of children's self-reported psychotic symptoms. For researchers, the findings indicate that children who have psychotic symptoms can be recruited for neuroscience research to determine the pathogenesis of schizophrenia. For clinicians, the findings indicate that psychotic symptoms in childhood are often a marker of an impaired developmental process and should be actively assessed.}, Doi = {10.1001/archgenpsychiatry.2010.14}, Key = {fds273529} } @article{fds354390, Author = {Reichenberg, A and Caspi, A and Harrington, H and Houts, R and Keefe, RS and Murray, RM and Poulton, R and Moffitt, TE}, Title = {Static and Dynamic Cognitive Deficits in Childhood Precede Adult Schizophrenia: A 30-Year Study}, Journal = {Biological Psychiatry}, Volume = {67}, Number = {9}, Pages = {12S-12S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2010}, Month = {May}, Key = {fds354390} } @article{fds273483, Author = {Seidman, LJ and Giuliano, AJ and Meyer, EC and Addington, J and Cadenhead, KS and Cannon, TD and McGlashan, TH and Perkins, DO and Tsuang, MT and Walker, EF and Woods, SW and Bearden, CE and Christensen, BK and Hawkins, K and Heaton, R and Keefe, RSE and Heinssen, R and Cornblatt, BA and North American Prodrome Longitudinal Study (NAPLS) Group}, Title = {Neuropsychology of the prodrome to psychosis in the NAPLS consortium: relationship to family history and conversion to psychosis.}, Journal = {Arch Gen Psychiatry}, Volume = {67}, Number = {6}, Pages = {578-588}, Year = {2010}, Month = {June}, ISSN = {0003-990X}, url = {http://dx.doi.org/10.1001/archgenpsychiatry.2010.66}, Abstract = {CONTEXT: Early detection and prospective evaluation of clinical high-risk (CHR) individuals who may develop schizophrenia or other psychotic disorders is critical for predicting psychosis onset and for testing preventive interventions. OBJECTIVES: To elucidate the neuropsychology of the CHR syndrome, to determine the association of neuropsychological function with conversion to psychosis and family history of psychosis, and to examine whether baseline neuropsychological functioning predicts subsequent psychosis. DESIGN: Longitudinal study with 2(1/2) years of follow-up. SETTING: Eight centers participating in the North American Prodrome Longitudinal Study. PARTICIPANTS: Three hundred four prospectively identified CHR individuals meeting Structured Interview for Prodromal Syndromes criteria, 52 non-CHR persons with a family history of psychosis in first- or second-degree relatives (family high-risk group), and 193 normal controls with neither a family history of psychosis nor a CHR syndrome, all of whom underwent baseline neuropsychological evaluations. MAIN OUTCOME MEASURES: A neurocognitive composite score, 8 individual neuropsychological measures, an IQ estimate, and high-risk status. RESULTS: Global ("composite") neuropsychological functioning was comparably impaired in the CHR and family high-risk groups compared with controls, but profiles differed significantly between groups. Neuropsychological functioning in the CHR group was significantly lower in persons who progressed to psychosis than in those who did not and was worst in the subgroup with a family history of psychosis. Tests of processing speed and verbal learning and memory were most sensitive in discriminating CHR individuals from controls, although reductions were less severe than in established schizophrenia. Neuropsychological functioning did not contribute uniquely to the prediction of psychosis beyond clinical criteria, but worse verbal memory predicted more rapid conversion. CONCLUSIONS: These findings document that CHR individuals have significant neuropsychological difficulties, particularly those who later develop psychosis. This dysfunction is generally of moderate severity but less than in first-episode schizophrenia, suggesting that further decline may occur after baseline CHR assessment.}, Doi = {10.1001/archgenpsychiatry.2010.66}, Key = {fds273483} } @article{fds273484, Author = {Chan, W-Y and Yang, G-L and Chia, M-Y and Woon, P-S and Lee, J and Keefe, R and Sitoh, Y-Y and Nowinski, WL and Sim, K}, Title = {Cortical and subcortical white matter abnormalities in adults with remitted first-episode mania revealed by Tract-Based Spatial Statistics.}, Journal = {Bipolar Disord}, Volume = {12}, Number = {4}, Pages = {383-389}, Year = {2010}, Month = {June}, ISSN = {1398-5647}, url = {http://dx.doi.org/10.1111/j.1399-5618.2010.00829.x}, Abstract = {OBJECTIVES: Abnormalities of brain white matter have been noted in structural magnetic resonance imaging and diffusion tensor imaging (DTI) studies of bipolar disorder, but there are fewer investigations specifically examining white matter integrity early in the course of illness. In this study, we employed DTI to elucidate white matter changes in adult patients with remitted first-episode mania and hypothesized that first-episode mania was associated with decreased fractional anisotropy in cortical (frontal) and subcortical (thalamus, striatum) white matter as well as white matter tracts (cingulum, corpus callosum). METHODS: Diffusion tensor images were acquired from 16 patients with remitted first-episode mania and 16 healthy controls matched for age, gender, handedness, and years of education. Fractional anisotropy and radial and axial diffusivities were analyzed using Tract-Based Spatial Statistics. RESULTS: Patients had lower fractional anisotropy and higher radial diffusivity in the left anterior frontal white matter, right posterior thalamic radiation, left cingulum, and bilateral sagittal striatum. In addition, increased radial diffusivity was found in the left corpus callosum. CONCLUSION: Our findings highlighted that white matter abnormalities were present by the time of remission of first-episode mania. The widespread occurrence of these white matter abnormalities both in first-episode mania and chronic bipolar disorder suggested that disruption of white matter cortical-subcortical networks as well as projection, associative, and commissural tracts is a hallmark of the illness.}, Doi = {10.1111/j.1399-5618.2010.00829.x}, Key = {fds273484} } @article{fds273486, Author = {Chia, MY and Chan, WY and Chua, KY and Lee, H and Lee, J and Lee, R and Lim, C and Tay, E and Woon, PS and Keefe, RSE and Sim, K}, Title = {The Schizophrenia Cognition Rating Scale: validation of an interview-based assessment of cognitive functioning in Asian patients with schizophrenia.}, Journal = {Psychiatry Research}, Volume = {178}, Number = {1}, Pages = {33-38}, Year = {2010}, Month = {June}, ISSN = {0165-1781}, url = {http://dx.doi.org/10.1016/j.psychres.2010.03.020}, Abstract = {Growing interest in cognitive deficits associated with schizophrenia has led to the need for a clinician-friendly cognitive instrument. The Schizophrenia Cognition Rating Scale (SCoRS), recognized for its brevity and ease of administration, has proven to be a valid and reliable measure of overall cognition in schizophrenia patients. However, there has been no such validation in an Asian context. This SCoRS validation study involved 103 patient and 48 control subjects within an Asian population. Test-retest reliability, sensitivity of the instrument to cognitive differences between patients with schizophrenia and healthy controls as well as validity by comparing with a standardised performance-based cognitive battery, the Brief Assessment of Cognition in Schizophrenia (BACS) were assessed. Our findings indicated that SCoRS is highly reliable (ICC=0.984) and sensitive to cognitive dysfunction. SCoRS is significantly correlated with BACS composite scores and predicted functional outcomes as measured by Global Assessment of Functioning (GAF) and World Health Organisation-Quality of Life (WHO QOL) within an Asian population. SCoRS represents a clinician-friendly cognitive assessment tool that incorporates third-party feedback and might be employed in clinical practice to better evaluate and manage schizophrenia.}, Doi = {10.1016/j.psychres.2010.03.020}, Key = {fds273486} } @article{fds273485, Author = {Konneker, TI and Crowley, JJ and Quackenbush, CR and Keefe, RSE and Perkins, DO and Stroup, TS and Lieberman, JA and van den Oord, E and Sullivan, PF}, Title = {No association of the serotonin transporter polymorphisms 5-HTTLPR and RS25531 with schizophrenia or neurocognition.}, Journal = {Am J Med Genet B Neuropsychiatr Genet}, Volume = {153B}, Number = {5}, Pages = {1115-1117}, Year = {2010}, Month = {July}, ISSN = {1552-4841}, url = {http://dx.doi.org/10.1002/ajmg.b.31077}, Abstract = {A promoter polymorphism in the serotonin transporter gene has been widely studied in neuropsychiatry. We genotyped the 5-HTTLPR/rs25531 triallelic polymorphism in 728 schizophrenia cases from the CATIE study and 724 control subjects. In a logistic regression with case/control status as dependent variable and 7 ancestry-informative principal components as covariates, the effect of 5-HTTLPR/rs25531 composite genotype was not significant (odds ratio = 1.008, 95% CI 0.868-1.172, P = 0.91). In cases only, 5-HTTLPR/rs25531 was not associated with neurocognition (summary neurocognitive index P = 0.21, working memory P = 0.32) or symptomatology (PANSS positive P = 0.67 and negative symptoms P = 0.46). We were unable to identify association of the triallelic 5-HTTLPR with schizophrenia, neurocognition, or core psychotic symptoms even at levels of significance unadjusted for multiple comparisons.}, Doi = {10.1002/ajmg.b.31077}, Key = {fds273485} } @article{fds273487, Author = {Ventura, J and Reise, SP and Keefe, RSE and Baade, LE and Gold, JM and Green, MF and Kern, RS and Mesholam-Gately, R and Nuechterlein, KH and Seidman, LJ and Bilder, RM}, Title = {The Cognitive Assessment Interview (CAI): development and validation of an empirically derived, brief interview-based measure of cognition.}, Journal = {Schizophrenia Research}, Volume = {121}, Number = {1-3}, Pages = {24-31}, Year = {2010}, Month = {August}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2010.04.016}, Abstract = {BACKGROUND: Practical, reliable "real world" measures of cognition are needed to supplement neurocognitive performance data to evaluate possible efficacy of new drugs targeting cognitive deficits associated with schizophrenia. Because interview-based measures of cognition offer one possible approach, data from the MATRICS initiative (n=176) were used to examine the psychometric properties of the Schizophrenia Cognition Rating Scale (SCoRS) and the Clinical Global Impression of Cognition in Schizophrenia (CGI-CogS). METHOD: We used classical test theory methods and item response theory to derive the 10-item Cognitive Assessment Interview (CAI) from the SCoRS and CGI-CogS ("parent instruments"). Sources of information for CAI ratings included the patient and an informant. Validity analyses examined the relationship between the CAI and objective measures of cognitive functioning, intermediate measures of cognition, and functional outcome. RESULTS: The rater's score from the newly derived CAI (10 items) correlate highly (r=.87) with those from the combined set of the SCoRS and CGI-CogS (41 items). Both the patient (r=.82) and the informant (r=.95) data were highly correlated with the rater's score. The CAI was modestly correlated with objectively measured neurocognition (r=-.32), functional capacity (r=-.44), and functional outcome (r=-.32), which was comparable to the parent instruments. CONCLUSIONS: The CAI allows for expert judgment in evaluating a patient's cognitive functioning and was modestly correlated with neurocognitive functioning, functional capacity, and functional outcome. The CAI is a brief, repeatable, and potentially valuable tool for rating cognition in schizophrenia patients who are participating in clinical trials.}, Doi = {10.1016/j.schres.2010.04.016}, Key = {fds273487} } @article{fds371780, Author = {Volovyk, S and Keefe, R and Loganovsky, K and Bazyka, D}, Title = {Cognitive and behavioral dysfunction under ionizing radiation exposure}, Journal = {International Journal of Psychophysiology : Official Journal of the International Organization of Psychophysiology}, Volume = {77}, Number = {3}, Pages = {341-341}, Publisher = {Elsevier BV}, Year = {2010}, Month = {September}, url = {http://dx.doi.org/10.1016/j.ijpsycho.2010.06.285}, Doi = {10.1016/j.ijpsycho.2010.06.285}, Key = {fds371780} } @article{fds273488, Author = {Ascher-Svanum, H and Nyhuis, AW and Stauffer, V and Kinon, BJ and Faries, DE and Phillips, GA and Schuh, K and Awad, AG and Keefe, R and Naber, D}, Title = {Reasons for discontinuation and continuation of antipsychotics in the treatment of schizophrenia from patient and clinician perspectives.}, Journal = {Curr Med Res Opin}, Volume = {26}, Number = {10}, Pages = {2403-2410}, Year = {2010}, Month = {October}, ISSN = {0300-7995}, url = {http://dx.doi.org/10.1185/03007995.2010.515900}, Abstract = {OBJECTIVE: To identify reasons for discontinuation and continuation of antipsychotic medications in the treatment of schizophrenia from the patients' and their clinicians' perspectives. RESEARCH DESIGN AND METHODS: Two measures were previously developed to assess the Reasons for Antipsychotic Discontinuation/Continuation (RAD), one from the patient's perspective and another from the clinician's perspective. These measures were administered to acutely ill schizophrenia patients enrolled in a 12-week study of antipsychotic medications (N = 596) and to their clinicians. The RAD was assessed at baseline and at endpoint. Reasons were rated on a 5-point scale from 'primary reason' to 'not a reason.' The single most important reason was also identified. The 'single most important reason' and the 'primary reasons' for discontinuing the drug used prior to enrollment, and for discontinuing or continuing the study drug were identified. Levels of concordance between patients' and clinicians' reasons were assessed. CLINICAL TRIAL REGISTRATION: The data source for this study is a clinical trial registered at www.clinicaltrials.gov (NCT00337662). MAIN OUTCOME MEASURES: Reasons for Antipsychotic Discontinuation/Continuation (RAD). RESULTS: Patients and clinicians identified several reasons for medication discontinuation and continuation (2.3 to 6.3 reasons, on average). The top 'single most important' reason for discontinuing the drug used prior to enrollment and for discontinuing the study drug was 'positive symptoms not sufficiently improved or made worse,' followed by 'medication-related adverse events.' The most frequent 'single most important' reason for medication continuation was 'improved positive symptoms,' followed by 'patient's perception of improvement,' and 'functional improvement.' A high level of concordance was observed between patients' and clinicians' ratings. CONCLUSIONS: Medication efficacy appears to be the core driver of medication discontinuation and continuation, especially with regard to positive symptoms. There was a high level of concordance between patients' and clinicians' perspectives. Limitations include the study requirement that patients be at least moderately ill and experiencing acute psychotic exacerbation, a potential selection bias in the readiness to respond to measures, and small sample sizes for some analyses. Further research is needed to replicate findings in patients who are not acutely ill.}, Doi = {10.1185/03007995.2010.515900}, Key = {fds273488} } @article{fds273489, Author = {Kane, JM and D'Souza, DC and Patkar, AA and Youakim, JM and Tiller, JM and Yang, R and Keefe, RSE}, Title = {Armodafinil as adjunctive therapy in adults with cognitive deficits associated with schizophrenia: a 4-week, double-blind, placebo-controlled study.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {71}, Number = {11}, Pages = {1475-1481}, Year = {2010}, Month = {November}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20816042}, Abstract = {OBJECTIVE: To evaluate the efficacy and tolerability of armodafinil, the longer-lasting isomer of modafinil, as adjunctive therapy in patients with schizophrenia. METHOD: This 4-week, randomized, double-blind, placebo-controlled, proof-of-concept study was conducted between July and December 2007. Patients had a history of stable schizophrenia (DSM-IV-TR criteria) for ≥ 8 weeks and were treated with oral risperidone, olanzapine, or paliperidone for ≥ 6 weeks at stable doses for ≥ 4 weeks. Patients were randomly assigned to once-daily placebo or armodafinil 50, 100, or 200 mg. The primary efficacy measure was the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery. Secondary outcome measures included the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessment of Negative Symptoms (SANS). RESULTS: Sixty patients were randomly assigned (15 in each group). No apparent differences between groups in the MATRICS composite score were observed (mean ± SD change from baseline to final visit: armodafinil 50 mg, 1.9 ± 6.22; 100 mg, 2.8 ± 7.98; 200 mg, 2.9 ± 4.72; placebo, 2.2 ± 5.06). The mean ± SD changes in PANSS total scores were -6.3 ± 7.25 for armodafinil 200 mg and -1.7 ± 4.89 for placebo at final visit (effect size=0.73; 95% CI, -0.08 to 1.54) and PANSS negative symptoms scores were -3.4 ± 2.07 and 0.1 ± 1.93 (effect size=1.69; 95% CI, 0.78 to 2.60), respectively. Although reductions in SANS total score were observed with both armodafinil and placebo at final visit, no between-group difference was shown. Armodafinil was generally well tolerated, with diarrhea and headache the most commonly reported adverse events. There was no evidence of worsening of psychosis with adjunctive armodafinil. CONCLUSIONS: In this 4-week study, adjunctive armodafinil was not associated with an improvement in cognitive measures, but armodafinil 200 mg/d appeared to mitigate the negative symptoms of schizophrenia. Treatment was generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00487942.}, Doi = {10.4088/JCP.09m05950gry}, Key = {fds273489} } @article{fds370738, Author = {Keefe, R}, Title = {A MODEL OF COGNITIVE OUTCOME MEASURE CHOICE IN EARLY TO LATE PHASE SCHIZOPHRENIA TRIALS}, Journal = {Schizophrenia Bulletin}, Volume = {37}, Pages = {309-309}, Year = {2011}, Key = {fds370738} } @article{fds370739, Author = {Buller, R and Mittoux, A and Green, MF and Keefe, R and Forray, C and Schooler, N and Marder, S}, Title = {A RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, FLEXIBLE-DOSE STUDY EXPLORING THE NEUROCOGNITIVE EFFECT OF SERTINDOLE VS. QUETIAPINE IN PATIENTS WITH SCHIZOPHRENIA USING THE MATRICS CONSENSUS COGNITIVE BATTERY (MCCB)}, Journal = {Schizophrenia Bulletin}, Volume = {37}, Pages = {298-298}, Year = {2011}, Key = {fds370739} } @article{fds370740, Author = {Sweeney, J and Keefe, R and Hill, S}, Title = {COGNITIVE PHENOTYPES FOR SCHIZOPHRENIA AND PSYCHOTIC BIPOLAR DISORDER IN THE BSNIP STUDY}, Journal = {Schizophrenia Bulletin}, Volume = {37}, Pages = {230-230}, Year = {2011}, Key = {fds370740} } @article{fds370741, Author = {Kraus, M and Keefe, R and Krishnan, R}, Title = {DEFICITS IN LEARNING-DEPENDENT PREDICTIVE PERCEPTION AND THEIR RELATIONSHIP TO COGNITIVE IMPAIRMENT AND REALITY DISTORTION IN SCHIZOPHRENIA}, Journal = {Schizophrenia Bulletin}, Volume = {37}, Pages = {215-215}, Year = {2011}, Key = {fds370741} } @article{fds370742, Author = {Keefe, R}, Title = {FAILURES IN LEARNING- DEPENDENT PREDICTIVE PERCEPTION AS THE KEY VULNERABILITY TO PSYCHOSIS IN SCHIZOPHRENIA}, Journal = {Schizophrenia Bulletin}, Volume = {37}, Pages = {17-18}, Year = {2011}, Key = {fds370742} } @article{fds327072, Author = {Sarkisyan, G and Gurovich, I and Keefe, RSE}, Title = {NORMATIVE DATA FOR RUSSIAN POPULATION AND STANDARDIZATION OF THE SCALE "BRIEF ASSESSMENT OF COGNITION IN SCHIZOPHRENIA"}, Journal = {European Psychiatry}, Volume = {26}, Pages = {1 pages}, Publisher = {ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER}, Year = {2011}, Month = {January}, Key = {fds327072} } @article{fds273490, Author = {Keefe, RSE and Kraus, MS and Krishnan, RR}, Title = {Failures in learning-dependent predictive perception as the key cognitive vulnerability to psychosis in schizophrenia.}, Journal = {Neuropsychopharmacology}, Volume = {36}, Number = {1}, Pages = {367-368}, Year = {2011}, Month = {January}, ISSN = {0893-133X}, url = {http://dx.doi.org/10.1038/npp.2010.153}, Doi = {10.1038/npp.2010.153}, Key = {fds273490} } @article{fds273491, Author = {McClay, JL and Adkins, DE and Aberg, K and Bukszár, J and Khachane, AN and Keefe, RSE and Perkins, DO and McEvoy, JP and Stroup, TS and Vann, RE and Beardsley, PM and Lieberman, JA and Sullivan, PF and van den Oord, EJCG}, Title = {Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia.}, Journal = {Neuropsychopharmacology}, Volume = {36}, Number = {3}, Pages = {616-626}, Year = {2011}, Month = {February}, ISSN = {0893-133X}, url = {http://dx.doi.org/10.1038/npp.2010.193}, Abstract = {Neurocognitive deficits are a core feature of schizophrenia and, therefore, represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18-month period, measuring processing speed, verbal memory, vigilance, reasoning, and working memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only 1 in 10 findings is a false discovery. These six SNPs were located within, or in close proximity to, genes EHF, SLC26A9, DRD2, GPR137B, CHST8, and IL1A. The more robust findings, that is those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the EHF gene (p-value 6.99 × 10(-8), q-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at SLC26A9 (p-value 1.4 × 10(-7), q-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at IL1A (p-value 6.67 × 10(-7), q-value 0.081, mediating the effects of olanzapine on working memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS p-values for download.}, Doi = {10.1038/npp.2010.193}, Key = {fds273491} } @article{fds273492, Author = {Krishnan, RR and Fivaz, M and Kraus, MS and Keefe, RSE}, Title = {Hierarchical temporal processing deficit model of reality distortion and psychoses.}, Journal = {Mol Psychiatry}, Volume = {16}, Number = {2}, Pages = {129-144}, Year = {2011}, Month = {February}, ISSN = {1359-4184}, url = {http://dx.doi.org/10.1038/mp.2010.63}, Abstract = {We posit in this article that hierarchical temporal processing deficit is the underlying basis of reality distortion and psychoses. Schizophrenia is a prototypical reality distortion disorder in which the patient manifests with auditory hallucinations, delusions, disorganized speech and thinking, cognitive impairment, avolition and social and occupational dysfunction. Reality distortion can be present in many other disorders including bipolar disorder, major depression and even dementia. Conceptually, schizophrenia is a heterogeneous entity likely to be because of numerous causes similar to dementia. Although no single symptom or set of symptoms is pathognomonic, a cardinal feature in all patients with schizophrenia is chronic distortion of reality. The model that we have proposed accounts for the varied manifestations of reality distortion including hallucinations and delusions. In this paper we consider the implications of this model for the underlying biology of psychoses and also for the neurobiology of schizophrenia and suggest potential targets to consider for the etiology and pathophysiology of reality distortion, especially in the context of schizophrenia.}, Doi = {10.1038/mp.2010.63}, Key = {fds273492} } @article{fds273493, Author = {Keefe, RSE and Fox, KH and Harvey, PD and Cucchiaro, J and Siu, C and Loebel, A}, Title = {Characteristics of the MATRICS Consensus Cognitive Battery in a 29-site antipsychotic schizophrenia clinical trial.}, Journal = {Schizophrenia Research}, Volume = {125}, Number = {2-3}, Pages = {161-168}, Year = {2011}, Month = {February}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2010.09.015}, Abstract = {OBJECTIVE: The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project produced a battery of tests, the MATRICS Consensus Cognitive Battery (MCCB), designed to assess cognitive treatment effects in clinical trials of patients with schizophrenia. In validation studies, the MCCB demonstrated excellent reliability, minimal practice effects and significant correlations with measures of functional capacity. This study addresses whether the MCCB demonstrates these favorable characteristics when administered in the context of the type of large multi-site industry trial for which it was designed. METHODS: In a clinical trial comparing risperidone and lurasidone, 323 clinically-stable outpatients with schizophrenia at 29 sites were assessed with MCCB at screening and a median of 15days later at baseline. A measure of functional capacity, the UCSD Performance-based Skills Assessment-Brief (UPSA-B) was administered at baseline. RESULTS: All 323 (100%) patients had sufficient data for computing a composite score according to the MCCB criteria. The test-retest reliability of the MCCB composite score was excellent (ICC=0.88). The severity of cognitive impairment was T=24.7 (SD=12.1) at screening and T=26.7 (SD=12.4) at baseline. The MCCB composite score demonstrated a large correlation with the UPSA-B composite score (r=.60, df=304, p<.001). The practice effect on the composite score was small (z=0.18). DISCUSSION: In the context of a 29-site antipsychotic trial in stable outpatients with schizophrenia, the MCCB is sensitive to cognitive deficits in all domains, demonstrates excellent test-retest reliability and small practice effects, and is strongly correlated with a leading measure of functional capacity.}, Doi = {10.1016/j.schres.2010.09.015}, Key = {fds273493} } @article{fds370568, Author = {Davidson, M and Reichenberg, AA and Levine, SZ and Rabinowitz, J and Keefe, R and Murray, R and Moffitt, T and Caspi, A}, Title = {MODELING THE EXPRESSION AND COURSE OF DEVELOPMENTAL ABNORMALITIES PRECEDING ADULT SCHIZOPHRENIA: CHARACTERIZATION OF A NEW DEVELOPMENTAL ULTRA-HIGH-RISK GROUP IN 2 BIRTH COHORTS}, Journal = {Schizophrenia Bulletin}, Volume = {37}, Pages = {49-50}, Publisher = {OXFORD UNIV PRESS}, Year = {2011}, Month = {March}, Key = {fds370568} } @article{fds273494, Author = {Sachs, G and Winklbaur, B and Jagsch, R and Keefe, RSE}, Title = {Validation of the German version of the brief assessment of cognition in Schizophrenia (BACS) - preliminary results.}, Journal = {Eur Psychiatry}, Volume = {26}, Number = {2}, Pages = {74-77}, Year = {2011}, Month = {March}, ISSN = {0924-9338}, url = {http://dx.doi.org/10.1016/j.eurpsy.2009.10.006}, Abstract = {The German version of the BACS showed high test-retest reliability. Sensitivity and specificity scores demonstrated good ability to differentiate between patients and controls. The study suggests that the German Version of the BACS is a useful scale to evaluate cognitive functioning.}, Doi = {10.1016/j.eurpsy.2009.10.006}, Key = {fds273494} } @article{fds273495, Author = {Buchanan, RW and Keefe, RSE and Lieberman, JA and Barch, DM and Csernansky, JG and Goff, DC and Gold, JM and Green, MF and Jarskog, LF and Javitt, DC and Kimhy, D and Kraus, MS and McEvoy, JP and Mesholam-Gately, RI and Seidman, LJ and Ball, MP and McMahon, RP and Kern, RS and Robinson, J and Marder, SR}, Title = {A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia.}, Journal = {Biol Psychiatry}, Volume = {69}, Number = {5}, Pages = {442-449}, Year = {2011}, Month = {March}, ISSN = {0006-3223}, url = {http://dx.doi.org/10.1016/j.biopsych.2010.09.052}, Abstract = {BACKGROUND: In a previous pilot study, MK-0777--a γ-aminobutyric acid (GABA)(A) α2/α3 partial agonist--was reported to improve delayed memory and cognitive measures of prefrontal cortical function in people with schizophrenia. The current study was designed to further examine the efficacy and safety of MK-0777 for the treatment of cognitive impairments in schizophrenia. METHODS: Sixty people with DSM-IV schizophrenia entered a 4-week, multi-center, double-blind, placebo-controlled, randomized clinical trial. Participants were randomized to: MK-0777 3 mg b.i.d. (n = 18); MK-0777 8 mg b.i.d. (n = 21); or placebo (n = 21). Participants were clinically stable. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, AX-Continuous Performance Test, and N-Back were used to assess cognition. The University of California San Diego (UCSD) Performance Based Skills Assessment-2 and the Schizophrenia Cognition Rating Scale assessed functional capacity and served as functional outcome coprimary measures. RESULTS: There were no significant group differences on the primary outcome measure, the MATRICS Consensus Cognitive Battery composite score. Secondary analyses suggested that participants randomized to placebo performed significantly better on visual memory and reasoning/problem-solving tests than participants assigned to either MK-0777 dose. There were no significant group differences on the AX-Continuous Performance Test or N-Back d prime scores or UCSD Performance-Based Skills Assessment-2 and Schizophrenia Cognition Rating Scale total scores. In general, MK-0777 was well-tolerated with minimal side effects. CONCLUSIONS: The study results suggest that MK-0777 has little benefit for cognitive impairments in people with schizophrenia. The GABA(A) receptor remains a promising target, but a more potent partial agonist with greater intrinsic activity at the GABA(A) α2 site might be needed for cognitive enhancement in schizophrenia.}, Doi = {10.1016/j.biopsych.2010.09.052}, Key = {fds273495} } @article{fds273496, Author = {Segarra, N and Bernardo, M and Gutierrez, F and Justicia, A and Fernadez-Egea, E and Allas, M and Safont, G and Contreras, F and Gascon, J and Soler-Insa, PA and Menchon, JM and Junque, C and Keefe, RSE}, Title = {Spanish validation of the Brief Assessment in Cognition in Schizophrenia (BACS) in patients with schizophrenia and healthy controls.}, Journal = {Eur Psychiatry}, Volume = {26}, Number = {2}, Pages = {69-73}, Year = {2011}, Month = {March}, ISSN = {0924-9338}, url = {http://dx.doi.org/10.1016/j.eurpsy.2009.11.001}, Abstract = {Neurocognitive impairment is a core feature of schizophrenia and is closely associated with functional outcome. The importance of cognitive assessment is broadly accepted today, and an easy-to-use, internationality validated cognitive assessment tool is needed by researchers and in daily clinical practice. The Brief Assessment of Cognition in Schizophrenia (BACS) has been validated in English, French, Japanese and Italian. It is as sensitive to cognitive dysfunction as a standard test battery, with the advantage of requiring less than 35minutes to complete. In our study, we tested the psychometric characteristics of a Spanish version of the BACS in 117 patients with schizophrenia-spectrum disorders and 36 healthy controls. All BACS cognitive subtests discriminated between patients and controls (P<.001), and the concurrent validity between the BACS and a traditional neuropsychological test battery was similar to that reported in other languages. We conclude that the BACS can facilitate the comparison of the cognitive performance of patients with schizophrenia in many different countries.}, Doi = {10.1016/j.eurpsy.2009.11.001}, Key = {fds273496} } @article{fds273497, Author = {Kern, RS and Gold, JM and Dickinson, D and Green, MF and Nuechterlein, KH and Baade, LE and Keefe, RSE and Mesholam-Gately, RI and Seidman, LJ and Lee, C and Sugar, CA and Marder, SR}, Title = {The MCCB impairment profile for schizophrenia outpatients: results from the MATRICS psychometric and standardization study.}, Journal = {Schizophrenia Research}, Volume = {126}, Number = {1-3}, Pages = {124-131}, Year = {2011}, Month = {March}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2010.11.008}, Abstract = {The MATRICS Psychometric and Standardization Study was conducted as a final stage in the development of the MATRICS Consensus Cognitive Battery (MCCB). The study included 176 persons with schizophrenia or schizoaffective disorder and 300 community residents. Data were analyzed to examine the cognitive profile of clinically stable schizophrenia patients on the MCCB. Secondarily, the data were analyzed to identify which combination of cognitive domains and corresponding cut-off scores best discriminated patients from community residents, and patients competitively employed vs. those not. Raw scores on the ten MCCB tests were entered into the MCCB scoring program which provided age- and gender-corrected T-scores on seven cognitive domains. To test for between-group differences, we conducted a 2 (group)×7 (cognitive domain) MANOVA with follow-up independent t-tests on the individual domains. Classification and regression trees (CART) were used for the discrimination analyses. Examination of patient T-scores across the seven cognitive domains revealed a relatively compact profile with T-scores ranging from 33.4 for speed of processing to 39.3 for reasoning and problem-solving. Speed of processing and social cognition best distinguished individuals with schizophrenia from community residents; speed of processing along with visual learning and attention/vigilance optimally distinguished patients competitively employed from those who were not. The cognitive profile findings provide a standard to which future studies can compare results from other schizophrenia samples and related disorders; the classification results point to specific areas and levels of cognitive impairment that may advance work rehabilitation efforts.}, Doi = {10.1016/j.schres.2010.11.008}, Key = {fds273497} } @article{fds273498, Author = {Marder, SR and Daniel, DG and Alphs, L and Awad, AG and Keefe, RSE}, Title = {Methodological issues in negative symptom trials.}, Journal = {Schizophrenia Bulletin}, Volume = {37}, Number = {2}, Pages = {250-254}, Year = {2011}, Month = {March}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbq161}, Abstract = {Individuals from academia, the pharmaceutical industry, and the US Food and Drug Administration used a workshop format to discuss important methodological issues in the design of trials of pharmacological agents for improving negative symptoms in schizophrenia. The issues addressed included the need for a coprimary functional measure for registration trials; the characteristics of individuals who should enter negative symptom trials; the optimal duration for a proof-of-concept or registration trial; the optimal design of a study of a broad-spectrum agent that treats both positive and negative symptoms or a co-medication that is added to an antipsychotic; the relative strengths and weaknesses of available instruments for measuring negative symptoms; the definition of clinically meaningful improvement for these trials; and whether drugs can be approved for a subdomain of negative symptoms.}, Doi = {10.1093/schbul/sbq161}, Key = {fds273498} } @article{fds273499, Author = {Caroff, SN and Davis, VG and Miller, DD and Davis, SM and Rosenheck, RA and McEvoy, JP and Campbell, EC and Saltz, BL and Riggio, S and Chakos, MH and Swartz, MS and Keefe, RSE and Stroup, TS and Lieberman, JA and CATIE Investigators}, Title = {Treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {72}, Number = {3}, Pages = {295-303}, Year = {2011}, Month = {March}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20816031}, Abstract = {OBJECTIVE: We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD. METHOD: This analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with χ(2) tests. Data were collected from January 2001 to December 2004. RESULTS: Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (χ(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a ≥ 50% decrease in AIMS score, and 7% showed a ≥ 50% increase in AIMS score. CONCLUSIONS: Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00014001.}, Doi = {10.4088/JCP.09m05793yel}, Key = {fds273499} } @article{fds273500, Author = {Reise, SP and Ventura, J and Keefe, RSE and Baade, LE and Gold, JM and Green, MF and Kern, RS and Mesholam-Gately, R and Nuechterlein, KH and Seidman, LJ and Bilder, R}, Title = {Bifactor and item response theory analyses of interviewer report scales of cognitive impairment in schizophrenia.}, Journal = {Psychol Assess}, Volume = {23}, Number = {1}, Pages = {245-261}, Year = {2011}, Month = {March}, ISSN = {1040-3590}, url = {http://dx.doi.org/10.1037/a0021501}, Abstract = {A psychometric analysis of 2 interview-based measures of cognitive deficits was conducted: the 21-item Clinical Global Impression of Cognition in Schizophrenia (CGI-CogS; Ventura et al., 2008), and the 20-item Schizophrenia Cognition Rating Scale (SCoRS; Keefe et al., 2006), which were administered on 2 occasions to a sample of people with schizophrenia. Traditional psychometrics, bifactor analysis, and item response theory methods were used to explore item functioning and dimensionality and to compare instruments. Despite containing similar item content, responses to the CGI-CogS demonstrated superior psychometric properties (e.g., higher item intercorrelations, better spread of ratings across response categories) relative to the SCoRS. The authors argue that these differences arise mainly from the differential use of prompts and how the items are phrased and scored. Bifactor analysis demonstrated that although both measures capture a broad range of cognitive functioning (e.g., working memory, social cognition), the common variance on each is overwhelmingly explained by a single general factor. Item response theory analyses of the combined pool of 41 items showed that measurement precision is peaked in the mild to moderate range of cognitive impairment. Finally, simulated adaptive testing revealed that only about 10 to 12 items are necessary to achieve latent trait level estimates with reasonably small standard errors for most individuals. This suggests that these interview-based measures of cognitive deficits could be shortened without loss of measurement precision.}, Doi = {10.1037/a0021501}, Key = {fds273500} } @article{fds273501, Author = {Harvey, PD and Ogasa, M and Cucchiaro, J and Loebel, A and Keefe, RSE}, Title = {Performance and interview-based assessments of cognitive change in a randomized, double-blind comparison of lurasidone vs. ziprasidone.}, Journal = {Schizophrenia Research}, Volume = {127}, Number = {1-3}, Pages = {188-194}, Year = {2011}, Month = {April}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2011.01.004}, Abstract = {BACKGROUND: Improving cognitive functioning in people with schizophrenia is a major treatment goal. In addition, interview-based measures have been developed to supplement performance-based assessments. However, few data are available regarding whether interview-based measures are sensitive to treatment-related changes. METHODS: Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomized to 21 days of double-blind treatment with lurasidone 120 mg once daily (N=150) or ziprasidone 80 mg BID (N=151). A similar proportion of patients completed the study on lurasidone (67.5%) and ziprasidone (69.3%). Study participants were assessed with the majority of the tests from the MATRICS Consensus Cognitive Battery (MCCB) and an interview-based assessment of cognitive functioning, the Schizophrenia Cognition Rating Scale (SCoRS). SCoRS ratings were based on the interviewer's best judgment, after interviews with the patient and a caregiver when available. The study was conducted from April 2006 to January 2007. RESULTS: There were no between-group treatment differences in performance on the MCCB or the SCoRS ratings. Lurasidone patients demonstrated significant within group-improvement from baseline on the MCCB composite score (p=0.026) and on the SCoRS (p<0.001), but ziprasidone patients did not improve on either the MCCB composite (p=0.254) or the SCoRS (p=0.185). At endpoint there was a statistical trend (p=0.058) for lurasidone to demonstrate greater improvement from baseline in SCoRS ratings. Improvements in interview-based aspects of cognition were not related to MCCB test changes, and had minimal correlations with changes in symptoms. CONCLUSIONS: These data suggest that interview-based cognitive measures such as the SCoRS may be sensitive to changes after 3weeks of treatment in patients with schizophrenia. Lurasidone is being assessed further in ongoing clinical trials with additional outcome measures.}, Doi = {10.1016/j.schres.2011.01.004}, Key = {fds273501} } @article{fds273502, Author = {Hurford, IM and Marder, SR and Keefe, RSE and Reise, SP and Bilder, RM}, Title = {A brief cognitive assessment tool for schizophrenia: construction of a tool for clinicians.}, Journal = {Schizophrenia Bulletin}, Volume = {37}, Number = {3}, Pages = {538-545}, Year = {2011}, Month = {May}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbp095}, Abstract = {Cognitive impairment in schizophrenia is often severe, enduring, and contributes significantly to chronic disability. But clinicians have difficulty in assessing cognition due to a lack of brief instruments. We evaluated whether a brief battery of cognitive tests derived from larger batteries could generate a summary score representing global cognitive function. Using data from 3 previously published trials, we calculated the corrected item-total correlations (CITCs) or the correlation of each test with the battery total score. We computed the proportion of variance that each test shares with the global score excluding that test (R(t)(2)=CITC(2)) and the variance explained per minute of administration time for each test (R(t)(2)/min). The 3 tests with the highest R(t)(2)/min were selected for the brief battery. The composite score from the trail making test B, category fluency, and digit symbol correlated .86 with the global score of the larger battery in 2 of the studies and correlated between .73 and .82 with the total battery scores excluding these 3 tests. A Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) using the above 3 tests can be administered in 10-11 min. The full batteries of the larger studies have administration times ranging from 90 to 210 min. Given prior research suggesting that a single factor of global cognition best explains the pattern of cognitive deficit in schizophrenia, an instrument like B-CATS can provide clinicians with meaningful data regarding their patients' cognitive function. It can also serve researchers who want an estimate of global cognitive function without requiring a full neuropsychological battery.}, Doi = {10.1093/schbul/sbp095}, Key = {fds273502} } @article{fds273504, Author = {Sim, K and Lee, J and Subramaniam, M and Liu, JJ and Keefe, R and Zhang, XD and Lee, TS and Chong, SA}, Title = {Integrated genetic and genomic approach in the SingaporeTranslational and Clinical Research in Psychosis Study: an overview.}, Journal = {Early Interv Psychiatry}, Volume = {5}, Number = {2}, Pages = {91-99}, Year = {2011}, Month = {May}, ISSN = {1751-7885}, url = {http://dx.doi.org/10.1111/j.1751-7893.2011.00272.x}, Abstract = {AIMS: Schizophrenia is a severe mental disorder with onset frequently in adolescence and followed by a chronic and disabling course. Although the exact pathophysiology of this devastating disorder has not been clearly elucidated, a large part of it has been attributed to genetic influences. This article seeks to provide an overview on what our group has embarked on--to elucidate genetic risk factors for schizophrenia within the Chinese ethnic group. METHODS: We plan to conduct an integrated approach to interrogate comprehensively the genome from different angles and in stages. The first stage involves a genome-wide association study of 1000 cases of schizophrenia-control pairs, with a follow-up replication study in another 1000 cases of schizophrenia and in 1000 controls, and combination analyses with groups from other places including China and Hong Kong. Other than the genome-wide association study, gene sequencing for purported candidate genes and copy number variation analysis will be performed. Neurocognitive intermediate phenotypes will be employed to deconstruct the complex schizophrenia phenotype in a bid to improve association findings. Promising leads from longitudinal gene and protein expression in ultra-high-risk subjects who develop psychosis and schizophrenia (in a parallel study) will be followed up as candidate genes and sequenced in the genetic analysis. Functional analysis forms the last stage of this integrated approach. CONCLUSION: This integrated genetic and genomic approach will hopefully help in further characterizing and deepening our understanding of molecular pathophysiological mechanisms underlying schizophrenia.}, Doi = {10.1111/j.1751-7893.2011.00272.x}, Key = {fds273504} } @article{fds273503, Author = {Krishnan, RR and Kraus, MS and Keefe, RSE}, Title = {Comprehensive model of how reality distortion and symptoms occur in schizophrenia: could impairment in learning-dependent predictive perception account for the manifestations of schizophrenia?}, Journal = {Psychiatry and Clinical Neurosciences}, Volume = {65}, Number = {4}, Pages = {305-317}, Year = {2011}, Month = {June}, ISSN = {1323-1316}, url = {http://dx.doi.org/10.1111/j.1440-1819.2011.02203.x}, Abstract = {Conventional wisdom has not laid out a clear and uniform profile of schizophrenia as a unitary entity. One of the key first steps in elucidating the neurobiology of this entity would be to characterize the essential and common elements in the group of entities called schizophrenia. Kraepelin in his introduction notes 'the conviction seems to be more and more gaining ground that dementia praecox on the whole represents, a well characterized form of disease, and that we are justified in regarding the majority of the clinical pictures which are brought together here as the expression of a single morbid process, though outwardly they often diverge very far from one another'. But what is that single morbid process? We suggest that just as the uniform defect in all types of cancer is impaired regulation of cell proliferation, the primary defect in the group of entities called schizophrenia is persistent defective hierarchical temporal processing. This manifests in the form of chronic memory-prediction errors or deficits in learning-dependent predictive perception. These deficits account for the symptoms that present as reality distortion (delusions, thought disorder and hallucinations). This constellation of symptoms corresponds with the profile of most patients currently diagnosed as suffering from schizophrenia. In this paper we describe how these deficits can lead to the various symptoms of schizophrenia.}, Doi = {10.1111/j.1440-1819.2011.02203.x}, Key = {fds273503} } @article{fds273506, Author = {Burdick, KE and Goldberg, TE and Cornblatt, BA and Keefe, RS and Gopin, CB and Derosse, P and Braga, RJ and Malhotra, AK}, Title = {The MATRICS consensus cognitive battery in patients with bipolar I disorder.}, Journal = {Neuropsychopharmacology}, Volume = {36}, Number = {8}, Pages = {1587-1592}, Year = {2011}, Month = {July}, ISSN = {0893-133X}, url = {http://dx.doi.org/10.1038/npp.2011.36}, Abstract = {The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was devised to identify a neurocognitive battery to be used in clinical trials targeting cognition in schizophrenia, a process, which resulted in the MATRICS Consensus Cognitive Battery (MCCB). The MCCB has been selected by the United States Food and Drug Administration to be used as the primary outcome measure in registry trials for cognitive agents in schizophrenia. Given the clinical and cognitive overlap between schizophrenia and bipolar disorder (BPD), it is likely that any compound shown to have cognitive benefits in schizophrenia will subsequently be tested in BPD. Unlike the MCCB for schizophrenia, there remains no consensus regarding outcome measures if cognitive trials were to be undertaken in BPD. The utility of the MCCB in BPD has not yet been systematically investigated. We administered the MCCB to 80 bipolar I patients; 37 were strictly euthymic and 43 were symptomatic. We compared their performance with a demographically matched healthy sample (n=148) on seven MCCB domains, and the composite. BPD patients were statistically significantly impaired on five of seven MCCB domains at levels consistent with meta-analytic studies of cognition in BPD. In contrast, patients' performance was less impaired on the Reasoning and Problem-solving and Social Cognition domains, differences that did not survive statistical correction for multiple testing. Symptomatic status only modestly influenced performance. These data suggest that the MCCB, devised for use in schizophrenia, may also represent a useful outcome measure in cognitive trials for BPD. Additional studies should address important psychometric features such as repeatability and potential practice and/or ceiling effects.}, Doi = {10.1038/npp.2011.36}, Key = {fds273506} } @article{fds273505, Author = {Stroup, TS and Appelbaum, PS and Gu, H and Hays, S and Swartz, MS and Keefe, RSE and Kim, SY and Manschreck, TC and Boshes, RA and McEvoy, JP and Lieberman, JA}, Title = {Longitudinal consent-related abilities among research participants with schizophrenia: results from the CATIE study.}, Journal = {Schizophrenia Research}, Volume = {130}, Number = {1-3}, Pages = {47-52}, Year = {2011}, Month = {August}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2011.04.012}, Abstract = {OBJECTIVE: Research participants must have adequate consent-related abilities to provide informed consent at the time of study enrollment. We sought to determine if research participants with schizophrenia maintain adequate consent-related abilities during a longitudinal study. If participants lose abilities during a trial they may not be able to judge and protect their interests. If reduced abilities are common or can be predicted, special protections can be targeted appropriately. METHOD: We examined longitudinal consent-related abilities of participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study using the MacArthur Competence Assessment Tool-Clinical Research (MacCAT-CR) at protocol-specified times over 18 months. RESULTS: Of 1158 research participants in this analysis, most (n=650, 56%) had a stable pattern of MacCAT-CR Understanding scores, 235 (20%) improved substantially with no evidence of decline, 273 (24%) had at least one assessment with substantial worsening. During the course of the trial, 43 (4%) fell below the initial threshold for adequate capacity, which was predicted by lower Understanding scores, more severe positive symptoms, and poorer neurocognitive functioning at baseline, and by increases in negative symptoms and deteriorating global status. CONCLUSIONS: Most participants in this long-term study had stable or improved consent-related abilities, but almost one-fourth experienced substantial worsening and 4% of participants fell below the study's capacity threshold for enrollment. Clinical investigators should monitor with special care individuals with marginal capacity or higher levels of psychotic symptoms at study entry and those who exhibit clinical worsening during a study.}, Doi = {10.1016/j.schres.2011.04.012}, Key = {fds273505} } @article{fds273508, Author = {Vigen, CLP and Mack, WJ and Keefe, RSE and Sano, M and Sultzer, DL and Stroup, TS and Dagerman, KS and Hsiao, JK and Lebowitz, BD and Lyketsos, CG and Tariot, PN and Zheng, L and Schneider, LS}, Title = {Cognitive effects of atypical antipsychotic medications in patients with Alzheimer's disease: outcomes from CATIE-AD.}, Journal = {American Journal of Psychiatry}, Volume = {168}, Number = {8}, Pages = {831-839}, Year = {2011}, Month = {August}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.2011.08121844}, Abstract = {OBJECTIVE: The impact of the atypical antipsychotics olanzapine, quetiapine, and risperidone on cognition in patients with Alzheimer's disease is unclear. The authors assessed the effects of time and treatment on neuropsychological functioning during the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease study (CATIE-AD). METHOD: CATIE-AD included 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behavior who were randomly assigned to receive masked, flexible-dose olanzapine, quetiapine, risperidone, or placebo. Based on their clinicians' judgment, patients could discontinue the originally assigned medication and receive another randomly assigned medication. Patients were followed for 36 weeks, and cognitive assessments were obtained at baseline and at 12, 24, and 36 weeks. Outcomes were compared for 357 patients for whom data were available for at least one cognitive measure at baseline and one follow-up assessment that took place after they had been on their prescribed medication or placebo for at least 2 weeks. RESULTS: Overall, patients showed steady, significant declines over time in most cognitive areas, including in scores on the Mini-Mental State Examination (MMSE; -2.4 points over 36 weeks) and the cognitive subscale of the Alzheimer's Disease Assessment Scale (-4.4 points). Cognitive function declined more in patients receiving antipsychotics than in those given placebo on multiple cognitive measures, including the MMSE, the cognitive subscale of the Brief Psychiatric Rating Scale, and a cognitive summary score summarizing change on 18 cognitive tests. CONCLUSIONS: In CATIE-AD, atypical antipsychotics were associated with worsening cognitive function at a magnitude consistent with 1 year's deterioration compared with placebo. Further cognitive impairment is an additional risk of treatment with atypical antipsychotics that should be considered when treating patients with Alzheimer's disease.}, Doi = {10.1176/appi.ajp.2011.08121844}, Key = {fds273508} } @article{fds273507, Author = {Keefe, RSE and Vinogradov, S and Medalia, A and Silverstein, SM and Bell, MD and Dickinson, D and Ventura, J and Marder, SR and Stroup, TS}, Title = {Report from the working group conference on multisite trial design for cognitive remediation in schizophrenia.}, Journal = {Schizophrenia Bulletin}, Volume = {37}, Number = {5}, Pages = {1057-1065}, Year = {2011}, Month = {September}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbq010}, Abstract = {The National Institute of Mental Health (NIMH)-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project and related efforts have stimulated the initiation of several studies of pharmacologic treatments for cognitive impairment in schizophrenia. Cognitive remediation may provide an excellent platform for the provision of new learning opportunities and the acquisition of new skills for patients who are engaged in pharmacologic trials to improve cognition. However, it is not clear how a cognitive remediation intervention would be employed in multisite clinical trials. A meeting of experts on cognitive remediation and related methodological topics was convened to address the feasibility and study design issues for the development of a multisite trial of cognitive remediation in schizophrenia called the Cognitive Remediation in the Schizophrenia Trials Network study. This report details the findings from this meeting, which included the following 4 conclusions. (1) A multisite trial of a cognitive remediation intervention using a network of diverse research sites would be of great scientific value. (2) Various interventions could be employed for this multisite trial. (3) Programs that do not address key motivational and interpersonal aspects of cognitive remediation may benefit from supplementation with "bridging groups" that allows patients to meet with others and to apply their newly acquired cognitive skills to everyday life. (4) Before a multisite efficacy trial is initiated, a pilot study could demonstrate the feasibility of conducting a trial using a cognitive remediation intervention.}, Doi = {10.1093/schbul/sbq010}, Key = {fds273507} } @article{fds273509, Author = {Buchanan, RW and Keefe, RSE and Umbricht, D and Green, MF and Laughren, T and Marder, SR}, Title = {The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later?}, Journal = {Schizophrenia Bulletin}, Volume = {37}, Number = {6}, Pages = {1209-1217}, Year = {2011}, Month = {November}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbq038}, Abstract = {The Food and Drug Administration (FDA)-National Institute of Mental Health (NIMH)-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) clinical trial guidelines for cognitive-enhancing drugs in schizophrenia and the MATRICS Consensus Cognitive Battery (MCCB) were designed to facilitate novel compound development in the treatment of cognitive impairments. Several studies have recently utilized the FDA-NIMH-MATRICS guidelines and MCCB and allow an evaluation of the feasibility of guideline implementation and MCCB performance. In light of the study results, we would recommend the following inclusion criteria revisions-(1) clinical status and symptom inclusion criteria: maximum allowed score for hallucinations and delusions should be increased from moderate to moderately severe and the negative symptom criterion should be dropped in phase 2 studies; (2) antipsychotic medication inclusion criteria: first-generation antipsychotics should be allowed, but only in the context of no concomitant anticholinergic agents and minimal extrapyramidal symptoms, and antipsychotic polypharmacy should be allowed in the absence of pertinent pharmacokinetic or pharmacodynamic considerations; and (3) people who use illicit substances should not be allowed in phase 1B or 2A proof-of-concept studies but may be included in phase 2B and 3 studies in which proof of effectiveness and generalizability of results become more important goals. These revisions are recommended to enhance recruitment while maintaining sufficient methodological rigor to ensure the validity of study results. The MCCB has been shown to have excellent psychometric characteristics, including reliability for multisite clinical trials, clinical relevance for real-world functioning, and possible sensitivity to behavioral treatment, and should continue to serve as the standard outcome measure for cognitive enhancement studies in schizophrenia.}, Doi = {10.1093/schbul/sbq038}, Key = {fds273509} } @article{fds273510, Author = {Kerfoot, KE and Rosenheck, RA and Petrakis, IL and Swartz, MS and Keefe, RSE and McEvoy, JP and Stroup, TS and CATIE Investigators}, Title = {Substance use and schizophrenia: adverse correlates in the CATIE study sample.}, Journal = {Schizophrenia Research}, Volume = {132}, Number = {2-3}, Pages = {177-182}, Year = {2011}, Month = {November}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2011.07.032}, Abstract = {OBJECTIVE: This study examined the relationship between severity of illicit substance use at the time of study entry in a sample of patients diagnosed with schizophrenia and 18-month longitudinal outcomes, including psychopathology, depression, neurocognition, and quality of life. METHODS: Subjects in the Clinical Antipsychotic Trials of Intervention Effectiveness (N=1432) were divided into three groups according to baseline data: (1) those with moderate/severe drug use, (2) those with mild drug use, and (3) non-users of illicit substances. The groups were compared on other baseline characteristics. Mixed model analysis was used to compare outcomes between the groups using all available outcome data over 18 months, controlling for potential confounding baseline characteristics. Least square means were compared between pairs of groups in the mixed models. RESULTS: Significantly poorer outcomes were observed in the domains of psychosis, symptoms of depression, and quality of life for moderate/severe drug users in comparison with both mild users and abstainers. No significant differences were found on neurocognitive functioning or days of employment. CONCLUSIONS: This study suggests that drug use-related impairment co-morbid with schizophrenia may not be a function of use per se but rather, of the severity of use. It highlights the importance of comprehensive assessment and treatment of illicit substance abuse in schizophrenia. Long-term treatment approaches that integrate harm reduction strategies may offer promise in maximizing positive outcomes for such dually diagnosed patients.}, Doi = {10.1016/j.schres.2011.07.032}, Key = {fds273510} } @article{fds273511, Author = {Chong, S-A and Campbell, A and Chee, M and Liu, J and Marx, C and McGorry, P and Subramaniam, M and Yung, A and Keefe, RSE}, Title = {The Singapore flagship programme in translational and clinical research in psychosis.}, Journal = {Early Interv Psychiatry}, Volume = {5}, Number = {4}, Pages = {290-300}, Year = {2011}, Month = {November}, ISSN = {1751-7885}, url = {http://dx.doi.org/10.1111/j.1751-7893.2011.00304.x}, Abstract = {AIM: This paper describes the rationale, aims and development of the Singapore Translational and Clinical Research in Psychosis, which is a 5-year programme. METHODS: The authors provide a selective review of the pertinent findings from the clinical, neuropsychological, genetics and neuroimaging studies on high-risk population and how they were factored in the hypotheses and design of this translational clinical research programme. RESULTS: This programme, which draws upon the previous work of various groups and the experience of the investigators of this consortium, comprises three interlinked studies. The first is a genome-wide association and copy number variation analysis using the diagnostic phenotype of schizophrenia and cognitive phenotypes, and a joint genome-wide analysis performed by combining our data with other datasets to increase the power to detect genetic risk factors. The second is a prospective study of a large group of individuals who are assessed to be at ultra-high risk of psychosis, and the third is a randomized controlled trial to improve neurocognition in patients with schizophrenia. CONCLUSION: The convergence of various factors including the unique structured characteristics of the Singaporean society, the presence of political will with availability of funding and the established research infrastructure make it possible to accrue the sample size for adequate power to elucidate biomarkers of disease risk and resilience.}, Doi = {10.1111/j.1751-7893.2011.00304.x}, Key = {fds273511} } @article{fds273512, Author = {Greenberg, G and Rosenheck, RA and Erickson, SK and Desai, RA and Stefanovics, EA and Swartz, M and Keefe, RSE and McEvoy, J and Stroup, TS and CATIE Investigators}, Title = {Criminal justice system involvement among people with schizophrenia.}, Journal = {Community Mental Health Journal}, Volume = {47}, Number = {6}, Pages = {727-736}, Year = {2011}, Month = {December}, ISSN = {0010-3853}, url = {http://dx.doi.org/10.1007/s10597-010-9362-9}, Abstract = {There is growing concern that people with schizophrenia and other severe mental illnesses are increasingly at risk for unnecessary criminal justice system (CJS) involvement. There has been limited examination, however, of which individual characteristics predict future CJS involvement. This study uses data from the Clinical Antipsychotic Trials of Intervention Effectiveness on sociodemograhic characteristics, baseline clinical status, and service use among patients diagnosed with schizophrenia to prospectively identify predictors of CJS involvement during the following year. A series of bivariate chi-square and F tests were conducted to examine whether significant relationships existed between CJS involvement during the first 12 months of the trial and baseline measures of sociodemographic characteristics, psychiatric status, substance abuse, and other patient characteristics. Multivariate logistic regression analysis was then used to identify the independent strength of the relationship between 12-month CJS involvement and potential risk factors that were found to be significant in bivariate analyses. Multivariate logistic regression analyses indicated that past adolescent conduct disorder, being younger and male, symptoms of Akathisia (movement disorder, most often develops as a side effect of antipsychotic medications), and particularly drug abuse increase the risk for CJS involvement. Since CJS involvement among people with schizophrenia was most strongly associated with drug abuse, treatment of co-morbid drug abuse could reduce the risk of stigma, pain, and other adverse consequences of CJS involvement as well as save CJS expenditures.}, Doi = {10.1007/s10597-010-9362-9}, Key = {fds273512} } @article{fds371779, Author = {Nasrallah, HA and Keefe, R and Lasser, R and Dirks, B and Kirsch, C and Wang, J and Scheckner, B and Lindenmayer, J-P}, Title = {Lisdexamfetamine Dimesylate as Adjunctive Treatment with Antipsychotics for Predominant Negative Symptoms of Schizophrenia: Concurrent Neurocognitive and Negative Symptom Improvement}, Journal = {Biological Psychiatry}, Volume = {71}, Number = {8}, Pages = {65S-65S}, Year = {2012}, Key = {fds371779} } @article{fds273382, Author = {Matza, LS and Phillips, GA and Revicki, DA and Ascher-Svanum, H and Malley, KG and Palsgrove, AC and Faries, DE and Stauffer, V and Kinon, BJ and Awad, AG and Keefe, RS and Naber, D}, Title = {Validation of a patient interview for assessing reasons for antipsychotic discontinuation and continuation.}, Journal = {Patient Preference and Adherence}, Volume = {6}, Pages = {521-532}, Year = {2012}, ISSN = {1177-889X}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000306468600001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Abstract = {INTRODUCTION: The Reasons for Antipsychotic Discontinuation Interview (RAD-I) was developed to assess patients' perceptions of reasons for discontinuing or continuing an antipsychotic. The current study examined reliability and validity of domain scores representing three factors contributing to these treatment decisions: treatment benefits, adverse events, and distal reasons other than direct effects of the medication. METHODS: Data were collected from patients with schizophrenia or schizoaffective disorder and their treating clinicians. For approximately 25% of patients, a second rater completed the RAD-I for assessment of inter-rater reliability. RESULTS: All patients (n = 121; 81 discontinuation, 40 continuation) reported at least one reason for discontinuation or continuation (mean = 2.8 reasons for discontinuation; 3.4 for continuation). Inter-rater reliability was supported (kappas = 0.63-1.0). Validity of the discontinuation domain scores was supported by associations with symptom measures (the Positive and Negative Syndrome Scale for Schizophrenia, the Clinical Global Impression - Schizophrenia Scale; r = 0.30 to 0.51; all P < 0.01), patients' primary reasons for discontinuation, and adverse events. However, the continuation domain scores were not significantly associated with these other indicators. DISCUSSION: Results support the reliability, convergent validity, and known-groups validity of the RAD-I for assessing patients' reasons for antipsychotic discontinuation. Further research is needed to examine validity of the RAD-I continuation section.}, Doi = {10.2147/PPA.S25635}, Key = {fds273382} } @article{fds273514, Author = {Keefe, RSE and Harvey, PD}, Title = {Cognitive impairment in schizophrenia.}, Journal = {Handbook of Experimental Pharmacology}, Volume = {213}, Number = {213}, Pages = {11-37}, Year = {2012}, ISSN = {0171-2004}, url = {http://dx.doi.org/10.1007/978-3-642-25758-2_2}, Abstract = {Cognitive functioning is moderately to severely impaired in patients with schizophrenia. This impairment is the prime driver of the significant disabilities in occupational, social, and economic functioning in patients with schizophrenia and an important treatment target. The profile of deficits in schizophrenia includes many of the most important aspects of human cognition: attention, memory, reasoning, and processing speed. While various efforts are under way to identify specific aspects of neurocognition that may lie closest to the neurobiological etiology and pathophysiology of the illness, and may provide relevant convergence with animal models of cognition, standard neuropsychological measures continue to demonstrate the greatest sensitivity to functionally relevant cognitive impairment.The effects of antipsychotic medications on cognition in schizophrenia and first-episode psychosis appear to be minimal. Important work on the effects of add-on pharmacologic treatments is ongoing. Very few of the studies completed to date have had sufficient statistical power to generate firm conclusions; recent studies examining novel add-on treatments have produced some encouraging findings. Cognitive remediation programs have generated considerable interest as these methods are far less costly than pharmacologic treatment and are likely to be safer. A growing consensus suggests that these interventions produce modest gains for patients with schizophrenia, but the efficacy of the various methods used has not been empirically investigated.}, Doi = {10.1007/978-3-642-25758-2_2}, Key = {fds273514} } @article{fds273517, Author = {Krishnan, RR and Fivaz, M and Kraus, MS and Keefe, RSE}, Title = {Erratum: Hierarchical temporal processing deficit model of reality distortion and psychoses (Molecular Psychiatry (2011) 16, (129-144) DOI: 10.1038/mp.2010.63)}, Journal = {Molecular Psychiatry}, Volume = {17}, Number = {4}, Pages = {470}, Publisher = {Springer Nature}, Year = {2012}, Month = {January}, ISSN = {1359-4184}, url = {http://dx.doi.org/10.1038/mp.2011.54}, Doi = {10.1038/mp.2011.54}, Key = {fds273517} } @article{fds327069, Author = {Uchida, H and Sakurai, H and Bies, RR and Stroup, S and Keefe, RSE and Suzuki, T and Tsuboi, T and Mimura, M and Pollock, BG and Mamo, DC}, Title = {DOPAMINE D2 RECEPTOR OCCUPANCY AND COGNITION IN SCHIZOPHRENIA: ANALYSIS OF THE CATIE DATA}, Journal = {Schizophrenia Research}, Volume = {136}, Pages = {S359-S359}, Publisher = {ELSEVIER SCIENCE BV}, Year = {2012}, Month = {April}, Key = {fds327069} } @article{fds327070, Author = {Colijn, MA and Barbato, M and Keefe, RSE and Perkins, DO and Woods, SW and Addington, J}, Title = {Poster #143 AT RISK FOR PSYCHOSIS: THE ROLE OF COGNITION}, Journal = {Schizophrenia Research}, Volume = {136}, Pages = {S237-S237}, Publisher = {Elsevier BV}, Year = {2012}, Month = {April}, url = {http://dx.doi.org/10.1016/s0920-9964(12)70715-6}, Doi = {10.1016/s0920-9964(12)70715-6}, Key = {fds327070} } @article{fds327071, Author = {Keefe, RSE and Buchanan, RW and Marder, SR and Schooler, NR and Dugar, A and Zivkov, M and Stewart, M}, Title = {Poster #199 CLINICAL TRIALS OF POTENTIAL COGNITIVE-ENHANCING DRUGS IN SCHIZOPHRENIA: WHAT HAVE WE LEARNED SO FAR?}, Journal = {Schizophrenia Research}, Volume = {136}, Pages = {S352-S352}, Publisher = {Elsevier BV}, Year = {2012}, Month = {April}, url = {http://dx.doi.org/10.1016/s0920-9964(12)71031-9}, Doi = {10.1016/s0920-9964(12)71031-9}, Key = {fds327071} } @article{fds371754, Author = {Lee, J and Rapisarda, A and Kraus, M and Chong, S-A and Keefe, R}, Title = {LONGITUDINAL YOUTH-AT-RISK STUDY (LYRIKS): EXAMINING THE PRODROME FROM ANOTHER PERSPECTIVE}, Journal = {Schizophrenia Research}, Volume = {136}, Pages = {S308-S309}, Publisher = {ELSEVIER SCIENCE BV}, Year = {2012}, Month = {April}, Key = {fds371754} } @article{fds371777, Author = {Rapisarda, A and Lim, T and Lim, M and Collinson, S and Kraus, M and Keefe, R}, Title = {Poster #163 APPLICABILITY OF THE MATRICS CONSENSUS COGNITIVE BATTERY IN SINGAPORE}, Journal = {Schizophrenia Research}, Volume = {136}, Pages = {S150-S150}, Publisher = {Elsevier BV}, Year = {2012}, Month = {April}, url = {http://dx.doi.org/10.1016/s0920-9964(12)70477-2}, Doi = {10.1016/s0920-9964(12)70477-2}, Key = {fds371777} } @article{fds371778, Author = {Harvey, PD and Ruse, S and Davis, V and Solomon, M and Keefe, R}, Title = {14:30 COMPUTERIZED FUNCTIONAL CAPACITY ASSESSMENTIN SCHIZOPHRENIA: EVIDENCE FOR CONVERGENT VALIDITY}, Journal = {Schizophrenia Research}, Volume = {136}, Pages = {S78-S79}, Publisher = {Elsevier BV}, Year = {2012}, Month = {April}, url = {http://dx.doi.org/10.1016/s0920-9964(12)70284-0}, Doi = {10.1016/s0920-9964(12)70284-0}, Key = {fds371778} } @article{fds273518, Author = {Javitt, DC and Buchanan, RW and Keefe, RSE and Kern, R and McMahon, RP and Green, MF and Lieberman, J and Goff, DC and Csernansky, JG and McEvoy, JP and Jarskog, F and Seidman, LJ and Gold, JM and Kimhy, D and Nolan, KS and Barch, DS and Ball, MP and Robinson, J and Marder, SR}, Title = {Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {136}, Number = {1-3}, Pages = {25-31}, Year = {2012}, Month = {April}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2011.11.001}, Abstract = {BACKGROUND: Cognitive dysfunction is a key predictor of functional disability in schizophrenia. Davunetide (AL-108, NAP) is an intranasally administered peptide currently being developed for treatment of Alzheimer's disease and related disorders. This study investigates effects of davunetide on cognition in schizophrenia. METHOD: Sixty-three subjects with schizophrenia received davunetide at one of two different doses (5, 30 mg) or placebo for 12 weeks in a multicenter, double-blind, parallel-group randomized clinical trial. The MATRICS Consensus Cognitive Battery (MCCB) assessed cognitive effects. The UCSD Performance-based Skills Assessment (UPSA) and the Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity. Subjects continued their current antipsychotic treatment during the trial. RESULTS: There were no significant differences in MCCB change between davunetide and placebo over the three treatment arms (p=.45). Estimated effect-size (d) values were .34 and .21 favoring the 5 and 30 mg doses vs. placebo, respectively. For UPSA, there was a significant main effect of treatment across study arms (p=.048). Between-group effect size (d) values were.74 and .48, favoring the 5 and 30 mg doses, respectively. No significant effects were observed on the SCoRS or on symptom ratings. No significant side effects or adverse events were observed. CONCLUSION: Davunetide was well tolerated. Effects of davunetide on MCCB-rated cognition were not significant relative to placebo. In contrast, a significant beneficial effect was detected for the UPSA. Based upon effect-size considerations, sample sizes of at least 45-50 subjects/group would be required to obtain significant effects on both MCCB and UPSA, providing guidance for continued clinical development in schizophrenia.}, Doi = {10.1016/j.schres.2011.11.001}, Key = {fds273518} } @article{fds273519, Author = {Keefe, RSE and Kraus, MS}, Title = {Clues to the cognitive and perceptual origins of social isolation and psychosis in schizophrenia.}, Journal = {American Journal of Psychiatry}, Volume = {169}, Number = {4}, Pages = {354-357}, Year = {2012}, Month = {April}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.2012.12010042}, Doi = {10.1176/appi.ajp.2012.12010042}, Key = {fds273519} } @article{fds326766, Author = {Jarskog, FF and Grove, RA and McEvoy, JP and Keefe, RSE and Lowy, MT and Horrigan, JP and Peykamian, MA}, Title = {Randomized, Double-Blind, Placebo Controlled, Parallel Group Exploratory Study of GSK239512 for Cognitive Impairment in Stable Schizophrenia Subjects on Background Antipsychotic Therapy}, Journal = {Biological Psychiatry}, Volume = {71}, Number = {8}, Pages = {63S-64S}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2012}, Month = {April}, Key = {fds326766} } @article{fds327067, Author = {Madhoo, M and Keefe, RSE and Roth, RM and Sambunaris, A and Wu, J and Trivedi, MH and Anderson, CS and Lasser, R}, Title = {Efficacy and safety of lisdexamfetamine dimesylate in adults with executive dysfunction and partial or full remission of major depressive disorder}, Journal = {The International Journal of Neuropsychopharmacology}, Volume = {15}, Pages = {189-189}, Publisher = {OXFORD UNIV PRESS}, Year = {2012}, Month = {June}, Key = {fds327067} } @article{fds327068, Author = {Supina, D and Endicott, J and Madhoo, M and Keefe, RSE and Trivedi, M and Wu, J and Scheckner, B and Lasser, R}, Title = {PMH61 Effects of Lisdexamfetamine Dimesylate Augmentation on Functional Outcomes in Adults with Partially or Fully Remitted Major Depressive Disorder}, Journal = {Value in Health}, Volume = {15}, Number = {4}, Pages = {A93-A93}, Publisher = {Elsevier BV}, Year = {2012}, Month = {June}, url = {http://dx.doi.org/10.1016/j.jval.2012.03.506}, Doi = {10.1016/j.jval.2012.03.506}, Key = {fds327068} } @article{fds273520, Author = {Weiser, M and Gershon, AA and Rubinstein, K and Petcu, C and Ladea, M and Sima, D and Podea, D and Keefe, RSE and Davis, JM}, Title = {A randomized controlled trial of allopurinol vs. placebo added on to antipsychotics in patients with schizophrenia or schizoaffective disorder.}, Journal = {Schizophrenia Research}, Volume = {138}, Number = {1}, Pages = {35-38}, Year = {2012}, Month = {June}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2012.02.014}, Abstract = {Adenosine agonists produce behavioral effects similar to dopamine antagonists, hence increasing adenosine levels might improve symptoms of schizophrenia. This hypothesis is supported by three single-site studies indicating that allopurinol, which increases adenosine levels, improved symptoms in patients with schizophrenia. We performed a multi-center, 8-week RCT of allopurinol vs. placebo added to anti-psychotic medications in 248 patients with schizophrenia or schizoaffective disorder. Both groups showed improvement in the PANSS (effect size 1.13) and in clinical and cognitive measures. No difference was observed between groups in primary (t=0.01, p=0.992) or secondary outcome measures. These findings do not support allopurinol as a treatment for schizophrenia.}, Doi = {10.1016/j.schres.2012.02.014}, Key = {fds273520} } @article{fds273521, Author = {Keefe, RSE and Vinogradov, S and Medalia, A and Buckley, PF and Caroff, SN and D'Souza, DC and Harvey, PD and Graham, KA and Hamer, RM and Marder, SM and Miller, DD and Olson, SJ and Patel, JK and Velligan, D and Walker, TM and Haim, AJ and Stroup, TS}, Title = {Feasibility and pilot efficacy results from the multisite Cognitive Remediation in the Schizophrenia Trials Network (CRSTN) randomized controlled trial.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {73}, Number = {7}, Pages = {1016-1022}, Year = {2012}, Month = {July}, ISSN = {0160-6689}, url = {http://dx.doi.org/10.4088/JCP.11m07100}, Abstract = {BACKGROUND: The true benefit of pharmacologic intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment. Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential. However, the feasibility of large-scale multisite studies using cognitive remediation at clinical trials sites has not been established. METHOD: 53 adult patients with DSM-IV schizophrenia from 9 university-affiliated sites were randomized to a cognitive remediation condition that included the Posit Science Brain Fitness auditory training program with weekly Neuropsychological and Educational Approach to Remediation (NEAR) "bridging groups" or a control condition of computer games and weekly healthy lifestyles groups. Patients were expected to complete 3 to 5 one-hour sessions weekly for 40 sessions or 12 weeks, whichever came first. The primary outcomes were feasibility results as measured by rate of enrollment, retention, and completion rate of primary outcome measures. The study was conducted from July 2009 through January 2010. RESULTS: During a 3-month enrollment period, 53 (of a projected 54) patients were enrolled, and 41 (77%) met criteria for study completion. Thirty-one patients completed all 40 sessions, and all patients completed all primary outcome measures. Preliminary efficacy results indicated that, after 20 sessions, patients in the cognitive remediation condition demonstrated mean MATRICS Consensus Cognitive Battery composite score improvements that were 3.7 (95% CI, 0.05-7.34) T-score points greater than in patients in the computer-games control group (F(1,46) = 4.16, P = .047). At the end of treatment, a trend favoring cognitive remediation was not statistically significant (F(1,47) = 2.26, P = .14). CONCLUSION: Multisite clinical trials of cognitive remediation using the Posit Science Brain Fitness auditory training program with the NEAR method of weekly bridging groups at traditional clinical sites appear to be feasible. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00930150.}, Doi = {10.4088/JCP.11m07100}, Key = {fds273521} } @article{fds273522, Author = {Geffen, Y and Keefe, R and Rabinowitz, J and Anand, R and Davidson, M}, Title = {Bl-1020, a new γ-aminobutyric acid-enhanced antipsychotic: results of 6-week, randomized, double-blind, controlled, efficacy and safety study.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {73}, Number = {9}, Pages = {e1168-e1174}, Year = {2012}, Month = {September}, ISSN = {0160-6689}, url = {http://dx.doi.org/10.4088/JCP.12m07642}, Abstract = {OBJECTIVE: BL-1020 is a γ-aminobutyric acid (GABA)-enhanced antipsychotic that combines dopamine antagonism with GABA agonist activity. On the basis of animal models, we tested the hypotheses that BL-1020 would be effective in ameliorating both psychotic symptoms and cognitive impairments, with a favorable safety profile in acutely ill schizophrenia patients. METHOD: 363 hospital-based psychiatric patients in India, Romania, and United States aged 18 to 65 years and meeting criteria for DSM-IV-TR diagnosis of chronic schizophrenia were randomized double-blind to receive BL-1020 10 mg/d, BL-1020 20-30 mg/d, placebo, or risperidone (2-8 mg/d) for 6 weeks. The main outcome measures were the positive and negative syndrome scale (PANSS), brief assessment of cognition in schizophrenia, readiness for discharge questionnaire, clinical global impressions scale (CGI) , and extrapyramidal symptom rating scale. The study ran from July 2008 to June 2009. RESULTS: BL-1020 20-30 mg was significantly better than placebo on PANSS (P = .02) and CGI (P < .001) measurements, with no significant differences noted between BL-1020 20-30 mg and risperidone. There were no significant differences in the maximum change on extrapyramidal symptom rating scale between risperidone and BL-1020 20-30 mg, and both were significantly worse (P < .001) than placebo. BL-1020 20-30 mg was associated with significantly greater improvements on cognitive functioning as measured by the brief assessment of cognition in schizophrenia composite score when compared to placebo (effect size = 0.50, P = .009), risperidone (effect size = 0.43, P = .019), and BL-1020 10 mg (effect size = 0.42, P = .013) after 6 weeks. CONCLUSIONS: BL-1020 appears to be an effective antipsychotic with possible procognitive effects that will need to be further tested for short- and long-term effects. A further randomized controlled trial using the U.S. Food and Drug Administration-recommended Measurement and Treatment Research to Improve Cognition in Schizophrenia cognitive battery is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00567710.}, Doi = {10.4088/JCP.12m07642}, Key = {fds273522} } @article{fds327066, Author = {Madhoo, M and Roth, RM and Keefe, RSE and Sambunaris, A and Scheckner, B and Nielsen, J and Adeyi, B and Wu, J and Lasser, R}, Title = {P.2.a.017 Lisdexamfetamine dimesylate augmentation effects on executive function in major depressive disorder based on depressive symptom levels}, Journal = {European Neuropsychopharmacology}, Volume = {22}, Pages = {S233-S234}, Publisher = {Elsevier BV}, Year = {2012}, Month = {October}, url = {http://dx.doi.org/10.1016/s0924-977x(12)70346-2}, Doi = {10.1016/s0924-977x(12)70346-2}, Key = {fds327066} } @article{fds273562, Author = {Meier, MH and Caspi, A and Ambler, A and Harrington, H and Houts, R and Keefe, RSE and McDonald, K and Ward, A and Poulton, R and Moffitt, TE}, Title = {Persistent cannabis users show neuropsychological decline from childhood to midlife.}, Journal = {Proc Natl Acad Sci U S A}, Volume = {109}, Number = {40}, Pages = {E2657-E2664}, Year = {2012}, Month = {October}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22927402}, Abstract = {Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health. Concomitantly, adolescents are initiating cannabis use at younger ages, and more adolescents are using cannabis on a daily basis. The purpose of the present study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users. Participants were members of the Dunedin Study, a prospective study of a birth cohort of 1,037 individuals followed from birth (1972/1973) to age 38 y. Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 y. Neuropsychological testing was conducted at age 13 y, before initiation of cannabis use, and again at age 38 y, after a pattern of persistent cannabis use had developed. Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning, even after controlling for years of education. Informants also reported noticing more cognitive problems for persistent cannabis users. Impairment was concentrated among adolescent-onset cannabis users, with more persistent use associated with greater decline. Further, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users. Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents.}, Doi = {10.1073/pnas.1206820109}, Key = {fds273562} } @article{fds273373, Author = {Harvey, PD and Keefe, RS}, Title = {Technology, society, and mental illness: Challenges and opportunities for assessment and treatment}, Journal = {Innovations in Clinical Neuroscience}, Volume = {9}, Number = {11-12}, Pages = {47-50}, Year = {2012}, Month = {December}, ISSN = {2158-8333}, Abstract = {Technology is rapidly changing society, and many activities now require the ability to use technology. This situation has the potential to lead to problems for several populations, including the elderly, the disadvantaged, and people with severe mental illness. In this column, we review the state of technology as it affects daily activities. We then review previous efforts to use technology positively for both the assessment and treatment of psychiatric conditions, including posttraumatic stress disorder and severe mental illness. We conclude that technology-based interventions and assessment strategies have the potential to deliver benefit to a wide array of older people and those with severe mental illness, including reaching people who would not have had access otherwise.}, Key = {fds273373} } @article{fds273523, Author = {Kahn, PV and Walker, TM and Williams, TS and Cornblatt, BA and Mohs, RC and Keefe, RSE}, Title = {Standardizing the use of the Continuous Performance Test in schizophrenia research: a validation study.}, Journal = {Schizophrenia Research}, Volume = {142}, Number = {1-3}, Pages = {153-158}, Year = {2012}, Month = {December}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2012.09.009}, Abstract = {BACKGROUND: The Continuous Performance Test (CPT) has emerged as the most commonly administered measure of sustained attention, but use of discrepant versions reduces the ability of researchers and clinicians to accurately draw cross-study conclusions. In an effort to standardize use of the CPT, this study compared four versions of the Identical Pairs CPT for their reliability and ability to discriminate between patients with schizophrenia and healthy volunteers. The relationship of performance on the different versions of the CPT with measures of psychopathology, functioning, and other aspects of cognition was also examined. METHODS: Performance on the 2-digit, 3-digit, 4-digit, and Shapes Identical Pairs CPT was assessed at three test sessions over five weeks, during which subjects also completed the Brief Assessment of Cognition in Schizophrenia (BACS) and questionnaires assessing psychopathology and functioning. RESULTS: All four CPTs discriminated between patients with schizophrenia and healthy volunteers, but there were no statistical differences in sensitivity among the versions. The 3-digit CPT showed non-statistical advantages in that it had high test-retest reliability, low potential for a ceiling effect, and a very low rate of false alarms. There were also moderate correlations between CPT performance and performance of the BACS subtests, but no significant correlations between CPT performance and measures of psychopathology and functioning. CONCLUSIONS: While all versions of the CPT tested here had good psychometric characteristics, the 3-digit CPT-IP has some advantages in repeated measures studies such as clinical trials.}, Doi = {10.1016/j.schres.2012.09.009}, Key = {fds273523} } @article{fds273513, Author = {Matza, LS and Phillips, GA and Revicki, DA and Ascher-Svanum, H and Malley, KG and Palsgrove, AC and Faries, DE and Stauffer, V and Kinon, BJ and George Awad and A and Keefe, RSE and Naber, D}, Title = {Validation of a clinician questionnaire to assess reasons for antipsychotic discontinuation and continuation among patients with schizophrenia.}, Journal = {Psychiatry Research}, Volume = {200}, Number = {2-3}, Pages = {835-842}, Year = {2012}, Month = {December}, ISSN = {0165-1781}, url = {http://dx.doi.org/10.1016/j.psychres.2012.05.005}, Abstract = {The Reasons for Antipsychotic Discontinuation Questionnaire (RAD-Q) was designed to assess clinicians' perceptions of reasons for antipsychotic discontinuation or continuation. The current study examined psychometric properties of this instrument and patterns of antipsychotic discontinuation. The sample of 121 patients (81 discontinuation, 40 continuation) with schizophrenia or schizoaffective disorder was 66.9% male, with a mean age of 41.6 years. Treating clinicians reported a mean of 4.1 reasons for discontinuation and 7.5 reasons for continuation. RAD-Q domain scores were derived to quantify the impact of three factors on the decision to discontinue or continue: treatment benefits, adverse events, and distal reasons other than direct effects of the medication. Analysis of inter-rater reliability indicated an acceptable degree of agreement between clinicians (weighted Kappa for discontinuation scores=0.70-0.78). Correlations with symptom measures (Clinical Global Impression-Schizophrenia Scale (CGI-SCH), Positive and Negative Syndrome Scale (PANSS)) supported convergent validity of the benefits domain score (r=0.28-0.47; all p<0.05). Domain scores discriminated among groups of patients differing in clinician and patient-reported clinical variables. Results suggest that the RAD-Q is a useful detailed measure of reasons for antipsychotic discontinuation and continuation. Findings indicate that clinicians usually report multiple reasons for discontinuation, rather than a single reason for each patient.}, Doi = {10.1016/j.psychres.2012.05.005}, Key = {fds273513} } @article{fds273343, Author = {Lee, T-S and Goh, SJA and Quek, SY and Phillips, R and Guan, C and Cheung, YB and Feng, L and Teng, SSW and Wang, CC and Chin, ZY and Zhang, H and Ng, TP and Lee, J and Keefe, R and Krishnan, KRR}, Title = {A brain-computer interface based cognitive training system for healthy elderly: a randomized control pilot study for usability and preliminary efficacy.}, Journal = {Plos One}, Volume = {8}, Number = {11}, Pages = {e79419}, Year = {2013}, url = {http://dx.doi.org/10.1371/journal.pone.0079419}, Abstract = {UNLABELLED: Cognitive decline in aging is a pressing issue associated with significant healthcare costs and deterioration in quality of life. Previously, we reported the successful use of a novel brain-computer interface (BCI) training system in improving symptoms of attention deficit hyperactivity disorder. Here, we examine the feasibility of the BCI system with a new game that incorporates memory training in improving memory and attention in a pilot sample of healthy elderly. This study investigates the safety, usability and acceptability of our BCI system to elderly, and obtains an efficacy estimate to warrant a phase III trial. Thirty-one healthy elderly were randomized into intervention (n = 15) and waitlist control arms (n = 16). Intervention consisted of an 8-week training comprising 24 half-hour sessions. A usability and acceptability questionnaire was administered at the end of training. Safety was investigated by querying users about adverse events after every session. Efficacy of the system was measured by the change of total score from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) before and after training. Feedback on the usability and acceptability questionnaire was positive. No adverse events were reported for all participants across all sessions. Though the median difference in the RBANS change scores between arms was not statistically significant, an effect size of 0.6SD was obtained, which reflects potential clinical utility according to Simon's randomized phase II trial design. Pooled data from both arms also showed that the median change in total scores pre and post-training was statistically significant (Mdn = 4.0; p<0.001). Specifically, there were significant improvements in immediate memory (p = 0.038), visuospatial/constructional (p = 0.014), attention (p = 0.039), and delayed memory (p<0.001) scores. Our BCI-based system shows promise in improving memory and attention in healthy elderly, and appears to be safe, user-friendly and acceptable to senior users. Given the efficacy signal, a phase III trial is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01661894.}, Doi = {10.1371/journal.pone.0079419}, Key = {fds273343} } @article{fds273347, Author = {Kim, JL and Rele, S and Marks, DM and Masand, PS and Yerramsetty, P and Millet, RA and Keefe, RS and Patkar, AA}, Title = {Effects of milnacipran on neurocognition, pain, and fatigue in fibromyalgia: a 13-week, randomized, placebo-controlled, crossover trial.}, Journal = {The Primary Care Companion for Cns Disorders}, Volume = {15}, Number = {6}, Year = {2013}, ISSN = {2155-7772}, url = {http://dx.doi.org/10.4088/PCC.13m01555}, Abstract = {OBJECTIVE: To investigate whether milnacipran is safe and effective in improving cognitive function in patients with fibromyalgia. METHOD: Patients were randomly assigned to receive milnacipran or placebo for 6 weeks, followed by a 1-week washout and then crossover to the other arm for another 6 weeks. The overall trial lasted 13 weeks and was conducted between July 2011 and May 2013. Assessments were performed at each visit. Neurocognition was measured by the Brief Assessment of Cognition (BAC) and MATRICS. Pain was assessed by the visual analog scale (VAS) for pain. Global assessment of fibromyalgia symptoms was measured by the Fibromyalgia Impact Questionnaire (FIQ) and tender point examination. Depression was assessed by the Beck Depression Inventory (BDI). Fatigue was assessed by the Fatigue Severity Scale. Functional outcome was evaluated by the Health Assessment Questionnaire. The Clinical Global Impressions-Severity of Illness (CGI-S) and Improvement (CGI-I) scales and the Patients Clinical Global Impression of Change were used to measure the global impression of severity and improvement. RESULTS: 26 subjects were screened, and 20 subjects completed the trial. The change in verbal memory (P = .001) and the composite T score (P = .044) of the BAC and the change in the attention-vigilance domain T score (P = .042) were significantly improved, but there were no differences between the drug and placebo groups. The changes in the CGI-S scores were not significant, but the changes in the Clinical Impression-Improvement (CGI-I) scores showed worsening in the placebo group at week 1 (P = .032), week 2 (P = .024), week 4 (P = .024), and week 6 (P = .60) compared to baseline. The change in FIQ scores was not significant. CONCLUSIONS: Milnacipran may have a potential role in the improvement of pain, disability, and mood. The effect of milnacipran on cognition in fibromyalgia needs further research. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01829243.}, Doi = {10.4088/PCC.13m01555}, Key = {fds273347} } @article{fds273375, Author = {Rapisarda, A and Lim, TF and Lim, M and Collinson, SL and Kraus, MS and Keefe, RSE}, Title = {Applicability of the MATRICS Consensus Cognitive Battery in Singapore.}, Journal = {Clin Neuropsychol}, Volume = {27}, Number = {3}, Pages = {455-469}, Year = {2013}, ISSN = {1385-4046}, url = {http://dx.doi.org/10.1080/13854046.2012.762120}, Abstract = {The MATRICS Consensus Cognitive Battery (MCCB) was developed to provide a reliable, valid, and standard battery for clinical trials on cognitive enhancers in schizophrenia. In this study we tested the applicability of the MCCB to Singapore's English speakers. Healthy ethnic Chinese, Malay, and Indian English speakers (N = 171) of both genders were recruited within three age groups and three levels of education to match as closely as possible the US norming sample, and were administered the MCCB. Descriptive data, T scores, age, gender, education, and ethnicity effects on performance were explored and compared with the US norming study. Age, education, and ethnicity affected the battery's composite scores, with young and highly educated participants generally outperforming the old, less-educated ones. Male participants outperformed their female counterparts in two out of seven cognitive domains. Although generally lower when compared to the US norming sample, Singaporean scores reflected the same relationship with age, education, and gender, with the exception of a substantially worse performance in the social cognition domain. Differences among the ethnic groups in Singapore-and the poorer performance measured in these groups with respect to the US sample-call for the necessity of an extended norming study in Singapore.}, Doi = {10.1080/13854046.2012.762120}, Key = {fds273375} } @article{fds273378, Author = {Keefe, RSE and Buchanan, RW and Marder, SR and Schooler, NR and Dugar, A and Zivkov, M and Stewart, M}, Title = {Clinical trials of potential cognitive-enhancing drugs in schizophrenia: what have we learned so far?}, Journal = {Schizophrenia Bulletin}, Volume = {39}, Number = {2}, Pages = {417-435}, Year = {2013}, Month = {March}, ISSN = {0586-7614}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000315556900026&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Abstract = {In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website "www.clinicaltrials.gov" using the terms "schizophrenia AND cognition," "schizophrenia AND neurocognition," "schizophrenia AND neurocognitive tests," "schizophrenia AND MATRICS," "schizophrenia AND MCCB," "schizophrenia AND BACS," "schizophrenia AND COGSTATE," and "schizophrenia AND CANTAB" and "first-episode schizophrenia AND cognition." The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia.}, Doi = {10.1093/schbul/sbr153}, Key = {fds273378} } @article{fds273379, Author = {Lam, M and Eng, GK and Rapisarda, A and Subramaniam, M and Kraus, M and Keefe, RSE and Collinson, SL}, Title = {Formulation of the age-education index: measuring age and education effects in neuropsychological performance.}, Journal = {Psychol Assess}, Volume = {25}, Number = {1}, Pages = {61-70}, Year = {2013}, Month = {March}, ISSN = {1040-3590}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000315974000006&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Abstract = {The complex interplay of education, age, and cognitive performance on various neuropsychological tests is examined in the current study. New education indices were formulated and further investigated to reveal how age and education variances work together to account for performance on neuropsychological tests. Participants were 830 English-speaking ethnic Chinese. Neuropsychological measures such as Verbal Memory, Digit Sequencing, Token Motor Task, Semantic Fluency, Symbol Coding, Tower of London, Judgment of Line Orientation, and Matrix Reasoning of the Wechsler Adult Intelligence Scale were administered. Education was measured by total years of education and adjusted years of education, as well as ratios of both measures with age. Age and education were associated with neuropsychological performance. Adjusted years of education was associated with fluency and higher cognitive processes, while the ratio between adjusted years of education and age was associated with tasks implicating working memory. Changes in education modalities implicated tasks requiring language abilities. Education and age represent key neurodevelopmental milestones. In light of our findings, special consideration should to be given when neuropsychological assessments are carried out in cross-cultural contexts and in societies where educational systems and pedagogy tend to be complex.}, Doi = {10.1037/a0030548}, Key = {fds273379} } @article{fds273515, Author = {Barbato, M and Colijn, MA and Keefe, RSE and Perkins, DO and Woods, SW and Hawkins, KA and Christensen, BK and Addington, J}, Title = {The course of cognitive functioning over six months in individuals at clinical high risk for psychosis.}, Journal = {Psychiatry Research}, Volume = {206}, Number = {2-3}, Pages = {195-199}, Year = {2013}, Month = {April}, ISSN = {0165-1781}, url = {http://dx.doi.org/10.1016/j.psychres.2012.10.013}, Abstract = {Cognitive impairment is common in psychosis and has recently been observed in individuals at clinical high risk (CHR) of developing psychosis. The purpose of this study was to characterize longitudinal change in cognition among CHR individuals, and compare cognition of CHR individuals who later convert to psychosis to that of CHR who do not convert. Participants were tested at baseline and followed-up after six months using a comprehensive cognitive test battery. Individuals who did not convert to psychosis either remained stable or significantly improved in their cognitive performance. At baseline participants who converted to psychosis compared to non-converters exhibited poorer performance in several cognitive tests, suggesting that some cognitive impairment is already present before conversion. Future longitudinal research should address if further decline takes place during the prodrome or after conversion to psychosis.}, Doi = {10.1016/j.psychres.2012.10.013}, Key = {fds273515} } @article{fds273354, Author = {Keefe, RSE and Kraemer, HC and Epstein, RS and Frank, E and Haynes, G and Laughren, TP and McNulty, J and Reed, SD and Sanchez, J and Leon, AC}, Title = {Defining a clinically meaningful effect for the design and interpretation of randomized controlled trials.}, Journal = {Innovations in Clinical Neuroscience}, Volume = {10}, Number = {5-6 Suppl A}, Pages = {4S-19S}, Year = {2013}, Month = {May}, ISSN = {2158-8333}, Abstract = {<h4>Objective</h4>This article captures the proceedings of a meeting aimed at defining clinically meaningful effects for use in randomized controlled trials for psychopharmacological agents.<h4>Design</h4>Experts from a variety of disciplines defined clinically meaningful effects from their perspectives along with viewpoints about how to design and interpret randomized controlled trials.<h4>Setting</h4>The article offers relevant, practical, and sometimes anecdotal information about clinically meaningful effects and how to interpret them.<h4>Participants</h4>The concept for this session was the work of co-chairs Richard Keefe and the late Andy Leon. Faculty included Richard Keefe, PhD; James McNulty, AbScB; Robert S. Epstein, MD, MS; Shelby D. Reed, PhD; Juan Sanchez, MD; Ginger Haynes, PhD; Andrew C. Leon, PhD; Helena Chmura Kraemer, PhD; Ellen Frank, PhD, and Kenneth L. Davis, MD.<h4>Results</h4>The term clinically meaningful effect is an important aspect of designing and interpreting randomized controlled trials but can be particularly difficult in the setting of psychopharmacology where effect size may be modest, particularly over the short term, because of a strong response to placebo. Payers, regulators, patients, and clinicians have different concerns about clinically meaningful effects and may describe these terms differently. The use of moderators in success rate differences may help better delineate clinically meaningful effects.<h4>Conclusion</h4>There is no clear consensus on a single definition for clinically meaningful differences in randomized controlled trials, and investigators must be sensitive to specific concerns of stakeholders in psychopharmacology in order to design and execute appropriate clinical trials.}, Key = {fds273354} } @article{fds273370, Author = {Ventura, J and Reise, SP and Keefe, RSE and Hurford, IM and Wood, RC and Bilder, RM}, Title = {The Cognitive Assessment Interview (CAI): reliability and validity of a brief interview-based measure of cognition.}, Journal = {Schizophrenia Bulletin}, Volume = {39}, Number = {3}, Pages = {583-591}, Year = {2013}, Month = {May}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbs001}, Abstract = {OBJECTIVE: To obtain Food and Drug Administration approval for the treatment of cognitive impairments associated with schizophrenia, a drug will need to demonstrate benefits beyond those that may be documented on objective cognitive tests. Interview-based measures of cognition such as the Cognitive Assessment Interview (CAI) are candidate coprimary outcome measures. METHODS: Psychiatrically stable schizophrenia outpatients (n=150) were studied using the CAI to obtain information about cognitive functioning from both the patient and an informant. Patients also received objective assessments of neurocognition, functional capacity, functional outcome, and symptoms, at baseline and 1 month later. RESULTS: The CAI had good internal consistency (Cronbach's alpha=.92) and good test-retest reliability (r=.83). The CAI was moderately correlated with objective neurocognitive test scores (r's=-.39 to -.41) and moderately correlated with social functioning (r=-.38), work functioning (r=-.48), and overall functional outcome (r=-.49). The correlations of CAI scores with external validity indicators did not differ significantly by source of information (patient alone ratings were valid). Overall functional outcome correlated more strongly with patient CAI scores (r=-.50) than with objective neurocognitive test scores (r=.29) or functional capacity (r=.29). CONCLUSIONS: Field testing of the CAI produced reliable ratings of cognitive functioning that were correlated with functional outcome. Patient ratings alone yielded scores with reliability and validity values appropriate for use in clinical trials. The CAI appears to provide useful complementary information and possesses practical advantages for rating cognitive functioning including an interview-based method of administration, brief assessment time (15 min for the patient assessment), little or no practice effects, and ease of scoring.}, Doi = {10.1093/schbul/sbs001}, Key = {fds273370} } @article{fds273371, Author = {Sakurai, H and Bies, RR and Stroup, ST and Keefe, RSE and Rajji, TK and Suzuki, T and Mamo, DC and Pollock, BG and Watanabe, K and Mimura, M and Uchida, H}, Title = {Dopamine D2 receptor occupancy and cognition in schizophrenia: analysis of the CATIE data.}, Journal = {Schizophrenia Bulletin}, Volume = {39}, Number = {3}, Pages = {564-574}, Year = {2013}, Month = {May}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbr189}, Abstract = {INTRODUCTION: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. METHODS: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions. RESULTS: D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%. DISCUSSION: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.}, Doi = {10.1093/schbul/sbr189}, Key = {fds273371} } @article{fds273376, Author = {Vita, A and Deste, G and Barlati, S and De Peri and L and Giambra, A and Poli, R and Keefe, RSE and Sacchetti, E}, Title = {Interview-based assessment of cognition in schizophrenia: applicability of the Schizophrenia Cognition Rating Scale (SCoRS) in different phases of illness and settings of care.}, Journal = {Schizophrenia Research}, Volume = {146}, Number = {1-3}, Pages = {217-223}, Year = {2013}, Month = {May}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2013.02.035}, Abstract = {INTRODUCTION: The Schizophrenia Cognition Rating Scale (SCoRS), an interview-based assessment of cognition, has proved to be a valid measure of cognitive performance in patients with schizophrenia. OBJECTIVE: The aims of this study were to analyze the validity of this scale in a naturalistic setting representative of the Italian system of psychiatric care, and to test whether the SCoRS could be appropriately used in different phases of illness and contexts of care. METHODS: Eighty-six patients with schizophrenia (DSM-IV-TR criteria) (N = 59 clinically stabilized patients; N = 27 recently hospitalized patients) were administered the SCoRS. The reliability of SCoRS was assessed and global ratings were correlated with neurocognitive, clinical, and psychosocial functioning measures. RESULTS: SCoRS inter-rater and test-retest reliability were high. In clinically stabilized patients, SCoRS global ratings were significantly correlated with composite scores of cognitive performance (global cognitive index: r = -0.570, P<0.001), symptoms (Positive and Negative Syndrome Scale (PANSS) total score: r = 0.602, P < 0.001), and psychosocial functioning (Global Assessment of Functioning (GAF): r = -0.532, P<0.001; Health of the Nation Outcome Scale (HoNOS): r = 0.433, P < 0.001). On the other hand, no such correlations were found in recently hospitalized patients. Correlations with neuropsychological and functional measures were less significant as the severity of the patients' symptoms, especially positive symptoms, increased. CONCLUSION: The SCoRS is a valid measure of cognitive performance and is related to psychosocial functioning, especially in clinically stable patients with schizophrenia. The usefulness of the SCoRS in patients recently admitted to hospital for an acute phase of illness is uncertain.}, Doi = {10.1016/j.schres.2013.02.035}, Key = {fds273376} } @article{fds273516, Author = {Cruz, BF and de Resende, CB and Abreu, MN and Rocha, FL and Teixeira, AL and Keefe, RSE and Salgado, JV}, Title = {How specific are negative symptoms and cognitive impairment in schizophrenia? An analysis of PANSS and SCoRS.}, Journal = {Cogn Neuropsychiatry}, Volume = {18}, Number = {3}, Pages = {243-251}, Year = {2013}, Month = {May}, ISSN = {1354-6805}, url = {http://dx.doi.org/10.1080/13546805.2012.730995}, Abstract = {INTRODUCTION: Interview-based scales can be used as coprimary measures to complement the assessment of cognitive impairment in schizophrenia. One major question that arises from the use of such tools is how specific they are in relation to other psychopathological domains. We analyse the specificity of the Positive and Negative Syndrome Scale (PANSS) negative subscale and the Schizophrenia Cognition Rating Scale (SCoRS). METHODS: We performed a principal component analysis (PCA) of PANSS negative subscale, rated by the interviewer, and SCoRS ratings from three different sources (patient, informant, and interviewer) in 101 patients with schizophrenia. Additionally, we correlated mean SCoRS ratings to PANSS negative subscale items to determine whether any PANSS item is particularly related to cognition. RESULTS: The PCA showed that the two first components, which explained approximately 40% of the total variance of the scales, represent the SCoRS ratings and the PANSS negative subscale ratings, respectively. The mean interviewer SCoRS was significantly correlated with the PANSS negative Item 5 (difficulty in abstract thinking) and with the mean PANSS negative subscale. The latter correlation was no longer significant when "difficulty in abstract thinking" was eliminated from PANSS negative subscale. CONCLUSIONS: In general, SCoRS and PANSS negative subscale scores address different constructs; however, the PANSS negative item "difficulty in abstract thinking" seems to address a cognitive dimension.}, Doi = {10.1080/13546805.2012.730995}, Key = {fds273516} } @article{fds273377, Author = {Jarskog, LF and Dong, Z and Kangarlu, A and Colibazzi, T and Girgis, RR and Kegeles, LS and Barch, DM and Buchanan, RW and Csernansky, JG and Goff, DC and Harms, MP and Javitt, DC and Keefe, RS and McEvoy, JP and McMahon, RP and Marder, SR and Peterson, BS and Lieberman, JA}, Title = {Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia.}, Journal = {Neuropsychopharmacology}, Volume = {38}, Number = {7}, Pages = {1245-1252}, Year = {2013}, Month = {June}, ISSN = {0893-133X}, url = {http://dx.doi.org/10.1038/npp.2013.23}, Abstract = {Schizophrenia is associated with extensive neurocognitive and behavioral impairments. Studies indicate that N-acetylaspartate (NAA), a marker of neuronal integrity, and choline, a marker of cell membrane turnover and white matter integrity, may be altered in schizophrenia. Davunetide is a neurotrophic peptide that can enhance cognitive function in animal models of neurodegeneration. Davunetide has recently demonstrated modest functional improvement in a study of people with schizophrenia. In a subset of these subjects, proton magnetic resonance spectroscopy ((1)H-MRS) was conducted to explore the effects of davunetide on change in NAA/creatine (NAA/Cr) and choline/creatine (choline/Cr) over 12 weeks of treatment. Of 63 outpatients with schizophrenia who received randomized davunetide (5 and 30 mg/day) or placebo in the parent clinical trial, 18 successfully completed (1)H-MRS in dorsolateral prefrontal cortex (DLPFC) at baseline and at 12 weeks. Cognition was assessed using the MATRICS Consensus Cognitive Battery (MCCB). NAA/Cr was unchanged for combined high- and low-dose davunetide groups (N=11). NAA/Cr in the high-dose davunetide group (N=8) suggested a trend increase of 8.0% (P=0.072) over placebo (N=7). Choline/Cr for combined high- and low-dose davunetide groups suggested a 6.4% increase (P=0.069), while the high-dose group showed a 7.9% increase (P=0.040) over placebo. Baseline NAA/Cr correlated with the composite MCCB score (R=0.52, P=0.033), as did individual cognitive domains of attention/vigilance, verbal learning, and social cognition; however, neither metabolite correlated with functional capacity. In this exploratory study, 12 weeks of adjunctive davunetide appeared to produce modest increases in NAA/Cr and choline/Cr in DLPFC in people with schizophrenia. This is consistent with a potential neuroprotective mechanism for davunetide. The data also support use of MRS as a useful biomarker of baseline cognitive function in schizophrenia. Future clinical and preclinical studies are needed to fully define the mechanism of action and cognitive effects of davunetide in schizophrenia.}, Doi = {10.1038/npp.2013.23}, Key = {fds273377} } @article{fds273367, Author = {Nutt, D and Gispen-de Wied and CC and Arango, C and Keefe, RSE and Penadés, R and Murphy, DG and Robbins, TW and Sahakian, BJ}, Title = {Cognition in schizophrenia: summary Nice Consultation Meeting 2012.}, Journal = {Eur Neuropsychopharmacol}, Volume = {23}, Number = {8}, Pages = {769-778}, Year = {2013}, Month = {August}, ISSN = {0924-977X}, url = {http://dx.doi.org/10.1016/j.euroneuro.2013.03.005}, Doi = {10.1016/j.euroneuro.2013.03.005}, Key = {fds273367} } @article{fds327065, Author = {Keefe, RSE and Mahableshwarkar, AR and Olsen, CK}, Title = {P.2.f.013 Clinical evidence for improvement in cognitive dysfunction in patients with major depressive disorder (MDD) after treatment with vortioxetine}, Journal = {European Neuropsychopharmacology}, Volume = {23}, Pages = {S402-S403}, Publisher = {Elsevier BV}, Year = {2013}, Month = {October}, url = {http://dx.doi.org/10.1016/s0924-977x(13)70636-9}, Doi = {10.1016/s0924-977x(13)70636-9}, Key = {fds327065} } @article{fds273360, Author = {Kahn, RS and Keefe, RSE}, Title = {Schizophrenia is a cognitive illness: time for a change in focus.}, Journal = {Jama Psychiatry}, Volume = {70}, Number = {10}, Pages = {1107-1112}, Year = {2013}, Month = {October}, ISSN = {2168-622X}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000325184100016&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Abstract = {Schizophrenia is currently classified as a psychotic disorder. This article posits that this emphasis on psychosis is a conceptual fallacy that has greatly contributed to the lack of progress in our understanding of this illness and hence has hampered the development of adequate treatments. Not only have cognitive and intellectual underperformance consistently been shown to be risk factors for schizophrenia, several studies have found that a decline in cognitive functioning precedes the onset of psychosis by almost a decade. Although the question of whether cognitive function continues to decline after psychosis onset is still debated, it is clear that cognitive function in schizophrenia is related to outcome and little influenced by antipsychotic treatment. Thus, our focus on defining (and preventing) the disorder on the basis of psychotic symptoms may be too narrow. Not only should cognition be recognized as the core component of the disorder, our diagnostic efforts should emphasize the changes in cognitive function that occur earlier in development. Putting the focus back on cognition may facilitate finding treatments for the illness before psychosis ever emerges.}, Doi = {10.1001/jamapsychiatry.2013.155}, Key = {fds273360} } @article{fds273357, Author = {Hill, SK and Reilly, JL and Keefe, RSE and Gold, JM and Bishop, JR and Gershon, ES and Tamminga, CA and Pearlson, GD and Keshavan, MS and Sweeney, JA}, Title = {Neuropsychological impairments in schizophrenia and psychotic bipolar disorder: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study.}, Journal = {American Journal of Psychiatry}, Volume = {170}, Number = {11}, Pages = {1275-1284}, Year = {2013}, Month = {November}, ISSN = {0002-953X}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000326724300010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Abstract = {OBJECTIVE: Familial neuropsychological deficits are well established in schizophrenia but remain less well characterized in other psychotic disorders. This study from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium 1) compares cognitive impairment in schizophrenia and bipolar disorder with psychosis, 2) tests a continuum model of cognitive dysfunction in psychotic disorders, 3) reports familiality of cognitive impairments across psychotic disorders, and 4) evaluates cognitive impairment among nonpsychotic relatives with and without cluster A personality traits. METHOD: Participants included probands with schizophrenia (N=293), psychotic bipolar disorder (N=227), schizoaffective disorder (manic, N=110; depressed, N=55), their first-degree relatives (N=316, N=259, N=133, and N=64, respectively), and healthy comparison subjects (N=295). All participants completed the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery. RESULTS: Cognitive impairments among psychotic probands, compared to healthy comparison subjects, were progressively greater from bipolar disorder (z=-0.77) to schizoaffective disorder (manic z=-1.08; depressed z=-1.25) to schizophrenia (z=-1.42). Profiles across subtests of the BACS were similar across disorders. Familiality of deficits was significant and comparable in schizophrenia and bipolar disorder. Of particular interest were similar levels of neuropsychological deficits in relatives with elevated cluster A personality traits across proband diagnoses. Nonpsychotic relatives of schizophrenia probands without these personality traits exhibited significant cognitive impairments, while relatives of bipolar probands did not. CONCLUSIONS: Robust cognitive deficits are present and familial in schizophrenia and psychotic bipolar disorder. Severity of cognitive impairments across psychotic disorders was consistent with a continuum model, in which more prominent affective features and less enduring psychosis were associated with less cognitive impairment. Cognitive dysfunction in first-degree relatives is more closely related to psychosis-spectrum personality disorder traits in psychotic bipolar disorder than in schizophrenia.}, Doi = {10.1176/appi.ajp.2013.12101298}, Key = {fds273357} } @article{fds273358, Author = {Yaakub, SN and Dorairaj, K and Poh, JS and Asplund, CL and Krishnan, R and Lee, J and Keefe, RSE and Adcock, RA and Wood, SJ and Chee, MWL}, Title = {Preserved working memory and altered brain activation in persons at risk for psychosis.}, Journal = {American Journal of Psychiatry}, Volume = {170}, Number = {11}, Pages = {1297-1307}, Year = {2013}, Month = {November}, ISSN = {0002-953X}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000326724300012&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Abstract = {OBJECTIVE: Patients with schizophrenia exhibit impairments in working memory that often appear in attenuated form in persons at high risk for the illness. The authors hypothesized that deviations in task-related brain activation and deactivation would occur in persons with an at-risk mental state performing a working memory task that entailed the maintenance and manipulation of letters. METHOD: Participants at ultra high risk for developing psychosis (N=60), identified using the Comprehensive Assessment of At-Risk Mental States, and healthy comparison subjects (N=38) 14 to 29 years of age underwent functional MRI while performing a verbal working memory task. Group differences in brain activation were identified using analysis of covariance. RESULTS: The two groups did not show significant differences in speed or accuracy of performance, even after accounting for differences in education. Irrespective of task condition, at-risk participants exhibited significantly less activation than healthy comparison subjects in the left anterior insula. During letter manipulation, at-risk persons exhibited greater task-related deactivation within the default-mode network than comparison subjects. Region-of-interest analysis in the at-risk group revealed significantly greater right dorsolateral prefrontal cortex activation during manipulation of letters. CONCLUSIONS: Despite comparable behavioral performance, at-risk participants performing a verbal working memory task exhibited altered brain activation compared with healthy subjects. These findings demonstrate an altered pattern of brain activation in at-risk persons that contains elements of reduced function as well as compensation.}, Doi = {10.1176/appi.ajp.2013.12081135}, Key = {fds273358} } @article{fds273361, Author = {Marder, SR and Alphs, L and Anghelescu, I-G and Arango, C and Barnes, TRE and Caers, I and Daniel, DG and Dunayevich, E and Fleischhacker, WW and Garibaldi, G and Green, MF and Harvey, PD and Kahn, RS and Kane, JM and Keefe, RSE and Kinon, B and Leucht, S and Lindenmayer, J-P and Malhotra, AK and Stauffer, V and Umbricht, D and Wesnes, K and Kapur, S and Rabinowitz, J}, Title = {Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {150}, Number = {2-3}, Pages = {328-333}, Year = {2013}, Month = {November}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2013.07.058}, Abstract = {A number of pharmacological agents for treating negative symptoms in schizophrenia are currently in development. Unresolved questions regarding the design of clinical trials in this area were discussed at an international meeting in Florence, Italy in April 2012. Participants included representatives from academia, the pharmaceutical industry, and the European Medicines Agency (EMA). Prior to the meeting, participants submitted key questions for debate and discussion. Responses to the questions guided the discussion during the meeting. The group reached agreement on a number of issues: (1) study subjects should be under the age of 65; (2) subjects should be excluded for symptoms of depression that do not overlap with negative symptoms; (3) functional measures should not be required as a co-primary in negative symptom trials; (4) information from informants should be included for ratings when available; (5) Phase 2 negative symptom trials should be 12weeks and 26weeks is preferred for Phase 3 trials; (6) prior to entry into a negative symptom study, subjects should demonstrate clinical stability for a period of 4 to 6months by collection of retrospective information; and (7) prior to entry, the stability of negative and positive symptoms should be confirmed prospectively for four weeks or longer. The participants could not reach agreement on whether predominant or prominent negative symptoms should be required for study subjects.}, Doi = {10.1016/j.schres.2013.07.058}, Key = {fds273361} } @article{fds273364, Author = {Barbato, M and Liu, L and Penn, DL and Keefe, RSE and Perkins, DO and Woods, SW and Addington, J}, Title = {Social cognition as a mediator between neurocognition and functional outcome in individuals at clinical high risk for psychosis.}, Journal = {Schizophrenia Research}, Volume = {150}, Number = {2-3}, Pages = {542-546}, Year = {2013}, Month = {November}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2013.08.015}, Abstract = {In schizophrenia, neurocognition, social cognition and functional outcome are all inter-related, with social cognition mediating the impact that impaired neurocognition has on functional outcome. Less clear is the nature of the relationship between neurocognition, social cognition and functional outcome in individuals at clinical high risk (CHR) for psychosis. 137 CHR participants completed a neurocognitive test battery, a battery of social cognition tasks and the Social Functioning Scale. Confirmatory factor analysis showed that all social cognition tasks were reliable and valid measures of the latent variable. The path from neurocognition to functioning was statistically significant (standardized coefficient β=0.22, p<0.01). The path from social cognition to functioning was also statistically significant (β=0.27, p<0.05). In the mediation model the bootstrapping estimate revealed a nonsignificant indirect effect that was the association of social cognition with neurocognition and with functional outcome (β=0.20, 95% CI=-0.07 to 0.52, p=0.11). However, social cognition was significantly associated with neurocognition (β=0.80, p<0.001) and the path from neurocognition to functioning was no longer significant as soon as the mediator (social cognition) was entered into the mediation model (β=0.02, p=0.92). All of the model fit indices were very good. Unlike what has been observed with psychotic patients, social cognition does not seem to mediate the pathway from neurocognition to functional outcome when assessed with a measure of social attainment in individuals at CHR for psychosis.}, Doi = {10.1016/j.schres.2013.08.015}, Key = {fds273364} } @article{fds273351, Author = {Eng, GK and Lam, M and Bong, YL and Subramaniam, M and Bautista, D and Rapisarda, A and Kraus, M and Lee, J and Collinson, SL and Chong, SA and Keefe, RSE}, Title = {Brief assessment of cognition in schizophrenia: normative data in an English-speaking ethnic Chinese sample.}, Journal = {Arch Clin Neuropsychol}, Volume = {28}, Number = {8}, Pages = {845-858}, Year = {2013}, Month = {December}, ISSN = {0887-6177}, url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000327718700012&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92}, Abstract = {There is a dearth of non-Western normative data for neuropsychological batteries designed to measure cognitive deficits in schizophrenia. Here, we provide normative data for English-speaking ethnic Chinese on the widely used Brief Assessment of Cognition in Schizophrenia acquired from 595 healthy community participants between ages 14 and 55. Means and standard deviations of subtests and composite scores were stratified by age group and sex. We also explored linear regression approaches to generate continuous norms adjusted for age, sex, and education. Notable differences in subtest performances were found against a Western comparison sample. Normative data established in the current sample are essential for clinical and research purposes as it serves as a reference source of cognition for ethnic Chinese.}, Doi = {10.1093/arclin/act060}, Key = {fds273351} } @article{fds273352, Author = {Meier, MH and Shalev, I and Moffitt, TE and Kapur, S and Keefe, RSE and Wong, TY and Belsky, DW and Harrington, H and Hogan, S and Houts, R and Caspi, A and Poulton, R}, Title = {Microvascular abnormality in schizophrenia as shown by retinal imaging.}, Journal = {American Journal of Psychiatry}, Volume = {170}, Number = {12}, Pages = {1451-1459}, Year = {2013}, Month = {December}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24030514}, Abstract = {OBJECTIVE: Retinal and cerebral microvessels are structurally and functionally homologous, but unlike cerebral microvessels, retinal microvessels can be noninvasively measured in vivo by retinal imaging. The authors tested the hypothesis that individuals with schizophrenia exhibit microvascular abnormality and evaluated the utility of retinal imaging as a tool for schizophrenia research. METHOD: Participants were members of the Dunedin Study, a population-representative cohort followed from birth with 95% retention. Study members underwent retinal imaging at age 38. The authors assessed retinal arteriolar and venular caliber for all members of the cohort, including individuals who developed schizophrenia. RESULTS: Study members who developed schizophrenia were distinguished by wider retinal venules, suggesting microvascular abnormality reflective of insufficient brain oxygen supply. Analyses that controlled for confounding health conditions suggested that wider retinal venules are not simply an artifact of co-occurring health problems in schizophrenia patients. Wider venules were also associated with a dimensional measure of adult psychosis symptoms and with psychosis symptoms reported in childhood. CONCLUSIONS: The findings provide initial support for the hypothesis that individuals with schizophrenia show microvascular abnormality. Moreover, the results suggest that the same vascular mechanisms underlie subthreshold symptoms and clinical disorder and that these associations may begin early in life. These findings highlight the promise of retinal imaging as a tool for understanding the pathogenesis of schizophrenia.}, Doi = {10.1176/appi.ajp.2013.13020234}, Key = {fds273352} } @article{fds273359, Author = {Lee, J and Rekhi, G and Mitter, N and Bong, YL and Kraus, MS and Lam, M and Rapisarda, A and Lee, T-S and Subramaniam, M and Chong, SA and Keefe, RSE}, Title = {The Longitudinal Youth at Risk Study (LYRIKS)--an Asian UHR perspective.}, Journal = {Schizophrenia Research}, Volume = {151}, Number = {1-3}, Pages = {279-283}, Year = {2013}, Month = {December}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24139196}, Abstract = {Numerous studies have been published on the psychosis prodrome and have explored a wide array of its many aspects. However, the set of risk factors identified by these various efforts is not homogenous across studies. This could be due to unique population factors or relatively small sample sizes. Only few studies were conducted on Asian populations, whose socio-cultural characteristics differ - in some cases remarkably - from those in western populations. Singapore is a highly dense city-state in South-east Asia, with low rates of substance abuse. The Longitudinal Youth at Risk Study (LYRIKS) commenced in Singapore in 2008, designed to comprehensively assess a group of ultra high risk (UHR) individuals and identify clinical, social, neuropsychological and biological risk factors unique to the local population. 173 UHR individuals were recruited from this single-site study over 4 years. Here, we detail aspects of the study methodology and report on the baseline social and clinical characteristics of the sample population. 78% of the UHR sample suffered from a psychiatric disorder, with Major Depressive Disorder present in more than half of the sample. The mean Global Assessment of Functioning (GAF) score was 57.4, which indicated a moderate level of impairment. Although the recruited sample did not differ significantly by social and clinical characteristics when compared to previously published reports, the conversion rate to psychosis was 3.5% (n=6) at 6 months. Follow-up measures are currently underway to assess longitudinal incidence of psychosis and impact of risk factors on cognition, functioning and remission.}, Doi = {10.1016/j.schres.2013.09.025}, Key = {fds273359} } @article{fds273362, Author = {Rashid, NAA and Lim, J and Lam, M and Chong, S-A and Keefe, RSE and Lee, J}, Title = {Unraveling the relationship between obesity, schizophrenia and cognition.}, Journal = {Schizophrenia Research}, Volume = {151}, Number = {1-3}, Pages = {107-112}, Year = {2013}, Month = {December}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2013.09.020}, Abstract = {INTRODUCTION: Previous studies investigating the relationship between obesity and cognition as well as gender differences in these relationships reported equivocal results. Here, we examined age, years of education, schizophrenia, and gender differences which might affect the relationship between obesity and cognition. METHODS: 1012 healthy controls and 707 participants with schizophrenia were recruited. Information on body mass index (BMI) was obtained and a neurocognitive battery was administered. Structural equation modeling (SEM) was performed to examine the relationship between BMI, schizophrenia, cognition and its covariates. RESULTS: No significant direct effect of BMI on cognition was found when cognition was regressed on age, years of education, diagnosis of schizophrenia and BMI. Instead, two SEM models indicated that indirect effects between BMI and cognition exist. The indirect effect of BMI on cognition through schizophrenia was present in both genders, while the indirect effect of cognition on BMI through schizophrenia was only found in females. BMI affecting cognition through age, years of education and schizophrenia appears to be the most plausible model that explains the data. This indirect effect was larger in females and was masked by diagnosis of schizophrenia. CONCLUSION: With increased rates of obesity in schizophrenia, it is important to highlight the potentially deleterious effect of obesity on cognition. BMI could be used as a candidate risk marker to identify people at higher risk of cognitive deficits, and as an intervention target for modifications of cognitive outcomes.}, Doi = {10.1016/j.schres.2013.09.020}, Key = {fds273362} } @article{fds371773, Author = {Keefe, R and Ruse, S and Davis, V and Atkins, A and Patterson, T and Narasimhan, M and Harvey, P}, Title = {Validation of A Computerized Assessment of Functional Capacity}, Journal = {Neuropsychopharmacology}, Volume = {39}, Pages = {S475-S476}, Year = {2014}, Key = {fds371773} } @article{fds371774, Author = {Keefe, R and Mahableshwarkar, A and Zajecka, J and Jacobson, W and Chen, Y}, Title = {Efficacy of Vortioxetine on Cognitive Function in Patients with Major Depressive Disorder: Cognitive Test Performance Results: from a Randomized, Double-blind, Duloxetine-referenced, Placebo-controlled}, Journal = {Neuropsychopharmacology}, Volume = {39}, Pages = {S389-S390}, Year = {2014}, Key = {fds371774} } @article{fds371775, Author = {Rosenbaum, J and Keefe, R and Lieberman, J and Romano, S and McKinney, R and Orf, H}, Title = {Industry and Academic Science: Can Academia Work More Effectively and Ethically with Industry to Get New Therapies to the Market?}, Journal = {Neuropsychopharmacology}, Volume = {39}, Pages = {S37-S38}, Year = {2014}, Key = {fds371775} } @article{fds371776, Author = {Bauer, IE and Keefe, R and Suchting, R and Green, C and Zunta-Soares, GB and Soares, JC}, Title = {The Brief Cognitive Assessment Test for Affective Disorders (BAC-A): A New Instrument for Assessing Cognitive Functioning in Bipolar Disorder}, Journal = {Biological Psychiatry}, Volume = {75}, Number = {9}, Pages = {198S-198S}, Year = {2014}, Key = {fds371776} } @article{fds273300, Author = {Ruse, SA and Davis, VG and Atkins, AS and Krishnan, KRR and Fox, KH and Harvey, PD and Keefe, RSE}, Title = {Development of a virtual reality assessment of everyday living skills}, Journal = {Journal of Visualized Experiments : Jove}, Number = {86}, Year = {2014}, ISSN = {1940-087X}, url = {http://dx.doi.org/10.3791/51405}, Abstract = {Cognitive impairments affect the majority of patients with schizophrenia and these impairments predict poor long term psychosocial outcomes. Treatment studies aimed at cognitive impairment in patients with schizophrenia not only require demonstration of improvements on cognitive tests, but also evidence that any cognitive changes lead to clinically meaningful improvements. Measures of "functional capacity" index the extent to which individuals have the potential to perform skills required for real world functioning. Current data do not support the recommendation of any single instrument for measurement of functional capacity. The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a novel, interactive gaming based measure of functional capacity that uses a realistic simulated environment to recreate routine activities of daily living. Studies are currently underway to evaluate and establish the VRFCAT's sensitivity, reliability, validity, and practicality. This new measure of functional capacity is practical, relevant, easy to use, and has several features that improve validity and sensitivity of measurement of function in clinical trials of patients with CNS disorders.}, Doi = {10.3791/51405}, Key = {fds273300} } @article{fds273338, Author = {Keefe, RSE}, Title = {The longitudinal course of cognitive impairment in schizophrenia: an examination of data from premorbid through posttreatment phases of illness.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {75 Suppl 2}, Pages = {8-13}, Year = {2014}, ISSN = {0160-6689}, url = {http://dx.doi.org/10.4088/JCP.13065su1.02}, Abstract = {Cognitive impairment is a core feature of schizophrenia that is present across the course of the illness. However, due to complexities of studying cognitive decline in patients prior to the onset of illness, the longitudinal course is not fully understood. The cognitive effects in patients with schizophrenia are robust, with a 1.5 to 2.5 standard deviation gap between patients and healthy controls on composite scores. People with schizophrenia manifest a prior history of cognitive impairment in the premorbid phases of the illness. Examination of school records suggests that children who will eventually develop schizophrenia begin school at a level of functioning that is a full grade behind their peers, with the gap increasing by the time they finish high school. Epidemiologic work suggests that there are both static cognitive impairments and developmental lags in these patients during childhood, well before the illness is fully manifest. Although there was initial promise of improved cognitive function with second-generation antipsychotic treatment, more recent studies have suggested no differences among antipsychotics, with the initial appearance of improvement very likely attributable to practice effects, inappropriate medication dosing, and poor study design. Two large, prominent studies evaluating first- and second-generation antipsychotics suggested that, although there was slight to modest improvement in cognitive function for all treatments, there were no differences among medications, regardless of the generation of the agents. In summary, patients who develop schizophrenia, on average, demonstrate cognitive impairment beginning as early as the first grade, with deterioration seen across school years. Further, these patients had substantial cognitive deficits after the initiation of psychosis. Finally, while antipsychotic treatment improves symptoms, antipsychotics have little impact on cognition, and there appear to be no differences in the degree of cognitive improvement between first- and second-generation agents.}, Doi = {10.4088/JCP.13065su1.02}, Key = {fds273338} } @article{fds273348, Author = {Meier, MH and Caspi, A and Reichenberg, A and Keefe, RSE and Fisher, HL and Harrington, H and Houts, R and Poulton, R and Moffitt, TE}, Title = {Neuropsychological decline in schizophrenia from the premorbid to the postonset period: evidence from a population-representative longitudinal study.}, Journal = {American Journal of Psychiatry}, Volume = {171}, Number = {1}, Pages = {91-101}, Year = {2014}, Month = {January}, ISSN = {0002-953X}, url = {http://dx.doi.org/10.1176/appi.ajp.2013.12111438}, Abstract = {OBJECTIVE: Despite the widespread belief that neuropsychological decline is a cardinal feature of the progression from the premorbid stage to the chronic form of schizophrenia, few longitudinal studies have examined change in neuropsychological functioning from before to after illness onset. The authors examined whether neuropsychological decline is unique to schizophrenia, whether it is generalized or confined to particular mental functions, and whether individuals with schizophrenia also have cognitive problems in everyday life. METHOD: Participants were members of a representative cohort of 1,037 individuals born in Dunedin, New Zealand, in 1972 and 1973 and followed prospectively to age 38, with 95% retention. Assessment of IQ and specific neuropsychological functions was conducted at ages 7, 9, 11, and 13, and again at age 38. Informants also reported on any cognitive problems at age 38. RESULTS: Individuals with schizophrenia exhibited declines in IQ and in a range of mental functions, particularly those tapping processing speed, learning, executive function, and motor function. There was little evidence of decline in verbal abilities or delayed memory, however, and the developmental progression of deficits in schizophrenia differed across mental functions. Processing speed deficits increased gradually from childhood to beyond the early teen years, whereas verbal deficits emerged early but remained static thereafter. Neuropsychological decline was specific to schizophrenia, as no evidence of decline was apparent among individuals with persistent depression, children with mild cognitive impairment, individuals matched on childhood risk factors for schizophrenia, and psychiatrically healthy individuals. Informants also noticed more cognitive problems in individuals with schizophrenia. CONCLUSIONS: There is substantial neuropsychological decline in schizophrenia from the premorbid to the postonset period, but the extent and developmental progression of decline varies across mental functions. Findings suggest that different pathophysiological mechanisms may underlie deficits in different mental functions.}, Doi = {10.1176/appi.ajp.2013.12111438}, Key = {fds273348} } @article{fds273353, Author = {Mazhari, S and Parvaresh, N and Eslami Shahrbabaki and M and Sadeghi, MM and Nakhaee, N and Keefe, RSE}, Title = {Validation of the Persian version of the brief assessment of cognition in schizophrenia in patients with schizophrenia and healthy controls.}, Journal = {Psychiatry and Clinical Neurosciences}, Volume = {68}, Number = {2}, Pages = {160-166}, Year = {2014}, Month = {February}, ISSN = {1323-1316}, url = {http://dx.doi.org/10.1111/pcn.12107}, Abstract = {AIMS: The Brief Assessment of Cognition in Schizophrenia (BACS) is designed for assessment of cognitive function in patients with schizophrenia. Versions of the BACS in English and other languages have been shown to be as sensitive to cognitive dysfunction as a standard test battery, with the advantage of brief administration and scoring time. The present study aimed to test the concurrent validity of the Persian version of the BACS (Persian-BACS). METHODS: A group of 50 patients with schizophrenia-spectrum disorders and a group of 50 healthy controls received the Persian-BACS in a first session, and in a second session a standard neurocognitive battery. RESULTS: Cronbach's alpha for the Persian-BACS was 0.74. All the Persian-BACS subscales were significantly correlated with the corresponding standard neurocognitive subscales and the Pearson correlation of the composite scores from the two instruments was 0.71. Moreover, a one-factor solution was found that accounted for 67.9% of the variance. Finally, the Persian-BACS demonstrated high ability to discriminate patients with schizophrenia from healthy controls. CONCLUSION: Good psychometric properties of the Persian-BACS suggest that it is a useful tool for assessing cognition in schizophrenic patients with Persian as their primary language.}, Doi = {10.1111/pcn.12107}, Key = {fds273353} } @article{fds273329, Author = {Ruse, SA and Harvey, PD and Davis, VG and Atkins, AS and Fox, KH and Keefe, RSE}, Title = {Virtual Reality Functional Capacity Assessment In Schizophrenia: Preliminary Data Regarding Feasibility and Correlations with Cognitive and Functional Capacity Performance.}, Journal = {Schizophrenia Research. Cognition}, Volume = {1}, Number = {1}, Pages = {e21-e26}, Year = {2014}, Month = {March}, ISSN = {2215-0013}, url = {http://dx.doi.org/10.1016/j.scog.2014.01.004}, Abstract = {INTRODUCTION: Assessment of functional capacity is an intrinsic part of determining the functional relevance of response to treatment of cognitive impairment in schizophrenia. Existing methods are highly and consistently correlated with performance on neuropsychological tests, but most current assessments of functional capacity are still paper and pencil simulations. We developed a computerized virtual reality assessment that contains all of the components of a shopping trip. METHODS: We administered the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) to 54 healthy controls and to 51 people with schizophrenia to test its feasibility. Dependent variables for the VRFCAT included time to completion and errors on 12 objectives and the number of times that an individual failed to complete an objective. The MATRICS Consensus Cognitive Battery (MCCB) and a standard functional capacity measure, the UCSD Performance-Based Skills Assessment-Brief (UPSA-B) were administered to the patients with schizophrenia. RESULTS: Patients with schizophrenia performed more poorly than healthy controls on 10/11 of the time variables, as well as 2/12 error scores and 2/12 failed objectives. Pearson correlations for 7 of 15 VRFCAT variables with MCCB composite scores were statistically significant. CONCLUSION: These results provide support for the possibility of computerized functional capacity assessment, but more substantial studies are required.}, Doi = {10.1016/j.scog.2014.01.004}, Key = {fds273329} } @article{fds371750, Author = {Kelly, DL and Sullivan, KM and Wehring, HJ and McEvoy, JP and Keefe, R and McMahon, RP and Gold, JM and Feldman, S and Warfel, C and Kearns, AM and Osing, J and Russ, J and Vyas, G and Richardson, CM and August, S and Buchanan, RW}, Title = {ADJUNCTIVE MINOCYCLINE IN CLOZAPINE TREATED SCHIZOPHRENIA PATIENTS}, Journal = {Schizophrenia Research}, Volume = {153}, Pages = {S79-S79}, Publisher = {Elsevier BV}, Year = {2014}, Month = {April}, url = {http://dx.doi.org/10.1016/s0920-9964(14)70257-9}, Doi = {10.1016/s0920-9964(14)70257-9}, Key = {fds371750} } @article{fds371751, Author = {Lam, M and See, AY and Lee, J and Kang, S and Rapisarda, A and Kraus, M and Keefe, R and Collinson, S}, Title = {Poster #T129 NEUROCOGNITIVE ARCHITECTURE OF SCHIZOTYPY IN AN ASIAN POPULATION}, Journal = {Schizophrenia Research}, Volume = {153}, Pages = {S335-S336}, Publisher = {Elsevier BV}, Year = {2014}, Month = {April}, url = {http://dx.doi.org/10.1016/s0920-9964(14)70946-6}, Doi = {10.1016/s0920-9964(14)70946-6}, Key = {fds371751} } @article{fds371752, Author = {Lam, M and Collinson, S and Eng, GK and Rapisarda, A and Kraus, M and Lee, J and Chong, SA and Keefe, R}, Title = {Poster #M186 NEUROCOGNITIVE ARCHITECTURE OF SCHIZOPHRENIA}, Journal = {Schizophrenia Research}, Volume = {153}, Pages = {S258-S258}, Publisher = {Elsevier BV}, Year = {2014}, Month = {April}, url = {http://dx.doi.org/10.1016/s0920-9964(14)70736-4}, Doi = {10.1016/s0920-9964(14)70736-4}, Key = {fds371752} } @article{fds371753, Author = {Huang, W and Lee, J and Lam, M and Rapisarda, A and Kraus, M and Keefe, R}, Title = {Poster #S188 THE ROLE OF COGNITIVE RESERVE IN PREDICTING NEUROPSYCHOLOGICAL OUTCOME IN SCHIZOPHRENIA}, Journal = {Schizophrenia Research}, Volume = {153}, Pages = {S157-S158}, Publisher = {Elsevier BV}, Year = {2014}, Month = {April}, url = {http://dx.doi.org/10.1016/s0920-9964(14)70467-0}, Doi = {10.1016/s0920-9964(14)70467-0}, Key = {fds371753} } @article{fds371772, Author = {Hilt, D and Lombardo, I and Gawryl, M and Dgetluck, N and Keefe, R}, Title = {Poster #T94 OPTIMIZING TREATMENT AND SIGNAL DETECTION WITH EVP-6124 IN A CIAS PHASE 2B STUDY}, Journal = {Schizophrenia Research}, Volume = {153}, Pages = {S322-S322}, Publisher = {Elsevier BV}, Year = {2014}, Month = {April}, url = {http://dx.doi.org/10.1016/s0920-9964(14)70911-9}, Doi = {10.1016/s0920-9964(14)70911-9}, Key = {fds371772} } @article{fds273317, Author = {Ruse, SA and Davis, VG and Atkins, AS and Krishnan, KRR and Fox, KH and Harvey, PD and Keefe, RSE}, Title = {Development of a virtual reality assessment of everyday living skills.}, Journal = {Journal of Visualized Experiments : Jove}, Number = {86}, Year = {2014}, Month = {April}, url = {http://dx.doi.org/10.3791/51405}, Abstract = {Cognitive impairments affect the majority of patients with schizophrenia and these impairments predict poor long term psychosocial outcomes. Treatment studies aimed at cognitive impairment in patients with schizophrenia not only require demonstration of improvements on cognitive tests, but also evidence that any cognitive changes lead to clinically meaningful improvements. Measures of "functional capacity" index the extent to which individuals have the potential to perform skills required for real world functioning. Current data do not support the recommendation of any single instrument for measurement of functional capacity. The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a novel, interactive gaming based measure of functional capacity that uses a realistic simulated environment to recreate routine activities of daily living. Studies are currently underway to evaluate and establish the VRFCAT's sensitivity, reliability, validity, and practicality. This new measure of functional capacity is practical, relevant, easy to use, and has several features that improve validity and sensitivity of measurement of function in clinical trials of patients with CNS disorders.}, Doi = {10.3791/51405}, Key = {fds273317} } @article{fds273346, Author = {Madhoo, M and Keefe, RSE and Roth, RM and Sambunaris, A and Wu, J and Trivedi, MH and Anderson, CS and Lasser, R}, Title = {Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder.}, Journal = {Neuropsychopharmacology}, Volume = {39}, Number = {6}, Pages = {1388-1398}, Year = {2014}, Month = {May}, ISSN = {0893-133X}, url = {http://dx.doi.org/10.1038/npp.2013.334}, Abstract = {Evaluate lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy for executive dysfunction in partially or fully remitted major depressive disorder (MDD). This randomized, placebo-controlled study (NCT00985725) enrolled 143 adults (18-55 years) with mild MDD (Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤ 18) and executive dysfunction (Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Self-Report Global Executive Composite (GEC) T score ≥ 60) on stable antidepressant monotherapy for ≥ 8 weeks. After 2 weeks of screening, participants were randomized to 9 weeks of double-blind LDX (20-70 mg/day) or placebo augmentation, followed by 2 weeks of single-blind placebo. The primary end point was change from baseline to week 9/end of study (EOS) in BRIEF-A Self-Report GEC T score; secondary assessments included the BRIEF-A Informant Report, MADRS, and treatment-emergent adverse events (TEAEs). Of 143 randomized participants, 119 completed double-blind treatment (placebo, n=59; LDX, n=60). Mean ± standard deviation (SD) BRIEF-A GEC T scores decreased from baseline (placebo, 74.2 ± 8.88; LDX, 76.8 ± 9.66) to week 9/EOS (placebo, 61.4 ± 14.61; LDX, 55.2 ± 16.15); the LS mean (95% CI) treatment difference significantly favored LDX (-8.0 (-12.7, -3.3); P=0.0009). The LS mean (95% CI) treatment difference for MADRS total score also significantly favored LDX (-1.9 (-3.7, 0.0); P=0.0465). TEAE rates were 73.6% with placebo and 78.9% with LDX; serious TEAE rates were 4.2 and 2.8%. In this trial, LDX augmentation significantly improved executive dysfunction and depressive symptoms in participants with mild MDD. The safety profile of LDX was consistent with prior studies in adults with attention-deficit/hyperactivity disorder.}, Doi = {10.1038/npp.2013.334}, Key = {fds273346} } @article{fds273345, Author = {Umbricht, D and Keefe, RSE and Murray, S and Lowe, DA and Porter, R and Garibaldi, G and Santarelli, L}, Title = {A randomized, placebo-controlled study investigating the nicotinic α7 agonist, RG3487, for cognitive deficits in schizophrenia.}, Journal = {Neuropsychopharmacology}, Volume = {39}, Number = {7}, Pages = {1568-1577}, Year = {2014}, Month = {June}, ISSN = {0893-133X}, url = {http://dx.doi.org/10.1038/npp.2014.17}, Abstract = {Effective treatments for cognitive impairment associated with schizophrenia (CIAS) remain an unmet need. Nicotinic α7 receptor agonists may be effective in CIAS. This 8-week (week 1, inpatient; weeks 2-8, outpatient), double-blind, randomized study used Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) guidelines to investigate the nicotinic α7 partial agonist RG3487 (formerly MEM3454) in CIAS; 215 patients with chronic stable schizophrenia received placebo or RG3487 (5, 15, or 50 mg) added to ongoing treatment with risperidone, paliperidone, or aripiprazole. Primary end point was baseline to week 8 change in MATRICS Consensus Cognitive Battery (MCCB) composite t-score. Secondary outcomes were change in MCCB domain and negative symptom assessment (NSA) scores. The study did not allow for evaluation of nonsmokers. Each RG3487 dose was evaluated using a mixed-effects model repeated measures approach. Mean (SD) baseline MCCB composite t-score was 28.3 (12.0). No significant effect on MCCB composite t-scores was observed with RG3487 (adjusted mean difference (SE) vs placebo: 5 mg: 0.11 (1.39); 15 mg: -1.95 (1.39); 50 mg: -1.13 (1.37); p = 0.2-0.9). RG3487 did not improve MCCB domain scores. In a post hoc analysis of patients with moderate negative symptoms, 5 and 50 mg RG3487 vs placebo significantly improved NSA total (-4.45 (p = 0.04) and -4.75 (p = 0.02), respectively) and global (-0.39 (p = 0.04) and -0.55 (p = 0.003), respectively) scores. The MCCB did not lead to higher than expected patient withdrawal. RG3487 was generally well tolerated. In patients with stable schizophrenia, RG3487 did not improve cognitive deficits, as assessed by the MCCB; however, in patients with moderate negative symptoms, a post hoc analysis revealed significant improvement of negative symptoms.}, Doi = {10.1038/npp.2014.17}, Key = {fds273345} } @article{fds273332, Author = {Dandash, O and Fornito, A and Lee, J and Keefe, RSE and Chee, MWL and Adcock, RA and Pantelis, C and Wood, SJ and Harrison, BJ}, Title = {Altered striatal functional connectivity in subjects with an at-risk mental state for psychosis.}, Journal = {Schizophrenia Bulletin}, Volume = {40}, Number = {4}, Pages = {904-913}, Year = {2014}, Month = {July}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbt093}, Abstract = {Recent functional imaging work in individuals experiencing an at-risk mental state (ARMS) for psychosis has implicated dorsal striatal abnormalities in the emergence of psychotic symptoms, contrasting with earlier findings implicating the ventral striatum. Our aims here were to characterize putative dorsal and ventral striatal circuit-level abnormalities in ARMS individuals using resting-state functional magnetic resonance imaging (fMRI) and to investigate their relationship to positive psychotic symptoms. Resting-state fMRI was acquired in 74 ARMS subjects and 35 matched healthy controls. An established method for mapping ventral and dorsal striatal functional connectivity was used to examine corticostriatal functional integrity. Positive psychotic symptoms were assessed using the Comprehensive Assessment of At-Risk Mental State and the Positive and Negative Syndrome Scale. Compared with healthy controls, ARMS subjects showed reductions in functional connectivity between the dorsal caudate and right dorsolateral prefrontal cortex, left rostral medial prefrontal cortex, and thalamus, and between the dorsal putamen and left thalamic and lenticular nuclei. ARMS subjects also showed increased functional connectivity between the ventral putamen and the insula, frontal operculum, and superior temporal gyrus bilaterally. No differences in ventral striatal (ie, nucleus accumbens) functional connectivity were found. Altered functional connectivity in corticostriatal circuits were significantly correlated with positive psychotic symptoms. Together, these results suggest that risk for psychosis is mediated by a complex interplay of alterations in both dorsal and ventral corticostriatal systems.}, Doi = {10.1093/schbul/sbt093}, Key = {fds273332} } @article{fds273340, Author = {Rapisarda, A and Kraus, M and Tan, YW and Lam, M and Eng, GK and Lee, J and Subramaniam, M and Collinson, SL and Chong, SA and Keefe, RSE}, Title = {The continuous performance test, identical pairs: norms, reliability and performance in healthy controls and patients with schizophrenia in Singapore.}, Journal = {Schizophrenia Research}, Volume = {156}, Number = {2-3}, Pages = {233-240}, Year = {2014}, Month = {July}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2014.04.016}, Abstract = {AIM: To provide normative values for the healthy ethnic Chinese Singaporean population and a large sample of patients with schizophrenia for the Continuous Performance Task-Identical Pairs (CPT-IP). Participants Data were collected on 1011 healthy ethnic Chinese and 654 patients diagnosed with schizophrenia, all between 21 and 55 years of age. METHODS: Data were stratified by age and gender. The effects of age, gender and education were explored in patients and controls. Performance indices were assessed in their ability to predict group inclusion. Controls' performance was compared with that reported in a US sample. RESULTS: Performance was affected by age, sex, and education, with youth, male sex and higher education providing a performance advantage. Patients' performance was lower than controls' by more than 1 standard deviation, with the 3-digit d' score most significantly discriminating between controls and patients. The effects of socio-demographic factors on performance were in line with those conducted in the US and previously reported in the literature. CONCLUSIONS: This is the largest norming study ever conducted on the CPT-IP. It will enable investigators and clinicians to select appropriate indices to assess severity of cognitive decline and/or evaluate cognitive remediation therapy outcomes after taking into account age, gender and education factors.}, Doi = {10.1016/j.schres.2014.04.016}, Key = {fds273340} } @article{fds273321, Author = {Keefe, RSE and McClintock, SM and Roth, RM and Doraiswamy, PM and Tiger, S and Madhoo, M}, Title = {Cognitive effects of pharmacotherapy for major depressive disorder: a systematic review.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {75}, Number = {8}, Pages = {864-876}, Year = {2014}, Month = {August}, ISSN = {0160-6689}, url = {http://dx.doi.org/10.4088/JCP.13r08609}, Abstract = {OBJECTIVE: Cognitive impairment frequently accompanies major depressive disorder (MDD) and can persist during remission. This review examined pharmacotherapy effects on cognitive function in MDD. DATA SOURCES: PubMed and EMBASE searches were conducted on July 30, 2013, for English language reports of cognitive assessments following pharmacologic monotherapy or augmentation therapy in MDD. STUDY SELECTION: A total of 43 research reports were identified (31 monotherapy [8 placebo-controlled, 11 active-comparator, 12 open-label], 12 augmentation therapy [7 placebo-controlled, 5 open-label]). DATA EXTRACTION: Results reported in each publication were examined for open-label and placebo- or active comparator-controlled studies. RESULTS: Studies varied widely in terms of size (median, 50 participants; interquartile range, 21-143 participants), populations examined, duration (median, 8 weeks; interquartile range, 6-12 weeks), and neurocognitive assessments used. Most individual studies reported some benefit to cognition with pharmacotherapy, but there was no pattern of response in specific domains and only 12% of individually analyzed changes favored active treatment over placebo or untreated healthy controls. Sample weighted mean effect sizes revealed that verbal memory improved with monotherapy, while the largest treatment effect with augmentation therapy was for visual memory. CONCLUSIONS: Pharmacotherapy may have benefit in reducing cognitive impairment in MDD, with augmentation therapy being a potential approach for addressing cognitive deficits that persist after monotherapy has brought about clinical response or remission. However, given the wide variability in study design and treatment duration across studies, these findings should be interpreted cautiously. More definitive research is required before firm conclusions can be reached.}, Doi = {10.4088/JCP.13r08609}, Key = {fds273321} } @article{fds273341, Author = {Yong, E and Barbato, M and Penn, DL and Keefe, RSE and Woods, SW and Perkins, DO and Addington, J}, Title = {Exploratory analysis of social cognition and neurocognition in individuals at clinical high risk for psychosis.}, Journal = {Psychiatry Research}, Volume = {218}, Number = {1-2}, Pages = {39-43}, Year = {2014}, Month = {August}, ISSN = {0165-1781}, url = {http://dx.doi.org/10.1016/j.psychres.2014.04.003}, Abstract = {Neurocognition and social cognition are separate but related constructs known to be impaired in schizophrenia. The aim of this study was to extend the current knowledge of the relationship between social cognition and neurocognition in individuals at clinical high risk (CHR) of developing psychosis by examining, in a large sample, the associations between a wide range of neurocognitive tasks and social cognition. Participants included 136 young people at CHR. Specific domains within neurocognition and social cognition were compared using Spearman correlations. Results showed that poor theory of mind correlated with low ratings on a wide range of neurocognitive tasks. Facial affect was more often associated with low ratings on spatial working memory and attention. These results support a link between neurocognition and social cognition even at this early stage of potential psychosis, with indication that poorer performance on social cognition may be associated with deficits in attention and working memory. Understanding these early associations may have implications for early intervention.}, Doi = {10.1016/j.psychres.2014.04.003}, Key = {fds273341} } @article{fds273320, Author = {Stout, JC and Queller, S and Baker, KN and Cowlishaw, S and Sampaio, C and Fitzer-Attas, C and Borowsky, B and HD-CAB Investigators}, Title = {HD-CAB: a cognitive assessment battery for clinical trials in Huntington's disease 1,2,3.}, Journal = {Mov Disord}, Volume = {29}, Number = {10}, Pages = {1281-1288}, Year = {2014}, Month = {September}, ISSN = {0885-3185}, url = {http://dx.doi.org/10.1002/mds.25964}, Abstract = {Cognitive dysfunction is central to Huntington's disease (HD) and undermines quality of life. Clinical trials are now targeting cognitive outcomes in HD; however, no cognitive battery has been optimized for HD clinical trials. We evaluated 16 cognitive tests in a 20-site, five-country, observational study designed to mimic aspects of a clinical trial (e.g., data collection managed by a contract research organization, repeated testing, prespecified statistical analyses). Fifty-five early HD, 103 premanifest HD (pre-HD), and 105 controls were tested at visit 1, visit 2 (1-3 days later), and visit 3 (5-7 weeks after visit 1). For inclusion in a recommended battery, tests were evaluated for sensitivity, practice effects, reliability, domain coverage, feasibility, and tolerability. Most tests differentiated controls from pre-HD and early HD and showed excellent psychometric properties. We selected six tests to constitute the Huntington's Disease Cognitive Assessment Battery (HD-CAB): Symbol Digit Modalities Test, Paced Tapping, One Touch Stockings of Cambridge (abbreviated), Emotion Recognition, Trail Making B, and the Hopkins Verbal Learning Test. These tests demonstrated sensitivity to disease status (Cohen's d effect sizes: early HD= -1.38 to -1.90 and pre-HD= -0.41 to -0.78), and acceptable reliability (r's 0.73-0.93). A composite score yielded large effect sizes (early HD = -2.44 and pre-HD = -0.87) and high reliability (r = 0.95). HD-CAB is the first cognitive battery designed specifically for use in late premanifest and early HD clinical trials. Adoption of the HD-CAB will facilitate evaluation of treatments to improve cognition in HD.}, Doi = {10.1002/mds.25964}, Key = {fds273320} } @article{fds273325, Author = {Reilly, JL and Frankovich, K and Hill, S and Gershon, ES and Keefe, RSE and Keshavan, MS and Pearlson, GD and Tamminga, CA and Sweeney, JA}, Title = {Elevated antisaccade error rate as an intermediate phenotype for psychosis across diagnostic categories.}, Journal = {Schizophrenia Bulletin}, Volume = {40}, Number = {5}, Pages = {1011-1021}, Year = {2014}, Month = {September}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbt132}, Abstract = {BACKGROUND: Elevated antisaccade error rate, reflecting problems with inhibitory behavioral control, is a promising intermediate phenotype for schizophrenia. Here, we consider whether it marks liability across psychotic disorders via common or different neurophysiological mechanisms and whether it represents a neurocognitive risk indicator apart from the generalized cognitive deficit. METHODS: Schizophrenia (n = 267), schizoaffective (n = 150), and psychotic bipolar (n = 202) probands, their first-degree relatives (ns = 304, 193, 242, respectively), and healthy controls (n = 244), participating in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium, performed antisaccade and prosaccade tasks and completed a neuropsychological battery. RESULTS: Antisaccade error rate was elevated in proband groups with greatest deficit observed in schizophrenia and was unrelated to symptoms and antipsychotic treatment. Increased error rate was also observed among relatives, even those without history of psychosis or psychosis spectrum personality traits. Relatives' deficits were similar across proband diagnoses. Error rate was familial and remained elevated in proband and relative groups after accounting for generalized cognitive impairment. Speed of attentional shifting, indexed by prosaccade latency, was similarly influenced in all groups by manipulations that freed vs increasingly engaged attention systems and was inversely associated with antisaccade error rate in all but schizophrenia probands. CONCLUSIONS: These findings indicate that elevated antisaccade error rate represents an intermediate phenotype for psychosis across diagnostic categories, and that it tracks risk beyond that attributable to the generalized cognitive deficit. The greater severity of antisaccade impairment in schizophrenia and its independence from attention shifting processes suggest more severe and specific prefrontal inhibitory control deficits in this disorder.}, Doi = {10.1093/schbul/sbt132}, Key = {fds273325} } @article{fds273326, Author = {Keefe, RSE}, Title = {Cognition and motivation as treatment targets in schizophrenia.}, Journal = {Jama Psychiatry}, Volume = {71}, Number = {9}, Pages = {987-988}, Year = {2014}, Month = {September}, ISSN = {2168-622X}, url = {http://dx.doi.org/10.1001/jamapsychiatry.2014.1281}, Doi = {10.1001/jamapsychiatry.2014.1281}, Key = {fds273326} } @article{fds273331, Author = {Marx, CE and Lee, J and Subramaniam, M and Rapisarda, A and Bautista, DCT and Chan, E and Kilts, JD and Buchanan, RW and Wai, EP and Verma, S and Sim, K and Hariram, J and Jacob, R and Keefe, RSE and Chong, SA}, Title = {Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia.}, Journal = {Psychopharmacology (Berl)}, Volume = {231}, Number = {17}, Pages = {3647-3662}, Year = {2014}, Month = {September}, ISSN = {0033-3158}, url = {http://dx.doi.org/10.1007/s00213-014-3673-4}, Abstract = {RATIONALE: Preclinical and clinical data suggest that pregnenolone may be a promising therapeutic in schizophrenia. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Treatment with pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABAA receptor responses) and pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids. OBJECTIVE: The objective of this study is to conduct a randomized controlled trial of adjunctive pregnenolone in schizophrenia. METHODS: Following a placebo lead-in, 120 participants were randomized to pregnenolone or placebo for 8 weeks (Institute for Mental Health, Singapore). Primary endpoints were changes in MATRICS Consensus Cognitive Battery (MCCB) composite scores (cognitive symptoms), UCSD Performance-based Skills Assessment-Brief (UPSA-B) composite scores (functional capacity), and Scale for Assessment of Negative Symptoms (SANS) total scores (negative symptoms). A modified intent-to-treat analysis approach was utilized. RESULTS: No significant changes compared to placebo were demonstrated in composite MCCB scores. In contrast, participants randomized to pregnenolone (n = 56) demonstrated greater improvements in functional capacity (UPSA-B composite changes) compared to placebo (n = 55), p = 0.03. Pregnenolone was also superior to placebo in the communication subscale of the UPSA-B (p < 0.001). Serum pregnenolone changes post-treatment were correlated with UPSA-B composite score changes in females (r s = 0.497, p < 0.042, n = 17) but not in males. Mean total SANS scores were very low at baseline and did not improve further post-treatment. Pregnenolone was well-tolerated. CONCLUSIONS: Pregnenolone improved functional capacity in participants with schizophrenia, but did not improve cognitive symptoms over an 8-week treatment period. Neurosteroid changes correlated with functional improvements in female participants. Neurosteroid interventions may exhibit promise as new therapeutic leads for schizophrenia.}, Doi = {10.1007/s00213-014-3673-4}, Key = {fds273331} } @article{fds273334, Author = {Keefe, RSE and Fox, KH and Davis, VG and Kennel, C and Walker, TM and Burdick, KE and Harvey, PD}, Title = {The Brief Assessment of Cognition In Affective Disorders (BAC-A):performance of patients with bipolar depression and healthy controls.}, Journal = {J Affect Disord}, Volume = {166}, Pages = {86-92}, Year = {2014}, Month = {September}, ISSN = {0165-0327}, url = {http://dx.doi.org/10.1016/j.jad.2014.05.002}, Abstract = {BACKGROUND: Cognitive deficits in bipolar disorder are significant enough to impact everyday functioning. A key question for treatments aimed at cognition is which cognitive domains are most affected by bipolar disorder and which cognitive tests have the best psychometric characteristics for this population. METHOD: 432 patients assessed at study entry in a treatment study of bipolar depression were assessed with a version of a new cognitive measure - the Brief Assessment of Cognition in Affective Disorder (BAC-A), which assesses traditional cognitive constructs with six subtests measuring memory, processing speed, working memory, and reasoning and problem solving, and a new measure of affective processing. From the cohort of 432 patients, 309 were selected based upon their demographic similarities to a previously collected healthy control sample of 309 subjects. Patients and controls completed the traditional cognitive tests and the Affective Processing Test. Results. Patients with bipolar depression and healthy controls differed significantly on all cognitive measures (P<0.001). The two alternate forms of the Affective Processing Test were very similar in both groups. The most robust discriminator of the groups was a composite score that combined the six core cognitive subtests of the Brief Assessment of Cognition (BAC) with two of the measures from the Affective Processing Test. LIMITATIONS: Test-retest reliabilities of the individual Affective Processing Test measures were low. CONCLUSION: The BAC-A is sensitive to the cognitive impairments in bipolar disorder patients in traditional neuropsychological domains and in cognitive processes believed to be specifically impaired in affective disorders.}, Doi = {10.1016/j.jad.2014.05.002}, Key = {fds273334} } @article{fds273327, Author = {Gray, BE and McMahon, RP and Green, MF and Seidman, LJ and Mesholam-Gately, RI and Kern, RS and Nuechterlein, KH and Keefe, RS and Gold, JM}, Title = {Detecting reliable cognitive change in individual patients with the MATRICS Consensus Cognitive Battery.}, Journal = {Schizophrenia Research}, Volume = {159}, Number = {1}, Pages = {182-187}, Year = {2014}, Month = {October}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2014.07.032}, Abstract = {OBJECTIVE: Clinicians often need to evaluate the treatment response of an individual person and to know that observed change is true improvement or worsening beyond usual week-to-week changes. This paper gives clinicians tools to evaluate individual changes on the MATRICS Consensus Cognitive Battery (MCCB). We compare three different approaches: a descriptive analysis of MCCB test-retest performance with no intervention, a reliable change index (RCI) approach controlling for average practice effects, and a regression approach. METHOD: Data were gathered as part of the MATRICS PASS study (Nuechterlein et al., 2008). A total of 159 people with schizophrenia completed the MCCB at baseline and 4weeks later. Data were analyzed using an RCI and a regression formula establishing confidence intervals. RESULTS: The RCI and regression approaches agree within one point when baseline values are close to the sample mean. However, the regression approach offers more accurate limits for expected change at the tails of the distribution of baseline scores. CONCLUSIONS: Although both approaches have their merits, the regression approach provides the most accurate measure of significant change across the full range of scores. As the RCI does not account for regression to the mean and has confidence limits that remain constant across baseline scores, the RCI approach effectively gives narrower confidence limits around an inaccurately predicted average change value. Further, despite the high test-retest reliability of the MCCB, a change in an individual's score must be relatively large to be confident that it is beyond normal month-to-month variation.}, Doi = {10.1016/j.schres.2014.07.032}, Key = {fds273327} } @article{fds273328, Author = {Hufford, MR and Davis, VG and Hilt, D and Dgetluck, N and Geffen, Y and Loebel, A and Haig, G and Santarelli, L and Keefe, RSE}, Title = {Circadian rhythms in cognitive functioning among patients with schizophrenia: impact on signal detection in clinical trials of potential pro-cognitive therapies.}, Journal = {Schizophrenia Research}, Volume = {159}, Number = {1}, Pages = {205-210}, Year = {2014}, Month = {October}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2014.07.018}, Abstract = {OBJECTIVE: Cognition is affected by circadian rhythms over the course of a day. Circadian rhythms in cognitive functioning are driven by a variety of both endogenous and exogenous factors. Patients with schizophrenia are known to have disturbed circadian rhythms that can affect their cognitive functioning. We examined the impact of time of day on cognitive test scores from subjects participating in clinical trials of potential pro-cognitive therapies for schizophrenia and then explored how this diurnal variation affected signal detection. METHOD: Baseline data from 8 separate schizophrenia clinical trials using the MATRICS Consensus Cognitive Battery (MCCB) were aggregated (Total N=2032). The MCCB assessments were divided into five 2-hour time intervals based on the start-time of the assessments (varying from 8:00 am to 5:59 pm) and then analyzed for differences by time interval. Next, data from two Phase 2 schizophrenia clinical trials of potential pro-cognitive therapies were analyzed to explore the impact of this diurnal variation on placebo separation. RESULTS: Time of day exerted a significant effect on baseline composite MCCB scores (p=.002). Follow-up comparisons revealed significant differences among multiple temporal epochs. In both Phase 2 clinical trials, subjects whose cognitive functioning was assessed at consistent times of day between their baseline and endpoint visits showed a more robust treatment response as compared to subjects assessed at inconsistent times of day. CONCLUSION: Cognitive functioning ebbs and flows over the course of the day. Maintaining consistency in the time of day of cognitive test administrations between visits can help to reduce the noise introduced by circadian rhythms, thereby enhancing signal detection in clinical trials of potential pro-cognitive therapies.}, Doi = {10.1016/j.schres.2014.07.018}, Key = {fds273328} } @article{fds273316, Author = {Ethridge, LE and Soilleux, M and Nakonezny, PA and Reilly, JL and Hill, SK and Keefe, RSE and Gershon, ES and Pearlson, GD and Tamminga, CA and Keshavan, MS and Sweeney, JA}, Title = {Behavioral response inhibition in psychotic disorders: diagnostic specificity, familiality and relation to generalized cognitive deficit.}, Journal = {Schizophrenia Research}, Volume = {159}, Number = {2-3}, Pages = {491-498}, Year = {2014}, Month = {November}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2014.08.025}, Abstract = {Difficulty inhibiting context-inappropriate behavior is a common deficit in psychotic disorders. The diagnostic specificity of this impairment, its familiality, and its degree of independence from the generalized cognitive deficit associated with psychotic disorders remain to be clarified. Schizophrenia, schizoaffective and bipolar patients with history of psychosis (n=523), their available first-degree biological relatives (n=656), and healthy participants (n=223) from the multi-site B-SNIP study completed a manual Stop Signal task. A nonlinear mixed model was used to fit logistic curves to success rates on Stop trials as a function of parametrically varied Stop Signal Delay. While schizophrenia patients had greater generalized cognitive deficit than bipolar patients, their deficits were similar on the Stop Signal task. Further, only bipolar patients showed impaired inhibitory control relative to healthy individuals after controlling for generalized cognitive deficit. Deficits accounted for by the generalized deficit were seen in relatives of schizophrenia and schizoaffective patients, but not in relatives of bipolar patients. In clinically stable patients with psychotic bipolar disorder, impaired inhibitory behavioral control was a specific cognitive impairment, distinct from the generalized neuropsychological impairment associated with psychotic disorders. Thus, in bipolar disorder with psychosis, a deficit in inhibitory control may contribute to risk for impulsive behavior. Because the deficit was not familial in bipolar families and showed a lack of independence from the generalized cognitive deficit in schizophrenia spectrum disorders, it appears to be a trait related to illness processes rather than one tracking familial risk factors.}, Doi = {10.1016/j.schres.2014.08.025}, Key = {fds273316} } @article{fds273336, Author = {Lam, M and Collinson, SL and Eng, GK and Rapisarda, A and Kraus, M and Lee, J and Chong, SA and Keefe, RSE}, Title = {Refining the latent structure of neuropsychological performance in schizophrenia.}, Journal = {Psychol Med}, Volume = {44}, Number = {16}, Pages = {3557-3570}, Year = {2014}, Month = {December}, ISSN = {0033-2917}, url = {http://dx.doi.org/10.1017/S0033291714001020}, Abstract = {BACKGROUND: Elucidating the cognitive architecture of schizophrenia promises to advance understanding of the clinical and biological substrates of the illness. Traditional cross-sectional neuropsychological approaches differentiate impaired from normal cognitive abilities but are limited in their ability to determine latent substructure. The current study examined the latent architecture of abnormal cognition in schizophrenia via a systematic approach. METHOD: Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were carried out on a large neuropsychological dataset including the Brief Assessment of Cognition in Schizophrenia, Continuous Performance Test, Wisconsin Card Sorting Test, Benton Judgment of Line Orientation Test, and Wechsler Abbreviated Scale of Intelligence matrix reasoning derived from 1012 English-speaking ethnic Chinese healthy controls and 707 schizophrenia cases recruited from in- and out-patient clinics. RESULTS: An initial six-factor model fit cognitive data in healthy and schizophrenia subjects. Further modeling, which accounted for methodological variance between tests, resulted in a three-factor model of executive functioning, vigilance/speed of processing and memory that appeared to best discriminate schizophrenia cases from controls. Factor analytic-derived g estimands and conventionally calculated g showed similar case-control discrimination. However, agreement analysis suggested systematic differences between both g indices. CONCLUSIONS: Factor structures derived in the current study were broadly similar to those reported previously. However, factor structures between schizophrenia subjects and healthy controls were different. Roles of factor analytic-derived g estimands and conventional composite score g were further discussed. Cognitive structures underlying cognitive deficits in schizophrenia may prove useful for interrogating biological substrates and enriching effect sizes for subsequent work.}, Doi = {10.1017/S0033291714001020}, Key = {fds273336} } @article{fds370735, Author = {Keefe, R and Ruse, S and Davis, V and Atkins, A and Patterson, T and Narasimhan, M and Harvey, PD}, Title = {VALIDATION OF A COMPUTERIZED ASSESSMENT OF FUNCTIONAL CAPACITY}, Journal = {Schizophrenia Bulletin}, Volume = {41}, Pages = {S177-S178}, Year = {2015}, Key = {fds370735} } @article{fds370736, Author = {Keefe, R and Atkins, A and Davis, V and Spagnola, N and Hilt, D and Dgetluck, N and Ruse, S and Patterson, T and Narasimhan, M and Harvey, PD}, Title = {THE SCHIZOPHRENIA COGNITION RATING SCALE: RELIABILITY, VALIDITY AND SENSITIVITY}, Journal = {Schizophrenia Bulletin}, Volume = {41}, Pages = {S51-S52}, Year = {2015}, Key = {fds370736} } @article{fds370737, Author = {Iwata, Y and Nakajima, S and Uchida, H and Suzuki, T and Keefe, R and Plitman, E and Chung, JK and Caravaggio, F and Gerretsen, P and Mimura, M and Graff-Guerrero, A}, Title = {Effects of Glutamate Modulators on Cognitive Impairments In Schizophrenia: A Meta-Analysis of Double-Blind Controlled Trials}, Journal = {Biological Psychiatry}, Volume = {77}, Number = {9}, Year = {2015}, Key = {fds370737} } @article{fds371771, Author = {Kalali, A and Keefe, R and Pappadopulos, E and Vance, M}, Title = {Results of a Survey of Clinician Rated Outcome Measures in International Cns Clinical Trials}, Journal = {Neuropsychopharmacology}, Volume = {40}, Pages = {S523-S524}, Year = {2015}, Key = {fds371771} } @article{fds273303, Author = {Harvey, PD and Keefe, RSE}, Title = {Methods for delivering and evaluating the efficacy of cognitive enhancement.}, Journal = {Handbook of Experimental Pharmacology}, Volume = {228}, Pages = {5-25}, Year = {2015}, ISSN = {0171-2004}, url = {http://dx.doi.org/10.1007/978-3-319-16522-6_1}, Abstract = {Cognitive deficits are related to impaired everyday functioning in multiple conditions and in healthy individuals. Treatment of cognitive functioning can be facilitated through either pharmacological or remediation strategies. The critical goals of cognitive enhancement are to improve everyday functioning in multiple domains. This chapter describes the strategies that are most desirable for the treatment of cognitive impairments and detection of potential benefits of treatment in cognitive and functional domains. These strategies include the use of performance-based assessments of cognition and functioning and the appropriate use of observational strategies to detect changes. Finally, we define several outcome-related goals and discuss the practicality of their measurement.}, Doi = {10.1007/978-3-319-16522-6_1}, Key = {fds273303} } @article{fds273305, Author = {McCleery, A and Green, MF and Hellemann, GS and Baade, LE and Gold, JM and Keefe, RSE and Kern, RS and Mesholam-Gately, RI and Seidman, LJ and Subotnik, KL and Ventura, J and Nuechterlein, KH}, Title = {Latent structure of cognition in schizophrenia: a confirmatory factor analysis of the MATRICS Consensus Cognitive Battery (MCCB).}, Journal = {Psychol Med}, Volume = {45}, Number = {12}, Pages = {2657-2666}, Year = {2015}, ISSN = {0033-2917}, url = {http://dx.doi.org/10.1017/S0033291715000641}, Abstract = {BACKGROUND: The number of separable cognitive dimensions in schizophrenia has been debated. Guided by the extant factor analytic literature, the NIMH Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative selected seven cognitive domains relevant to treatment studies in schizophrenia: speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. These domains are assessed in the MATRICS Consensus Cognitive Battery (MCCB). The aim of this study was to conduct a confirmatory factor analysis (CFA) of the beta battery of the MCCB to compare the fit of the MATRICS consensus seven-domain model to other models in the current literature on cognition in schizophrenia. METHOD: Using data from 281 schizophrenia outpatients, we compared the seven correlated factors model with alternative models. Specifically, we compared the 7-factor model to (a) a single-factor model, (b) a three correlated factors model including speed of processing, working memory, and general cognition, and (c) a hierarchical model in which seven first-order factors loaded onto a second-order general cognitive factor. RESULTS: Multiple fit indices indicated the seven correlated factors model was the best fit for the data and provided significant improvement in model fit beyond the comparison models. CONCLUSIONS: These results support the assessment of these seven cognitive dimensions in clinical trials of interventions to improve cognition in schizophrenia. Because these cognitive factors are separable to some degree, it is plausible that specific interventions may have differential effects on the domains.}, Doi = {10.1017/S0033291715000641}, Key = {fds273305} } @article{fds273315, Author = {Healey, KM and Combs, DR and Gibson, CM and Keefe, RSE and Roberts, DL and Penn, DL}, Title = {Observable Social Cognition--A Rating Scale: an interview-based assessment for schizophrenia.}, Journal = {Cogn Neuropsychiatry}, Volume = {20}, Number = {3}, Pages = {198-221}, Year = {2015}, ISSN = {1354-6805}, url = {http://dx.doi.org/10.1080/13546805.2014.999915}, Abstract = {INTRODUCTION: Individuals with schizophrenia consistently show impairments in social cognition (SC). SC has become a potential treatment target due to its association with functional outcomes. An alternative method of assessment is to administer an observer-based scale incorporating an informant's "first hand" impressions in ratings. METHODS: The present study used the Observable Social Cognition: A Rating Scale (OSCARS) in 62 outpatients and 50 non-psychiatric controls (NPCs) to assess performance in domains of SC (e.g. emotion perception, theory of mind). RESULTS: The OSCARS demonstrated sufficient internal consistency and test-retest reliability. Construct validity was assessed through an exploratory factor analysis. Patient OSCARS indices were not significantly correlated with measures of SC with the exception of aggressive attributional style. Individuals with less impairment in SC reacted more aggressively to ambiguous situations. NPC OSCARS were significantly correlated with measures of theory of mind and attributional style. In a combined sample of patients and controls, six of eight items were significantly correlated with the SC task assessing the same domain, providing modest evidence of convergent validity. In patients, the OSCARS was significantly correlated with measures of functional outcome and neurocognition. Last, the OSCARS was found to be significantly associated with functional outcome after the influence of objective measures of SC was statistically removed. CONCLUSIONS: The present study provides preliminary evidence that the OSCARS may be useful for clinicians in collecting data about patients' potential real-world SC deficits, in turn increasing the degree to which these impairments may be targeted in treatment.}, Doi = {10.1080/13546805.2014.999915}, Key = {fds273315} } @article{fds273318, Author = {Bauer, IE and Keefe, RSE and Sanches, M and Suchting, R and Green, CE and Soares, JC}, Title = {Evaluation of cognitive function in bipolar disorder using the Brief Assessment of Cognition in Affective Disorders (BAC-A).}, Journal = {J Psychiatr Res}, Volume = {60}, Pages = {81-86}, Year = {2015}, Month = {January}, ISSN = {0022-3956}, url = {http://dx.doi.org/10.1016/j.jpsychires.2014.10.002}, Abstract = {BACKGROUND: Although cognitive impairment is a core feature of bipolar disorder (BD) there is no instrument of choice for the assessment of bipolar patients. The aim of this study is to assess cognitive performance using the Brief Assessment of Cognition in Affective Disorders (BAC-A), a comprehensive test battery developed specifically for BD, and determine its suitability to estimate global functioning. METHODS: The BAC-A was administered to 93 BD patients (M ± S.E: 35.18 ± 1.39 years) and 56 healthy controls (HC - M ± S.E: 36.17 ± 1.91 years). The scores of the BAC-A were combined in eight summary scores: visuomotor, immediate affective and non-affective memory, verbal fluency, delayed affective and non-affective memory, inhibition, and problem solving. Post hoc analyses were performed on subtests of the summary scores found to be significantly different between BD patients and HC. Correlational analyses explored the association between the Global Assessment of Functioning (GAF) score and cognitive functioning. RESULTS: Compared to HC, BD patients showed a significant impairment in short-term non-affective memory and verbal fluency. Poorer performance in verbal memory and verbal fluency summary scores correlated positively with reduced GAF. CONCLUSIONS: Our results are consistent with previous reports of verbal memory and verbal fluency impairment in BD. The deficits in short-term memory and semantic fluency may indicate inefficient learning strategies and/or difficulties in retrieving information. The BAC-A could be used to estimate global functioning in BD patients.}, Doi = {10.1016/j.jpsychires.2014.10.002}, Key = {fds273318} } @article{fds273335, Author = {Lui, S and Yao, L and Xiao, Y and Keedy, SK and Reilly, JL and Keefe, RS and Tamminga, CA and Keshavan, MS and Pearlson, GD and Gong, Q and Sweeney, JA}, Title = {Resting-state brain function in schizophrenia and psychotic bipolar probands and their first-degree relatives.}, Journal = {Psychol Med}, Volume = {45}, Number = {1}, Pages = {97-108}, Year = {2015}, Month = {January}, ISSN = {0033-2917}, url = {http://dx.doi.org/10.1017/S003329171400110X}, Abstract = {BACKGROUND: Schizophrenia (SCZ) and psychotic bipolar disorder (PBD) share considerable overlap in clinical features, genetic risk factors and co-occurrence among relatives. The common and unique functional cerebral deficits in these disorders, and in unaffected relatives, remain to be identified. METHOD: A total of 59 healthy controls, 37 SCZ and 57 PBD probands and their unaffected first-degree relatives (38 and 28, respectively) were studied using resting-state functional magnetic resonance imaging (rfMRI). Regional cerebral function was evaluated by measuring the amplitude of low-frequency fluctuations (ALFF). Areas with ALFF alterations were used as seeds in whole-brain functional connectivity analysis. We then tested whether abnormalities identified in probands were present in unaffected relatives. RESULTS: SCZ and PBD probands both demonstrated regional hypoactivity in the orbital frontal cortex and cingulate gyrus, as well as abnormal connectivity within striatal-thalamo-cortical networks. SCZ probands showed greater and more widely distributed ALFF alterations including the thalamus and bilateral parahippocampal gyri. Increased parahippocampal ALFF was related to positive symptoms and cognitive deficit. PBD patients showed uniquely increased functional connectivity between the thalamus and bilateral insula. Only PBD relatives showed abnormal connectivity within striatal-thalamo-cortical networks seen in both proband groups. CONCLUSIONS: The present findings reveal a common pattern of deficits in frontostriatal circuitry across SCZ and PBD, and unique regional and functional connectivity abnormalities that distinguish them. The abnormal network connectivity in PBD relatives that was present in both proband groups may reflect genetic susceptibility associated with risk for psychosis, but within-family associations of this measure were not high.}, Doi = {10.1017/S003329171400110X}, Key = {fds273335} } @article{fds273330, Author = {Keefe, RSE and Davis, VG and Spagnola, NB and Hilt, D and Dgetluck, N and Ruse, S and Patterson, TD and Narasimhan, M and Harvey, PD}, Title = {Reliability, validity and treatment sensitivity of the Schizophrenia Cognition Rating Scale.}, Journal = {Eur Neuropsychopharmacol}, Volume = {25}, Number = {2}, Pages = {176-184}, Year = {2015}, Month = {February}, ISSN = {0924-977X}, url = {http://dx.doi.org/10.1016/j.euroneuro.2014.06.009}, Abstract = {Cognitive functioning can be assessed with performance-based assessments such as neuropsychological tests and with interview-based assessments. Both assessment methods have the potential to assess whether treatments for schizophrenia improve clinically relevant aspects of cognitive impairment. However, little is known about the reliability, validity and treatment responsiveness of interview-based measures, especially in the context of clinical trials. Data from two studies were utilized to assess these features of the Schizophrenia Cognition Rating Scale (SCoRS). One of the studies was a validation study involving 79 patients with schizophrenia assessed at 3 academic research centers in the US. The other study was a 32-site clinical trial conducted in the US and Europe comparing the effects of encenicline, an alpha-7 nicotine agonist, to placebo in 319 patients with schizophrenia. The SCoRS interviewer ratings demonstrated excellent test-retest reliability in several different circumstances, including those that did not involve treatment (ICC> 0.90), and during treatment (ICC>0.80). SCoRS interviewer ratings were related to cognitive performance as measured by the MCCB (r=-0.35), and demonstrated significant sensitivity to treatment with encenicline compared to placebo (P<.001). These data suggest that the SCoRS has potential as a clinically relevant measure in clinical trials aiming to improve cognition in schizophrenia, and may be useful for clinical practice. The weaknesses of the SCoRS include its reliance on informant information, which is not available for some patients, and reduced validity when patient's self-report is the sole information source.}, Doi = {10.1016/j.euroneuro.2014.06.009}, Key = {fds273330} } @article{fds354389, Author = {Cella, M and Stahl, D and Morris, S and Keefe, R and Bell, MD and Heinssen, R and Wykes, T}, Title = {EFFECTS OF COGNITIVE REMEDIATION ON NEGATIVE SYMPTOMS DIMENSIONS: EXPLORING THE ROLE OF WORKING MEMORY}, Journal = {Schizophrenia Bulletin}, Volume = {41}, Pages = {S40-S41}, Publisher = {OXFORD UNIV PRESS}, Year = {2015}, Month = {March}, Key = {fds354389} } @article{fds370536, Author = {Sullivan, KM and McEvoy, J and McMahon, RP and Liu, F and Wehring, HJ and Vyas, G and Richardson, CM and Gale, E and Feldman, SM and Russ, JC and Keefe, R and Buchanan, RW and Kelly, DL}, Title = {ADJUNCTIVE MINOCYCLINE IN CLOZAPINE TREATED SCHIZOPHRENIA PATIENTS: IMPROVEMENTS IN GENERAL HEALTH AND WELL-BEING}, Journal = {Schizophrenia Bulletin}, Volume = {41}, Pages = {S335-S335}, Publisher = {OXFORD UNIV PRESS}, Year = {2015}, Month = {March}, Key = {fds370536} } @article{fds370578, Author = {Reilly, JL and Hill, S and Rubin, LH and Ruocco, A and Keefe, R and Keshavan, MS and Pearlson, G and Tamminga, C and Sweeney, JA}, Title = {GENERALIZED AND SPECIFIC COGNITIVE DEFICITS ACROSS THE PSYCHOSIS SPECTRUM}, Journal = {Schizophrenia Bulletin}, Volume = {41}, Pages = {S94-S94}, Publisher = {OXFORD UNIV PRESS}, Year = {2015}, Month = {March}, Key = {fds370578} } @article{fds370650, Author = {Lee, S-A and Lam, M and Rapisarda, A and Kraus, M and Keefe, R and Lee, J}, Title = {INVESTIGATING THE STRUCTURE OF SEMANTIC ORGANIZATION IN SCHIZOPHRENIA}, Journal = {Schizophrenia Bulletin}, Volume = {41}, Pages = {S85-S85}, Publisher = {OXFORD UNIV PRESS}, Year = {2015}, Month = {March}, Key = {fds370650} } @article{fds370651, Author = {Lam, M and Lee, J and Keefe, R and Teo, YY}, Title = {COGNITION AND PSYCHOMETRIC SUPPRESSOR EFFECTS OF SCN2A IN SCHIZOPHRENIA}, Journal = {Schizophrenia Bulletin}, Volume = {41}, Pages = {S52-S52}, Publisher = {OXFORD UNIV PRESS}, Year = {2015}, Month = {March}, Key = {fds370651} } @article{fds370753, Author = {Kraus, M and Walker, T and Jarskog, F and Keefe, R}, Title = {IMPAIRED AUDITORY PERCEPTION AND EMOTION IDENTIFICATION IN SCHIZOPHRENIA}, Journal = {Schizophrenia Bulletin}, Volume = {41}, Pages = {S84-S85}, Publisher = {OXFORD UNIV PRESS}, Year = {2015}, Month = {March}, Key = {fds370753} } @article{fds273314, Author = {Bauer, IE and Ouyang, A and Mwangi, B and Sanches, M and Zunta-Soares, GB and Keefe, RSE and Huang, H and Soares, JC}, Title = {Reduced white matter integrity and verbal fluency impairment in young adults with bipolar disorder: a diffusion tensor imaging study.}, Journal = {J Psychiatr Res}, Volume = {62}, Pages = {115-122}, Year = {2015}, Month = {March}, ISSN = {0022-3956}, url = {http://dx.doi.org/10.1016/j.jpsychires.2015.01.008}, Abstract = {BACKGROUND: Clinical evidence shows that bipolar disorder (BD) is characterized by white matter (WM) microstructural abnormalities. However, little is known about the biological mechanisms associated with these abnormalities and their relationship with cognitive functioning. METHODS: 49 adult BD patients ((M±SD): 29.27 ± 7.92 years; 17 males, 32 females; 34 BD-I, 10 BD-II, and 5 BD-NOS) and 28 age-matched normal subjects ((M±SD): 29.19 ± 7.35 years; 10 males and 18 females) underwent diffusion tensor imaging (DTI) imaging. DTI metrics were computed using whole-brain tract-based spatial statistics (TBSS) as part of the FMRIB Software Library. Measures of WM coherence (fractional anisotropy - FA) and axonal structure (mean, axial and radial diffusivity - MD, AD and RD) were employed to characterize the microstructural alterations in the limbic, commissural, association and projection fiber tracts. All participants performed the Brief Assessment of Cognition for Affective disorders (BAC-A). RESULTS: BD patients performed poorly on verbal fluency tasks and exhibited large clusters of altered FA, RD and MD values within the retrolenticular part of the internal capsule, the superior and anterior corona radiata, and the corpus callosum. Increased FA values in the left IFOF and the forceps minor correlated positively with verbal fluency scores. Altered RD parameters in the corticospinal tract and the forceps minor were associated with reduced visuomotor abilities. CONCLUSIONS: The reported verbal fluency deficits and FA, RD and MD alterations in WM structures are potential cognitive and neural markers of BD. Abnormal RD values may be associated with progressive demyelination.}, Doi = {10.1016/j.jpsychires.2015.01.008}, Key = {fds273314} } @article{fds273311, Author = {Araújo, GE and Resende, CBD and Cardoso, ACA and Teixeira, AL and Keefe, RSE and Salgado, JV}, Title = {Validity and reliability of the Brazilian Portuguese version of the BACS (Brief Assessment of Cognition in Schizophrenia).}, Journal = {Clinics (Sao Paulo, Brazil)}, Volume = {70}, Number = {4}, Pages = {278-282}, Year = {2015}, Month = {April}, ISSN = {1807-5932}, url = {http://dx.doi.org/10.6061/clinics/2015(04)10}, Abstract = {OBJECTIVE: To assess the validity and reliability of the Brazilian Portuguese version of the Brief Assessment of Cognition in Schizophrenia by examining its temporal stability, internal consistency, and discriminant and convergent validity. METHODS: The Brief Assessment of Cognition in Schizophrenia was administered to 116 stable patients with schizophrenia and 58 matched control subjects. To assess concurrent validity, a subset of patients underwent a traditional neuropsychological assessment. RESULTS: The patients with schizophrenia performed significantly worse than the controls (p<0.001) on all subtests of the Brief Assessment of Cognition in Schizophrenia and on the total score, which attests to the discriminant validity of the test. The global score of the Brief Assessment of Cognition in Schizophrenia was significantly correlated with all of the subtests and with the global score for the standard battery. The Brief Assessment of Cognition in Schizophrenia also had good test-retest reliability (rho>0.8). The internal consistency of the Brief Assessment of Cognition in Schizophrenia was high (Cronbach's α ϝ 0.874). CONCLUSION: The Brazilian Portuguese version of the Brief Assessment of Cognition in Schizophrenia exhibits good reliability and discriminant and concurrent validity and is a promising tool for easily assessing cognitive impairment in schizophrenia and for comparing the performance of Brazilian patients with that of patients from other countries.}, Doi = {10.6061/clinics/2015(04)10}, Key = {fds273311} } @article{fds372042, Author = {Keefe, R and Davis, V and Atkins, A and Harvey, P and Hilt, D and Lombardo, I and Bugarski-Kirola, D and Reid, C}, Title = {Magnitude and Predictors of MATRICS Consensus Cognitive Battery Change in Placebo Treated Patients with Schizophrenia}, Journal = {Biological Psychiatry}, Volume = {77}, Number = {9}, Pages = {1 pages}, Publisher = {ELSEVIER SCIENCE INC}, Year = {2015}, Month = {May}, Key = {fds372042} } @article{fds273312, Author = {Lim, J and Rekhi, G and Rapisarda, A and Lam, M and Kraus, M and Keefe, RSE and Lee, J}, Title = {Impact of psychiatric comorbidity in individuals at Ultra High Risk of psychosis - Findings from the Longitudinal Youth at Risk Study (LYRIKS).}, Journal = {Schizophrenia Research}, Volume = {164}, Number = {1-3}, Pages = {8-14}, Year = {2015}, Month = {May}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2015.03.007}, Abstract = {Recent studies have reported a high prevalence of psychiatric comorbidities in Ultra High Risk (UHR) for psychosis populations. This study examined the prevalence of comorbidity and its impact on symptoms, functioning, cognition and transition to psychosis in the Longitudinal Youth at Risk Study (LYRIKS) sample. The Comprehensive Assessment of At-Risk Mental State (CAARMS) was used to identify UHR individuals and 163 participants were included in the study. Comorbid disorders were identified using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders. Participants were evaluated on the CAARMS, Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, Beck Anxiety Inventory, Global Assessment of Functioning and Brief Assessment of Cognition in Schizophrenia. Clinical, functioning and cognitive characteristics by lifetime and current comorbidity groups were compared using multivariate tests. Independent predictors of comorbidity were identified through logistic regression. Chi-squared tests were used to compare comorbidity rates between those who had developed psychosis at one year and those who had not. We found that 131 UHR participants (80.4%) had a lifetime comorbidity while 82 (50.3%) had a current comorbidity with depressive disorders being the most common. UHR individuals with comorbidity had more severe symptoms, higher distress and lower functioning with no differences in general cognition. Lower functioning was associated with current comorbidity. Eleven participants (6.7%) had developed psychosis after one year and there were no differences in the comorbidity rates between those who developed psychosis and those who did not. Psychiatric comorbidities in the UHR group are associated with adverse clinical outcomes and warrant closer attention.}, Doi = {10.1016/j.schres.2015.03.007}, Key = {fds273312} } @article{fds273313, Author = {Jarskog, LF and Lowy, MT and Grove, RA and Keefe, RSE and Horrigan, JP and Ball, MP and Breier, A and Buchanan, RW and Carter, CS and Csernansky, JG and Goff, DC and Green, MF and Kantrowitz, JT and Keshavan, MS and Laurelle, M and Lieberman, JA and Marder, SR and Maruff, P and McMahon, RP and Seidman, LJ and Peykamian, MA}, Title = {A Phase II study of a histamine H₃ receptor antagonist GSK239512 for cognitive impairment in stable schizophrenia subjects on antipsychotic therapy.}, Journal = {Schizophrenia Research}, Volume = {164}, Number = {1-3}, Pages = {136-142}, Year = {2015}, Month = {May}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2015.01.041}, Abstract = {This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H₃ receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.}, Doi = {10.1016/j.schres.2015.01.041}, Key = {fds273313} } @article{fds327064, Author = {Atkins, AS and Stroescu, I and Spagnola, NB and Davis, VG and Patterson, TD and Narasimhan, M and Harvey, PD and Keefe, RSE}, Title = {Assessment of Age-Related Differences in Functional Capacity Using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT).}, Journal = {The Journal of Prevention of Alzheimer'S Disease}, Volume = {2}, Number = {2}, Pages = {121-127}, Year = {2015}, Month = {June}, url = {http://dx.doi.org/10.14283/jpad.2015.61}, Abstract = {Clinical trials for primary prevention and early intervention in preclinical AD require measures of functional capacity with improved sensitivity to deficits in healthier, non-demented individuals. To this end, the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) was developed as a direct performance-based assessment of functional capacity that is sensitive to changes in function across multiple populations. Using a realistic virtual reality environment, the VRFCAT assesses a subject's ability to complete instrumental activities associated with a shopping trip. The present investigation represents an initial evaluation of the VRFCAT as a potential co-primary measure of functional capacity in healthy aging and preclinical MCI/AD by examining test-retest reliability and associations with cognitive performance in healthy young and older adults. The VRFCAT was compared and contrasted with the UPSA-2-VIM, a traditional performance-based assessment utilizing physical props. Results demonstrated strong age-related differences in performance on each VRFCAT outcome measure, including total completion time, total errors, and total forced progressions. VRFCAT performance showed strong correlations with cognitive performance across both age groups. VRFCAT Total Time demonstrated good test-retest reliability (ICC=.80 in young adults; ICC=.64 in older adults) and insignificant practice effects, indicating the measure is suitable for repeated testing in healthy populations. Taken together, these results provide preliminary support for the VRFCAT as a potential measure of functionally relevant change in primary prevention and preclinical AD/MCI trials.}, Doi = {10.14283/jpad.2015.61}, Key = {fds327064} } @article{fds273308, Author = {Hill, SK and Reilly, JL and Ragozzino, ME and Rubin, LH and Bishop, JR and Gur, RC and Gershon, ES and Tamminga, CA and Pearlson, GD and Keshavan, MS and Keefe, RSE and Sweeney, JA}, Title = {Regressing to Prior Response Preference After Set Switching Implicates Striatal Dysfunction Across Psychotic Disorders: Findings From the B-SNIP Study.}, Journal = {Schizophrenia Bulletin}, Volume = {41}, Number = {4}, Pages = {940-950}, Year = {2015}, Month = {July}, ISSN = {0586-7614}, url = {http://dx.doi.org/10.1093/schbul/sbu130}, Abstract = {Difficulty switching behavioral response sets is established in psychotic disorders. In rodent models, prefrontal lesions cause difficulty initially switching to new response sets (perseverative errors) while striatal lesions cause difficulty suppressing responses to previous choice preferences (regressive errors). Studies of psychotic disorders have not previously assessed these 2 error types. Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) participants included probands with schizophrenia (N = 212), psychotic bipolar (N = 192), and schizoaffective disorder (N = 131), their first-degree relatives (N = 267,226,165 respectively), and healthy controls (N = 258). Participants completed the Penn Conditional Exclusion Test (PCET) to assess cognitive set switching and the Brief Assessment of Cognition in Schizophrenia (BACS) to assess generalized neuropsychological dysfunction. All proband groups displayed elevated rates of perseverative and regressive errors compared to controls. After correcting for generalized cognitive deficits to identify specific deficits in set shifting and maintenance, there were no significant group differences for perseverative errors, while the increased rate of regressive errors remained significant. Level of regressive errors was similar across proband groups with minimal correlations with antipsychotic medication dose, clinical ratings, and demographic characteristics. Relatives of schizophrenia patients showed increased rates of regressive errors, but familiality of this trait was significant only in bipolar pedigrees. Regressive errors were partially independent of generalized cognitive deficits, suggesting a potentially informative and specific cognitive deficit across psychotic disorders. Preclinical data indicate that this deficit could be related to altered function in a neural system that may include the dorsal striatum or other elements of frontostriatal systems.}, Doi = {10.1093/schbul/sbu130}, Key = {fds273308} } @article{fds273310, Author = {Mahableshwarkar, AR and Zajecka, J and Jacobson, W and Chen, Y and Keefe, RSE}, Title = {A Randomized, Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder.}, Journal = {Neuropsychopharmacology}, Volume = {40}, Number = {8}, Pages = {2025-2037}, Year = {2015}, Month = {July}, ISSN = {0893-133X}, url = {http://dx.doi.org/10.1038/npp.2015.52}, Abstract = {This multicenter, randomized, double-blind, placebo-controlled, active-referenced (duloxetine 60 mg), parallel-group study evaluated the short-term efficacy and safety of vortioxetine (10-20 mg) on cognitive function in adults (aged 18-65 years) diagnosed with major depressive disorder (MDD) who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test (DSST)-number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire (PDQ) and physician-assessed clinical global impression (CGI) were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment (UPSA) (ANCOVA) to measure functionality, MADRS (MMRM) to assess efficacy in depression, and a prespecified multiple regression analysis (path analysis) to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST (P < 0.05), PDQ (P < 0.01), CGI-I (P < 0.001), MADRS (P < 0.05), and UPSA (P < 0.001). Path analysis indicated that vortioxetine's cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events (incidence ⩾ 5%) for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated.}, Doi = {10.1038/npp.2015.52}, Key = {fds273310} } @article{fds273307, Author = {Kaneda, Y and Keefe, RSE}, Title = {An abbreviated version of the brief assessment of cognition in schizophrenia (BACS)}, Journal = {The European Journal of Psychiatry}, Volume = {29}, Number = {2}, Pages = {131-134}, Publisher = {Instituto de Salud Carlos III/BNCS/SciELO Espana}, Year = {2015}, Month = {July}, ISSN = {0213-6163}, url = {http://dx.doi.org/10.4321/s0213-61632015000200004}, Abstract = {Background and Objectives: A short version of the Brief Assessment of Cognition in Schizophrenia (BACS) was derived. Methods: We calculated the corrected item-total correlation (CITC) for each test score relative to the composite score, and then computed the proportion of variance that each test shares with the global score excluding that test (Rt2 = CITCt2) and the variance explained per minute of administration time for each test (Rt2/mint). Results and Conclusions: The 3 tests with the highest Rt2/mint, Symbol Coding, Digit Sequencing, and Token Motor, were selected for the Abbreviated BACS.}, Doi = {10.4321/s0213-61632015000200004}, Key = {fds273307} } @article{fds273306, Author = {Kristian Hill and S and Buchholz, A and Amsbaugh, H and Reilly, JL and Rubin, LH and Gold, JM and Keefe, RSE and Pearlson, GD and Keshavan, MS and Tamminga, CA and Sweeney, JA}, Title = {Working memory impairment in probands with schizoaffective disorder and first degree relatives of schizophrenia probands extend beyond deficits predicted by generalized neuropsychological impairment.}, Journal = {Schizophrenia Research}, Volume = {166}, Number = {1-3}, Pages = {310-315}, Year = {2015}, Month = {August}, ISSN = {0920-9964}, url = {http://dx.doi.org/10.1016/j.schres.2015.05.018}, Abstract = {OBJECTIVE: Working memory impairment is well established in psychotic disorders. However, the relative magnitude, diagnostic specificity, familiality pattern, and degree of independence from generalized cognitive deficits across psychotic disorders remain unclear. METHOD: Participants from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study included probands with schizophrenia (N=289), psychotic bipolar disorder (N=227), schizoaffective disorder (N=165), their first-degree relatives (N=315, N=259, N=193, respectively), and healthy controls (N=289). All were administered the WMS-III Spatial Span working memory test and the Brief Assessment of Cognition in Schizophrenia (BACS) battery. RESULTS: All proband groups displayed significant deficits for both forward and backward span compared to controls. However, after covarying for generalized cognitive impairments (BACS composite), all proband groups showed a 74% or greater effect size reduction with only schizoaffective probands showing residual backward span deficits compared to controls. Significant familiality was seen in schizophrenia and bipolar pedigrees. In relatives, both forward and backward span deficits were again attenuated after covarying BACS scores and residual backward span deficits were seen in relatives of schizophrenia patients. CONCLUSIONS: Overall, both probands and relatives showed a similar pattern of robust working memory deficits that were largely attenuated when controlling for generalized cognitive deficits.}, Doi = {10.1016/j.schres.2015.05.018}, Key = {fds273306} } @article{fds273309, Author = {Kelly, DL and Sullivan, KM and McEvoy, JP and McMahon, RP and Wehring, HJ and Gold, JM and Liu, F and Warfel, D and Vyas, G and Richardson, CM and Fischer, BA and Keller, WR and Koola, MM and Feldman, SM and Russ, JC and Keefe, RSE and Osing, J and Hubzin, L and August, S and Walker, TM and Buchanan, RW}, Title = {Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms.}, Journal = {J Clin Psychopharmacol}, Volume = {35}, Number = {4}, Pages = {374-381}, Year = {2015}, Month = {August}, ISSN = {0271-0749}, url = {http://dx.doi.org/10.1097/JCP.0000000000000345}, Abstract = {OBJECTIVE: Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes. METHODS: Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23). RESULTS: Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo. CONCLUSIONS: Minocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.}, Doi = {10.1097/JCP.0000000000000345}, Key = {fds273309} } @article{fds371770, Author = {Jacobson, W and Olsen, C and Mahableshwarkar, A and Yinzhong, C and Keefe, R}, Title = {P.2.h.012 Effect of vortioxetine on functional capacity in patients with major depressive disorder with self-reported cognitive dysfunction}, Journal = {European Neuropsychopharmacology}, Volume = {25}, Pages = {S460-S460}, Publisher = {Elsevier BV}, Year = {2015}, Month = {September}, url = {http://dx.doi.org/10.1016/s0924-977x(15)30622-2}, Doi = {10.1016/s0924-977x(15)30622-2}, Key = {fds371770} } @article{fds273344, Author = {Graham, KA and Keefe, RS and Lieberman, JA and Calikoglu, AS and Lansing, KM and Perkins, DO}, Title = {Relationship of low vitamin D status with positive, negative and cognitive symptom domains in people with first-episode schizophrenia.}, Journal = {Early Interv Psychiatry}, Volume = {9}, Number = {5}, Pages = {397-405}, Year = {2015}, Month = {October}, ISSN = {1751-7885}, url = {http://dx.doi.org/10.1111/eip.12122}, Abstract = {AIM: Deficient vitamin D levels are very common among Americans of all ages and ethnicities, but little is known about its prevalence or associated problems among those with schizophrenia. METHODS: Stored plasma from 20 recent onset schizophrenia subjects and 20 matched healthy comparison subjects were analysed for 25 OH vitamin D, and related to measures of symptom severity and neurocognition. RESULTS: There was no significant difference in mean 25 OH vitamin D between the schizophrenia and the healthy comparison subjects (28.2 standard deviation (SD) 12.6 ng mL(-1) vs. 29.9 SD 14.3 ng mL(-1) ), and about half the subjects in each group had insufficient levels (<30 ng mL(-1) ). Among psychosis subjects, greater severity of negative symptoms was correlated with lower vitamin D status (r = -0.55, P = 0.012); the correlations of overall symptom severity and positive symptom severity with 25 OH vitamin D levels approached significance (r = -0.42, P = 0.07 and r = -0.36, P = 0.12, respectively). There was no relationship of vitamin D with depressive symptoms. Among the schizophrenia subjects, lower 25 OH vitamin D levels were associated with more severe overall cognitive deficits (r = 0.56, P = 0.019). CONCLUSION: This study found that lower vitamin D levels in schizophrenia subjects were associated with more severe negative symptoms and overall cognitive deficits. However, the cross-sectional design precludes any conclusions about whether low vitamin D status in fact causes more severe negative symptoms and cognitive impairments. No relationship was found between lower vitamin D levels and depressive symptoms.}, Doi = {10.1111/eip.12122}, Key = {fds273344} } @article{fds273304, Author = {Iwata, Y and Nakajima, S and Suzuki, T and Keefe, RSE and Plitman, E and Chung, JK and Caravaggio, F and Mimura, M and Graff-Guerrero, A and Uchida, H}, Title = {Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials.}, Journal = {Mol Psychiatry}, Volume = {20}, Number = {10}, Pages = {1151-1160}, Year = {2015}, Month = {October}, ISSN = {1359-4184}, url = {http://dx.doi.org/10.1038/mp.2015.68}, Abstract = {Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.}, Doi = {10.1038/mp.2015.68}, Key = {fds273304} } @article{fds322124, Author = {Klauser, P and Zhou, J and Lim, JKW and Poh, JS and Zheng, H and Tng, HY and Krishnan, R and Lee, J and Keefe, RSE and Adcock, RA and Wood, SJ and Fornito, A and Chee, MWL}, Title = {Lack of Evidence for Regional Brain Volume or Cortical Thickness Abnormalities in Youths at Clinical High Risk for Psychosis: Findings From the Longitudinal Youth at Risk Study.}, Journal = {Schizophrenia Bulletin}, Volume = {41}, Number = {6}, Pages = {1285-1293}, Year = {2015}, Month = {November}, url = {http://dx.doi.org/10.1093/schbul/sbv012}, Abstract = {There is cumulative evidence that young people in an "at-risk mental state" (ARMS) for psychosis show structural brain abnormalities in frontolimbic areas, comparable to, but less extensive than those reported in established schizophrenia. However, most available data come from ARMS samples from Australia, Europe, and North America while large studies from other populations are missing. We conducted a structural brain magnetic resonance imaging study from a relatively large sample of 69 ARMS individuals and 32 matched healthy controls (HC) recruited from Singapore as part of the Longitudinal Youth At-Risk Study (LYRIKS). We used 2 complementary approaches: a voxel-based morphometry and a surface-based morphometry analysis to extract regional gray and white matter volumes (GMV and WMV) and cortical thickness (CT). At the whole-brain level, we did not find any statistically significant difference between ARMS and HC groups concerning total GMV and WMV or regional GMV, WMV, and CT. The additional comparison of 2 regions of interest, hippocampal, and ventricular volumes, did not return any significant difference either. Several characteristics of the LYRIKS sample like Asian origins or the absence of current illicit drug use could explain, alone or in conjunction, the negative findings and suggest that there may be no dramatic volumetric or CT abnormalities in ARMS.}, Doi = {10.1093/schbul/sbv012}, Key = {fds322124} } @article{fds323334, Author = {Keefe, RSE and Meltzer, HA and Dgetluck, N and Gawryl, M and Koenig, G and Moebius, HJ and Lombardo, I and Hilt, DC}, Title = {Randomized, Double-Blind, Placebo-Controlled Study of Encenicline, an α7 Nicotinic Acetylcholine Receptor Agonist, as a Treatment for Cognitive Impairment in Schizophrenia.}, Journal = {Neuropsychopharmacology}, Volume = {40}, Number = {13}, Pages = {3053-3060}, Year = {2015}, Month = {December}, url = {http://dx.doi.org/10.1038/npp.2015.176}, Abstract = {Encenicline is a novel, selective α7 nicotinic acetylcholine receptor agonist in development for treating cognitive impairment in schizophrenia and Alzheimer's disease. A phase 2, double-blind, randomized, placebo-controlled, parallel-design, multinational study was conducted. Patients with schizophrenia on chronic stable atypical antipsychotics were randomized to encenicline 0.27 or 0.9 mg once daily or placebo for 12 weeks. The primary efficacy end point was the Overall Cognition Index (OCI) score from the CogState computerized battery. Secondary end points include MATRICS Consensus Cognitive Battery (MCCB) (in US patients), the Schizophrenia Cognition Rating Scale (SCoRS) total score, SCoRS global rating, and Positive and Negative Syndrome Scale (PANSS) total and subscale and cognition factor scores. Of 319 randomized patients, 317 were included in the safety population, and 307 were included in the intent-to-treat population. Notable trends in improvement were demonstrated across all cognition scales. For the OCI score, the LS mean difference for encenicline 0.27 mg vs placebo was significant (Cohen's d=0.257; P=0.034). Mean SCoRS total scores decreased showing improvement in function over time, and the difference was significant for encenicline 0.9 mg vs placebo (P=0.011). Furthermore, the difference between encenicline 0.9 mg and placebo was significant for the PANSS Cognition Impairment Domain (P=0.0098, Cohen's d=0.40) and for the PANSS Negative scale (P=0.028, Cohen's d=0.33). Treatment-emergent adverse events were reported at similar frequencies across all treatment groups (39.0% with placebo, 23.4% with encenicline 0.27 mg, and 33.3% with encenicline 0.9 mg). Overall, encenicline was generally well tolerated and demonstrated clinically meaningful improvements in cognition and function in patients with schizophrenia.}, Doi = {10.1038/npp.2015.176}, Key = {fds323334} } @article{fds323335, Author = {Keefe, RSE and Harvey, PD}, Title = {Understanding symbol coding in schizophrenia.}, Journal = {Biol Psychiatry}, Volume = {78}, Number = {11}, Pages = {744-746}, Year = {2015}, Month = {December}, url = {http://dx.doi.org/10.1016/j.biopsych.2015.09.005}, Doi = {10.1016/j.biopsych.2015.09.005}, Key = {fds323335} } @article{fds371767, Author = {Keefe, R and Khan, A and Staner, C and Reilly, J and Saoud, J and Davidson, M and Luthringer, R}, Title = {Effect of MIN-101on Cognition of in Schizophrenia Patient With Predominant Negative Symptoms: A 12-Week Randomized, Double Blind, Placebo-Controlled Trial}, Journal = {Neuropsychopharmacology}, Volume = {41}, Pages = {S389-S390}, Year = {2016}, Key = {fds371767} } @article{fds371768, Author = {Bishop, J and Mills, L and Hill, S and Alliey-Rodriguez, N and Reilly, J and Nanda, P and Padmanabhan, J and Tandon, N and Shafee, R and McCarroll, S and Hyman, S and Keefe, R and Pearlson, G and Clementz, B and Tamminga, C and Keshavan, M and Gershon, E and Sweeney, J}, Title = {Genetic Associations With Cognitive Performance in Psychotic Disorders From the Bipolar-Schizophrenia Network on Intermediate Phenotypes Consortium}, Journal = {Neuropsychopharmacology}, Volume = {41}, Pages = {S595-S596}, Year = {2016}, Key = {fds371768} } @article{fds371769, Author = {Schooler, N and Khan, A and Keefe, R and Marcy, P and Robinson, D and Kane, J}, Title = {Cognitive Functioning in First Episode Psychosis: Comparison of a Two-Year Coordinated Specialty Care Program to Community Care}, Journal = {Neuropsychopharmacology}, Volume = {41}, Pages = {S593-S593}, Year = {2016}, Key = {fds371769} } @article{fds323333, Author = {Cruz, BF and Resende, CBD and Carvalhaes, CF and Cardoso, CS and Teixeira, AL and Keefe, RS and Rocha, FL and Salgado, JV}, Title = {Interview-based assessment of cognition is a strong predictor of quality of life in patients with schizophrenia and severe negative symptoms.}, Journal = {Braz J Psychiatry}, Volume = {38}, Number = {3}, Pages = {216-221}, Year = {2016}, url = {http://dx.doi.org/10.1590/1516-4446-2015-1776}, Abstract = {OBJECTIVE: To analyze the correlation between quality of life, symptoms, and cognition assessed by the interview-based Schizophrenia Cognition Rating Scale (SCoRS). METHODS: Seventy-nine outpatients diagnosed with schizophrenia were evaluated with the Quality of Life Scale - Brazilian version (QLS-BR), the SCoRS, and symptoms scales (Positive and Negative Syndrome Scale [PANSS]). After determining the potential explanatory variables using Spearman's correlation and Student's t test results, we ran simple, multivariate, and decision-tree regression analyses to assess the impact of SCoRS and PANSS ratings on mean overall quality of life. RESULTS: Cognitive deficits and negative symptoms were the best predictors of quality of life. A low degree of negative symptoms (PANSS negative < 11) was a strong predictor of better quality of life (QLS ∼ 75), regardless of SCoRS rating. Among participants with more severe negative symptoms, elevated cognitive impairment (interviewer SCoRS ∼ 44) was a predictor of worse quality of life (QLS ∼ 44). CONCLUSIONS: Cognitive impairment determined by interview-based assessment seems to be a strong predictor of quality of life in subjects with severe negative symptoms. These results support the usefulness of SCoRS for cognitive assessment that is relevant to the everyday life of patients with schizophrenia.}, Doi = {10.1590/1516-4446-2015-1776}, Key = {fds323333} } @article{fds323331, Author = {Hochberger, WC and Hill, SK and Nelson, CLM and Reilly, JL and Keefe, RSE and Pearlson, GD and Keshavan, MS and Tamminga, CA and Clementz, BA and Sweeney, JA}, Title = {Unitary construct of generalized cognitive ability underlying BACS performance across psychotic disorders and in their first-degree relatives.}, Journal = {Schizophrenia Research}, Volume = {170}, Number = {1}, Pages = {156-161}, Year = {2016}, Month = {January}, url = {http://dx.doi.org/10.1016/j.schres.2015.11.022}, Abstract = {Despite robust evidence of neurocognitive dysfunction in psychotic patients, the degree of similarity in cognitive architecture across psychotic disorders and among their respective first-degree relatives is not well delineated. The present study examined the latent factor structure of the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery. Analyses were conducted on 783 psychosis spectrum probands (schizophrenia, schizoaffective, psychotic bipolar), 887 of their first-degree relatives, and 396 non-psychiatric controls from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Exploratory factor analysis of BACS subtest scores indicated a single-factor solution that was similar across all groups and provided the best overall data fit in confirmatory analyses. Correlations between the standard BACS composite score and the sum of subscale scores weighted by their loadings on this unitary factor were very high in all groups (r≥.99). Thus, the BACS assesses a similar unitary cognitive construct in probands with different psychotic disorders, in their first-degree relatives, and in healthy controls, and this factor is well measured by the test's standard composite score.}, Doi = {10.1016/j.schres.2015.11.022}, Key = {fds323331} } @article{fds323332, Author = {Keefe, RSE and Haig, GM and Marder, SR and Harvey, PD and Dunayevich, E and Medalia, A and Davidson, M and Lombardo, I and Bowie, CR and Buchanan, RW and Bugarski-Kirola, D and Carpenter, WT and Csernansky, JT and Dago, PL and Durand, DM and Frese, FJ and Goff, DC and Gold, JM and Hooker, CI and Kopelowicz, A and Loebel, A and McGurk, SR and Opler, LA and Pinkham, AE and Stern, RG}, Title = {Report on ISCTM Consensus Meeting on Clinical Assessment of Response to Treatment of Cognitive Impairment in Schizophrenia.}, Journal = {Schizophrenia Bulletin}, Volume = {42}, Number = {1}, Pages = {19-33}, Year = {2016}, Month = {January}, url = {http://dx.doi.org/10.1093/schbul/sbv111}, Abstract = {If treatments for cognitive impairment are to be utilized successfully, clinicians must be able to determine whether they are effective and which patients should receive them. In order to develop consensus on these issues, the International Society for CNS Clinical Trials and Methodology (ISCTM) held a meeting of experts on March 20, 2014, in Washington, DC. Consensus was reached on several important issues. Cognitive impairment and functional disability were viewed as equally important treatment targets. The group supported the notion that sufficient data are not available to exclude patients from available treatments on the basis of age, severity of cognitive impairment, severity of positive symptoms, or the potential to benefit functionally from treatment. The group reached consensus that cognitive remediation is likely to provide substantial benefits in combination with procognitive medications, although a substantial minority believed that medications can be administered without nonpharmacological therapy. There was little consensus on the best methods for assessing cognitive change in clinical practice. Some participants supported the view that performance-based measures are essential for measurement of cognitive change; others pointed to their cost and time requirements as evidence of impracticality. Interview-based measures of cognitive and functional change were viewed as more practical, but lacking validity without informant involvement or frequent contact from clinicians. The lack of consensus on assessment methods was viewed as attributable to differences in experience and education among key stakeholders and significant gaps in available empirical data. Research on the reliability, validity, sensitivity, and practicality of competing methods will facilitate consensus.}, Doi = {10.1093/schbul/sbv111}, Key = {fds323332} } @article{fds322123, Author = {Walling, D and Marder, SR and Kane, J and Fleischhacker, WW and Keefe, RSE and Hosford, DA and Dvergsten, C and Segreti, AC and Beaver, JS and Toler, SM and Jett, JE and Dunbar, GC}, Title = {Phase 2 Trial of an Alpha-7 Nicotinic Receptor Agonist (TC-5619) in Negative and Cognitive Symptoms of Schizophrenia.}, Journal = {Schizophrenia Bulletin}, Volume = {42}, Number = {2}, Pages = {335-343}, Year = {2016}, Month = {March}, url = {http://dx.doi.org/10.1093/schbul/sbv072}, Abstract = {OBJECTIVES: This trial was conducted to test the effects of an alpha7 nicotinic receptor full agonist, TC-5619, on negative and cognitive symptoms in subjects with schizophrenia. METHODS: In 64 sites in the United States, Russia, Ukraine, Hungary, Romania, and Serbia, 477 outpatients (18-65 years; male 62%; 55% tobacco users) with schizophrenia, treated with a new-generation antipsychotic, were randomized to 24 weeks of placebo (n = 235), TC-5619, 5mg (n = 121), or TC-5619, 50 mg (n = 121), administered orally once daily. The primary efficacy measure was the Scale for the Assessment of Negative Symptoms (SANS) composite score. Key secondary measures were the Cogstate Schizophrenia Battery (CSB) composite score and the University of California San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) total score. Secondary measures included: Positive and Negative Syndrome Scale in Schizophrenia (PANSS) total and subscale scores, SANS domain scores, CSB item scores, Clinical Global Impression-Global Improvement (CGI-I) score, CGI-Severity (CGI-S) score, and Subject Global Impression-Cognition (SGI-Cog) total score. RESULTS: SANS score showed no statistical benefit for TC-5619 vs placebo at week 24 (5 mg, 2-tailed P = .159; 50 mg, P = .689). Likewise, no scores of CSB, UPSA-B, PANSS, CGI-I, CGI-S, or SGI-Cog favored TC-5619 (P > .05). Sporadic statistical benefit favoring TC-5619 in some of these outcome measures were observed in tobacco users, but these benefits did not show concordance by dose, country, gender, or other relevant measures. TC-5619 was generally well tolerated. CONCLUSION: These results do not support a benefit of TC-5619 for negative or cognitive symptoms in schizophrenia.}, Doi = {10.1093/schbul/sbv072}, Key = {fds322123} } @article{fds327063, Author = {McCleery, A and Green, MF and Hellemann, GS and Baade, LE and Gold, JM and Keefe, RSE and Kern, RS and Mesholam-Gately, RI and Seidman, LJ and Subotnik, KL and Ventura, J and Nuechterlein, KH}, Title = {Latent structure of cognition in schizophrenia: a confirmatory factor analysis of the MATRICS Consensus Cognitive Battery (MCCB).}, Journal = {Psychol Med}, Volume = {46}, Number = {5}, Pages = {1119}, Year = {2016}, Month = {April}, url = {http://dx.doi.org/10.1017/S0033291715002433}, Doi = {10.1017/S0033291715002433}, Key = {fds327063} } @article{fds323329, Author = {Keefe, RSE}, Title = {Treating cognitive impairment in depression: an unmet need.}, Journal = {Lancet Psychiatry}, Volume = {3}, Number = {5}, Pages = {392-393}, Year = {2016}, Month = {May}, url = {http://dx.doi.org/10.1016/S2215-0366(16)00095-X}, Doi = {10.1016/S2215-0366(16)00095-X}, Key = {fds323329} } @article{fds323330, Author = {Keefe, RSE and Reichenberg, A}, Title = {Predicting Schizophrenia.}, Journal = {Jama Psychiatry}, Volume = {73}, Number = {5}, Pages = {441-442}, Year = {2016}, Month = {May}, url = {http://dx.doi.org/10.1001/jamapsychiatry.2016.0138}, Doi = {10.1001/jamapsychiatry.2016.0138}, Key = {fds323330} } @article{fds323328, Author = {Kantrowitz, JT and Sharif, Z and Medalia, A and Keefe, RSE and Harvey, P and Bruder, G and Barch, DM and Choo, T and Lee, S and Lieberman, JA}, Title = {A Multicenter, Rater-Blinded, Randomized Controlled Study of Auditory Processing-Focused Cognitive Remediation Combined With Open-Label Lurasidone in Patients With Schizophrenia and Schizoaffective Disorder.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {77}, Number = {6}, Pages = {799-806}, Year = {2016}, Month = {June}, url = {http://dx.doi.org/10.4088/JCP.15m09998}, Abstract = {OBJECTIVE: Small-scale studies of auditory processing cognitive remediation programs have demonstrated efficacy in schizophrenia. We describe a multicenter, rater-blinded, randomized, controlled study of auditory-focused cognitive remediation, conducted from June 24, 2010, to June 14, 2013, and approved by the local institutional review board at all sites. METHOD: Prior to randomization, participants with schizophrenia (DSM-IV-TR) were stabilized on a standardized antipsychotic regimen (lurasidone [40-160 mg/d]), followed by randomization to adjunctive cognitive remediation: auditory focused (Brain Fitness) versus control (nonspecific video games), administered 1-2 times weekly for 30 sessions. Coprimary outcome measures included MATRICS Consensus Cognitive Battery (MCCB) and the University of California, San Diego, Performance-Based Skills Assessment-Brief scale. RESULTS: 120 participants were randomized and completed at least 1 auditory-focused cognitive remediation (n = 56) or video game control session (n = 64). 74 participants completed ≥ 25 sessions and postrandomization assessments. At study completion, the change from prestabilization was statistically significant for MCCB composite score (d = 0.42, P < .0001) across groups. Participants randomized to auditory-focused cognitive remediation had a trend-level higher mean MCCB composite score compared to participants randomized to control cognitive remediation (P = .08). After controlling for scores at the time of randomization, there were no significant between-treatment group differences at study completion. CONCLUSIONS: Auditory processing cognitive remediation combined with lurasidone did not lead to differential improvement over nonspecific video games. Across-group improvement from prestabilization baseline to study completion was observed, but since all participants were receiving lurasidone open label, it is difficult to interpret the source of these effects. Future studies comparing both pharmacologic and behavioral cognitive enhancers should consider a 2 × 2 design, using a control for both the medication and the cognitive remediation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01173874.}, Doi = {10.4088/JCP.15m09998}, Key = {fds323328} } @article{fds323327, Author = {Lim, J and Lee, S-A and Lam, M and Rapisarda, A and Kraus, M and Keefe, RSE and Lee, J}, Title = {The relationship between negative symptom subdomains and cognition.}, Journal = {Psychol Med}, Volume = {46}, Number = {10}, Pages = {2169-2177}, Year = {2016}, Month = {July}, url = {http://dx.doi.org/10.1017/S0033291716000726}, Abstract = {BACKGROUND: Negative symptoms and cognitive deficits in schizophrenia are partially overlapping. However, the nature of the relationship between negative symptoms and cognition remains equivocal. Recent reviews have demonstrated the presence of two negative symptom subdomains, diminished emotional expression (DEE) and avolition. In view of this, we sought to clarify the relationship between negative symptoms and cognitive domains. METHOD: A total of 687 participants with schizophrenia were assessed on measures of psychopathology and cognition. Three cognitive factors, namely executive function, fluency/memory and speed/vigilance were computed from the cognitive tests. Confirmatory factor analysis was utilized to examine if a one-factor or two-factor negative model was applicable to our sample. Subsequently, the relationships between negative symptoms and cognition were examined using structural equation modeling. RESULTS: Results demonstrated that the two-factor model fitted the data well. While negative symptoms were mildly to moderately associated with cognition, we found that DEE had unique associations with cognition compared to social avolition, contributing to the validity of the constructs and suggesting the possibility of common underlying substrates in negative symptoms and cognition. CONCLUSIONS: Our study highlighted the need to classify DEE and social avolition separately as both are necessary in refining the complex relationship between negative symptoms and cognition as well as potentially guiding treatment and management of schizophrenia.}, Doi = {10.1017/S0033291716000726}, Key = {fds323327} } @article{fds323326, Author = {Keefe, RSE and Davis, VG and Atkins, AS and Vaughan, A and Patterson, T and Narasimhan, M and Harvey, PD}, Title = {Validation of a Computerized test of Functional Capacity.}, Journal = {Schizophrenia Research}, Volume = {175}, Number = {1-3}, Pages = {90-96}, Year = {2016}, Month = {August}, url = {http://dx.doi.org/10.1016/j.schres.2016.03.038}, Abstract = {Regulatory guidance for schizophrenia cognition clinical trials requires that the assessment of cognitive change is accompanied by a functionally meaningful endpoint. However, currently available measures are challenged by resistance to change, psychometric weaknesses, and for interview-based assessments, dependence upon the presence of an informant. The aims of the current study were to: 1) assess the validity, sensitivity, and reliability of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) as a measure of functional capacity; 2) determine the association between performance on the VRFCAT and performance on the MATRICS Consensus Cognitive Battery (MCCB); and 3) compare the metrics of the VRFCAT with the UCSD Performance-based Skills Assessment (UPSA). 167 patients with schizophrenia and 166 healthy controls completed the VRFCAT, UPSA, and the MCCB at baseline. The VRFCAT and UPSA were completed again at follow-up. The VRFCAT, MCCB, and UPSA were very sensitive to impairment in schizophrenia (d=1.16 to 1.22). High test-retest reliability was demonstrated for VRFCAT total completion time and the UPSA total score in patients (ICC=0.81 and 0.78, respectively). The UPSA demonstrated significant practice effects in patients (d=0.35), while the VRFCAT did not (d=-0.04). VRFCAT total completion time was correlated with both UPSA (r=-0.56, p<0.0001 for patients and -0.58, p<0.0001 for controls) and MCCB Composite (r=-0.57, p<0.0001 for patients and -0.68, p<0.0001 for controls). The VRFCAT is a highly reliable and sensitive measure of functional capacity with associations to the UPSA and MCCB. These results provide encouraging support for a computerized functional capacity assessment for use in schizophrenia.}, Doi = {10.1016/j.schres.2016.03.038}, Key = {fds323326} } @article{fds322122, Author = {Wang, C and Ji, F and Hong, Z and Poh, JS and Krishnan, R and Lee, J and Rekhi, G and Keefe, RSE and Adcock, RA and Wood, SJ and Fornito, A and Pasternak, O and Chee, MWL and Zhou, J}, Title = {Disrupted salience network functional connectivity and white-matter microstructure in persons at risk for psychosis: findings from the LYRIKS study.}, Journal = {Psychol Med}, Volume = {46}, Number = {13}, Pages = {2771-2783}, Year = {2016}, Month = {October}, url = {http://dx.doi.org/10.1017/S0033291716001410}, Abstract = {BACKGROUND: Salience network (SN) dysconnectivity has been hypothesized to contribute to schizophrenia. Nevertheless, little is known about the functional and structural dysconnectivity of SN in subjects at risk for psychosis. We hypothesized that SN functional and structural connectivity would be disrupted in subjects with At-Risk Mental State (ARMS) and would be associated with symptom severity and disease progression. METHOD: We examined 87 ARMS and 37 healthy participants using both resting-state functional magnetic resonance imaging and diffusion tensor imaging. Group differences in SN functional and structural connectivity were examined using a seed-based approach and tract-based spatial statistics. Subject-level functional connectivity measures and diffusion indices of disrupted regions were correlated with CAARMS scores and compared between ARMS with and without transition to psychosis. RESULTS: ARMS subjects exhibited reduced functional connectivity between the left ventral anterior insula and other SN regions. Reduced fractional anisotropy (FA) and axial diffusivity were also found along white-matter tracts in close proximity to regions of disrupted functional connectivity, including frontal-striatal-thalamic circuits and the cingulum. FA measures extracted from these disrupted white-matter regions correlated with individual symptom severity in the ARMS group. Furthermore, functional connectivity between the bilateral insula and FA at the forceps minor were further reduced in subjects who transitioned to psychosis after 2 years. CONCLUSIONS: Our findings support the insular dysconnectivity of the proximal SN hypothesis in the early stages of psychosis. Further developed, the combined structural and functional SN assays may inform the prognosis of persons at-risk for psychosis.}, Doi = {10.1017/S0033291716001410}, Key = {fds322122} } @article{fds323325, Author = {Kantrowitz, JT and Medalia, A and Keefe, RSE and Harvey, PD and Bruder, G and Barch, DM and Choo, T and Lee, S and Lieberman, JA}, Title = {Dr Kantrowitz and Colleagues Reply.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {77}, Number = {10}, Pages = {e1353}, Year = {2016}, Month = {October}, url = {http://dx.doi.org/10.4088/JCP.16lr10887a}, Doi = {10.4088/JCP.16lr10887a}, Key = {fds323325} } @article{fds325512, Author = {Mahableshwarkar, AR and Zajecka, J and Jacobson, W and Chen, Y and Keefe, RS}, Title = {A Randomized, Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder.}, Journal = {Neuropsychopharmacology}, Volume = {41}, Number = {12}, Pages = {2961}, Year = {2016}, Month = {November}, url = {http://dx.doi.org/10.1038/npp.2016.181}, Doi = {10.1038/npp.2016.181}, Key = {fds325512} } @article{fds371766, Author = {Kraus, M and Walker, T and Jarskog, L and Jones, K and Millet, R and Keefe, R}, Title = {Comprehensive Assessment of Auditory Perception and its Relation to Impaired Emotion Recognition in Schizophrenia}, Journal = {Neuropsychopharmacology}, Volume = {41}, Pages = {S251-S252}, Publisher = {NATURE PUBLISHING GROUP}, Year = {2016}, Month = {December}, Key = {fds371766} } @article{fds323324, Author = {Kraus, M and Rapisarda, A and Lam, M and Thong, JYJ and Lee, J and Subramaniam, M and Collinson, SL and Chong, SA and Keefe, RSE}, Title = {Disrupted latent inhibition in individuals at ultra high-risk for developing psychosis.}, Journal = {Schizophrenia Research. Cognition}, Volume = {6}, Pages = {1-8}, Year = {2016}, Month = {December}, url = {http://dx.doi.org/10.1016/j.scog.2016.07.003}, Abstract = {The addition of off-the-shelf cognitive measures to established prodromal criteria has resulted in limited improvement in the prediction of conversion to psychosis. Tests that assess cognitive processes central to schizophrenia might better identify those at highest risk. The latent inhibition paradigm assesses a subject's tendency to ignore irrelevant stimuli, a process integral to healthy perceptual and cognitive function that has been hypothesized to be a key deficit underlying the development of schizophrenia. In this study, 142 young people at ultra high-risk for developing psychosis and 105 controls were tested on a within-subject latent inhibition paradigm. Additionally, we later inquired about the strategy that each subject employed to complete the test, and further investigated the relationship between reported strategy and the extent of latent inhibition exhibited. Unlike controls, ultra high-risk subjects did not demonstrate a significant latent inhibition effect. This difference between groups became greater when controlling for strategy. The lack of latent inhibition effect in our ultra high-risk sample suggests that individuals at ultra high-risk for psychosis are impaired in their allocation of attentional resources based on past predictive value of repeated stimuli. This fundamental deficit in the allocation of attention may contribute to the broader array of cognitive impairments and clinical symptoms displayed by individuals at ultra high-risk for psychosis.}, Doi = {10.1016/j.scog.2016.07.003}, Key = {fds323324} } @article{fds370649, Author = {Lam, M and Keefe, R and Jun Liu and J and Lee, J}, Title = {Pleiotropic Effects of Schizophrenia And Cognitive LOCI: A Meta-Analytic Approach}, Journal = {European Neuropsychopharmacology}, Volume = {27}, Pages = {S394-S395}, Publisher = {Elsevier BV}, Year = {2017}, url = {http://dx.doi.org/10.1016/j.euroneuro.2016.09.432}, Doi = {10.1016/j.euroneuro.2016.09.432}, Key = {fds370649} } @article{fds370733, Author = {Atkins, A and Tseng, T and Vaughan, A and Harvey, P and Narasimhan, M and Patterson, T and Khan, A and Keefe, R}, Title = {DEVELOPMENT AND VALIDATION OF THE BRIEF ASSESSMENT OF VALIDATION IN SCHIZOPHRENIA (BAC-APP)}, Journal = {Schizophrenia Bulletin}, Volume = {43}, Pages = {S220-S220}, Year = {2017}, Key = {fds370733} } @article{fds370734, Author = {Schooler, N and Khan, A and Keefe, R and Robinson, D and Kane, J}, Title = {COGNITIVE FUNCTIONING IN FIRST-EPISODE PSYCHOSIS:_X000B_COMPARISON OF A 2-YEAR COORDINATED SPECIALTY CARE PROGRAM TO COMMUNITY CARE}, Journal = {Schizophrenia Bulletin}, Volume = {43}, Pages = {S24-S24}, Year = {2017}, Key = {fds370734} } @article{fds372607, Author = {Keefe, R and Woods, S and Cannon, T and Ruhrmann, S and Mathalon, D and McGuire, P and Fillon, G and Rosenbrock, H and Sand, M}, Title = {EARLY INTERVENTION IN ATTENUATED PSYCHOSIS SYNDROME: A PHASE II STUDY EVALUATING EFFICACY, SAFETY, AND TOLERABILITY OF ORAL BI 409306}, Journal = {Schizophrenia Bulletin}, Volume = {43}, Pages = {S216-S216}, Year = {2017}, Key = {fds372607} } @article{fds325352, Author = {Addington, J and Liu, L and Perkins, DO and Carrion, RE and Keefe, RSE and Woods, SW}, Title = {The Role of Cognition and Social Functioning as Predictors in the Transition to Psychosis for Youth With Attenuated Psychotic Symptoms.}, Journal = {Schizophrenia Bulletin}, Volume = {43}, Number = {1}, Pages = {57-63}, Year = {2017}, Month = {January}, url = {http://dx.doi.org/10.1093/schbul/sbw152}, Abstract = {In the literature, there have been several attempts to develop prediction models for youth who are at clinical high risk (CHR) of developing psychosis. Although there are no specific clinical or demographic variables that seem to consistently predict the later transition to psychosis in those CHR youth, in addition to attenuated psychotic symptoms, the most commonly occuring predictors tend to be poor social functioning and certain cognitive tasks. Unfortunately, there has been little attempt to replicate alogorithms. A recently published article by Cornblatt et al suggested that, for individuals with attentuated psychotic symptoms (APS), disorganized communication, suspiciousness, verbal memory, and a decline in social functioning were the best predictors of later transition to psychosis (the RAP model). The purpose of this article was to first test the prediction model of Cornblatt et al with a new sample of individuals with APS from the PREDICT study. The RAP model was not the best fit for the PREDICT data. However, using other variables from PREDICT, it was demonstrated that unusual thought content, disorganized communication, baseline social functioning, verbal fluency, and memory, processing speed and age were predictors of later transition to psychosis in the PREDICT sample. Although the predictors were different in these 2 models, both supported that disorganized communication, poor social functioning, and verbal memory, were good candidates as predictors for later conversion to psychosis.}, Doi = {10.1093/schbul/sbw152}, Key = {fds325352} } @article{fds370577, Author = {Bishop, J and Hill, S and Mills, L and Alliey-Rodriguez, N and Reilly, J and Shaffee, R and McCarroll, S and Keefe, R and Pearlson, G and Clementz, B and Tamminga, C and Keshavan, M and Gershon, E and Sweeney, J}, Title = {GENETIC ANALYSES OF COGNITIVE PERFORMANCE IN PSYCHOTIC DISORDERS FROM THE BIPOLAR-SCHIZOPHRENIA NETWORK ON INTERMEDIATE PHENOTYPES (B-SNIP) CONSORTIUM}, Journal = {Schizophrenia Bulletin}, Volume = {43}, Pages = {S245-S245}, Publisher = {OXFORD UNIV PRESS}, Year = {2017}, Month = {March}, Key = {fds370577} } @article{fds370732, Author = {Marx, C and Naylor, J and Kilts, J and Allan, T and Smith, K and Szabo, S and Wagner, R and Buchanan, R and Keefe, R and Shampine, L}, Title = {RANDOMIZED CONTROLLED TRIAL OF A NEUROSTEROID INTERVENTION IN SCHIZOPHRENIA}, Journal = {Schizophrenia Bulletin}, Volume = {43}, Pages = {S14-S14}, Publisher = {OXFORD UNIV PRESS}, Year = {2017}, Month = {March}, Key = {fds370732} } @article{fds323546, Author = {Atkins, AS and Tseng, T and Vaughan, A and Twamley, EW and Harvey, P and Patterson, T and Narasimhan, M and Keefe, RSE}, Title = {Validation of the tablet-administered Brief Assessment of Cognition (BAC App).}, Journal = {Schizophrenia Research}, Volume = {181}, Pages = {100-106}, Year = {2017}, Month = {March}, url = {http://dx.doi.org/10.1016/j.schres.2016.10.010}, Abstract = {Computerized tests benefit from automated scoring procedures and standardized administration instructions. These methods can reduce the potential for rater error. However, especially in patients with severe mental illnesses, the equivalency of traditional and tablet-based tests cannot be assumed. The Brief Assessment of Cognition in Schizophrenia (BACS) is a pen-and-paper cognitive assessment tool that has been used in hundreds of research studies and clinical trials, and has normative data available for generating age- and gender-corrected standardized scores. A tablet-based version of the BACS called the BAC App has been developed. This study compared performance on the BACS and the BAC App in patients with schizophrenia and healthy controls. Test equivalency was assessed, and the applicability of paper-based normative data was evaluated. Results demonstrated the distributions of standardized composite scores for the tablet-based BAC App and the pen-and-paper BACS were indistinguishable, and the between-methods mean differences were not statistically significant. The discrimination between patients and controls was similarly robust. The between-methods correlations for individual measures in patients were r>0.70 for most subtests. When data from the Token Motor Test was omitted, the between-methods correlation of composite scores was r=0.88 (df=48; p<0.001) in healthy controls and r=0.89 (df=46; p<0.001) in patients, consistent with the test-retest reliability of each measure. Taken together, results indicate that the tablet-based BAC App generates results consistent with the traditional pen-and-paper BACS, and support the notion that the BAC App is appropriate for use in clinical trials and clinical practice.}, Doi = {10.1016/j.schres.2016.10.010}, Key = {fds323546} } @article{fds327062, Author = {Reilly, JL and Hill, SK and Gold, JM and Keefe, RSE and Clementz, BA and Gershon, E and Keshavan, MS and Pearlson, G and Tamminga, CA and Sweeney, JA}, Title = {Impaired Context Processing is Attributable to Global Neuropsychological Impairment in Schizophrenia and Psychotic Bipolar Disorder.}, Journal = {Schizophrenia Bulletin}, Volume = {43}, Number = {2}, Pages = {397-406}, Year = {2017}, Month = {March}, url = {http://dx.doi.org/10.1093/schbul/sbw081}, Abstract = {BACKGROUND: Context processing may reflect a specific cognitive impairment in schizophrenia. Whether impaired context processing is observed across psychotic disorders or among relatives of affected individuals, and whether it is a deficit that is independent from the generalized neuropsychological deficits seen in psychotic disorders, are less established. METHODS: Schizophrenia, schizoaffective, and psychotic bipolar probands (n = 660), their first-degree relatives (n = 741), and healthy individuals (n = 308) studied by the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium performed an expectancy task requiring use of contextual information to overcome a pre-potent response. Sensitivity for target detection and false alarm rates on trials requiring inhibition or goal maintenance were measured. RESULTS: Proband groups and relatives with psychosis spectrum personality traits demonstrated reduced target sensitivity and elevated false alarm rates. False alarm rate was higher under inhibition vs goal maintenance conditions although this difference was attenuated in schizophrenia and schizoaffective proband groups. After accounting for global neuropsychological impairment, as reflected by the composite score from the Brief Assessment of Cognition in Schizophrenia neuropsychological battery, deficits in schizophrenia and bipolar proband groups were no longer significant. Performance measures were moderately familial. CONCLUSION: Reduced target detection, but not a specific deficit in context processing, is observed across psychotic disorders. Impairments in both goal maintenance and response inhibition appear to contribute comparably to deficits in schizophrenia and schizoaffective disorder, whereas greater difficulty with response inhibition underlies deficits in bipolar disorder. Yet, these deficits are not independent from the generalized neurocognitive impairment observed in schizophrenia and psychotic bipolar disorder.}, Doi = {10.1093/schbul/sbw081}, Key = {fds327062} } @article{fds371749, Author = {Lam, M and Keefe, R and Liu, J-J and Lee, J}, Title = {700. Genetic Overlaps between Schizophrenia and Cognition in Asia}, Journal = {Biological Psychiatry}, Volume = {81}, Number = {10}, Pages = {S284-S284}, Publisher = {Elsevier BV}, Year = {2017}, Month = {May}, url = {http://dx.doi.org/10.1016/j.biopsych.2017.02.767}, Doi = {10.1016/j.biopsych.2017.02.767}, Key = {fds371749} } @article{fds371765, Author = {Keefe, R and Woods, S and Cannon, T and Ruhrmann, S and Mathalon, D and McGuire, P and Fillon, G and Rosenbrock, H and Sand, M}, Title = {868. Early Intervention in Attenuated Psychosis Syndrome: A Phase II Study Evaluating Efficacy, Safety, and Tolerability of Oral BI 409306}, Journal = {Biological Psychiatry}, Volume = {81}, Number = {10}, Pages = {S351-S351}, Publisher = {Elsevier BV}, Year = {2017}, Month = {May}, url = {http://dx.doi.org/10.1016/j.biopsych.2017.02.593}, Doi = {10.1016/j.biopsych.2017.02.593}, Key = {fds371765} } @article{fds327059, Author = {Keefe, RSE and Kahn, RS}, Title = {Cognitive Decline and Disrupted Cognitive Trajectory in Schizophrenia.}, Journal = {Jama Psychiatry}, Volume = {74}, Number = {5}, Pages = {535-536}, Year = {2017}, Month = {May}, url = {http://dx.doi.org/10.1001/jamapsychiatry.2017.0312}, Doi = {10.1001/jamapsychiatry.2017.0312}, Key = {fds327059} } @article{fds324823, Author = {Mazhari, S and Ghafaree-Nejad, AR and Soleymani-Zade, S and Keefe, RSE}, Title = {Validation of the Persian version of the Schizophrenia Cognition Rating Scale (SCoRS) in patients with schizophrenia.}, Journal = {Asian J Psychiatr}, Volume = {27}, Pages = {12-15}, Year = {2017}, Month = {June}, url = {http://dx.doi.org/10.1016/j.ajp.2017.02.007}, Abstract = {The Schizophrenia Cognition Rating Scale (SCoRS) is an interview-based assessment of cognition that involves interviews with patients and informants. The SCoRS has shown good reliability, validity, and sensitivity to cognitive impairment in schizophrenia, with the advantage of brief administration and scoring time. The present study aimed to test the concurrent validity of the Persian version of the SCoRS. A group of 35 patients with schizophrenia and a group of 35 healthy controls received the Persian-SCoRS in the first session, and a standardized performance-based cognitive battery, the Brief Assessment of Cognition in Schizophrenia (BACS), in the second session.Our results indicated that the Persian version of the SCoRS was sensitive to cognitive impairment in the patients. The Persian SCoRS global rating was significantly associated with the composite score generated from the Persian version of the BACS and predicted functional outcomes as measured by Global Assessment of Functioning (GAF) and World Health Organization Quality of Life (WHO QOL). A Persian version of the SCoRS, an interview based measure of cognition that included informants, is related to cognitive performance and global functioning.}, Doi = {10.1016/j.ajp.2017.02.007}, Key = {fds324823} } @article{fds327058, Author = {Keefe, RSE and Davis, VG and Harvey, PD and Atkins, AS and Haig, GM and Hagino, O and Marder, S and Hilt, DC and Umbricht, D}, Title = {Placebo Response and Practice Effects in Schizophrenia Cognition Trials.}, Journal = {Jama Psychiatry}, Volume = {74}, Number = {8}, Pages = {807-814}, Year = {2017}, Month = {August}, url = {http://dx.doi.org/10.1001/jamapsychiatry.2017.1574}, Abstract = {IMPORTANCE: Patients' previous experience with performance-based cognitive tests in clinical trials for cognitive impairment associated with schizophrenia can create practice-related improvements. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects. OBJECTIVES: To conduct a systematic evaluation of the magnitude of practice effects on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) in cognitive impairment associated with schizophrenia and to examine which demographic, clinical, and cognitive characteristics were associated with improvement in placebo conditions. DESIGN, SETTING, AND PARTICIPANTS: A blinded review was conducted of data from 813 patients with schizophrenia who were treated with placebo in 12 randomized placebo-controlled clinical trials conducted mostly in outpatient clinics in North America, Europe, Asia, and Latin America from February 22, 2007, to March 1, 2014. A total of 779 patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients. INTERVENTIONS: Placebo compared with various experimental drug treatments. MAIN OUTCOMES AND MEASURES: Composite score on the MCCB. RESULTS: Of the 813 patients in the study (260 women and 553 men; mean [SD] age, 41.2 [11.5] years), the mean MCCB composite score at baseline was 22.8 points below the normative mean, and the mean (SEM) total change in the MCCB during receipt of placebo was 1.8 (0.2) T-score points (95% CI, 1.40-2.18), equivalent to a change of 0.18 SD. Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Baseline factors associated with greater improvements in the MCCB during receipt of placebo included more depression/anxiety (F1,438 = 5.41; P = .02), more motivation (F1,272 = 4.63; P = .03), and less improvement from screening to baseline (F1,421 = 59.32; P < .001). CONCLUSIONS AND RELEVANCE: Placebo effects were minimal and associated with the number of postbaseline assessments and several patient characteristics. Given that the patients performed 2.28 SDs below normative standards on average at baseline, a mean placebo-associated improvement of less than 0.2 SD provides evidence that ceiling effects do not occur in these trials. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo.}, Doi = {10.1001/jamapsychiatry.2017.1574}, Key = {fds327058} } @article{fds326635, Author = {Lam, M and Wang, M and Huang, W and Eng, GK and Rapisarda, A and Kraus, M and Kang, S and Keefe, RSE and Lee, J}, Title = {Establishing the Brief Assessment of Cognition - Short form.}, Journal = {J Psychiatr Res}, Volume = {93}, Pages = {1-11}, Year = {2017}, Month = {October}, url = {http://dx.doi.org/10.1016/j.jpsychires.2017.05.006}, Abstract = {The study aims to identify and validate a parsimonious subset of tests in the commonly used Brief Assessment of Cognition in Schizophrenia (BACS) that allows the evaluation of global cognitive ability. Several permutations of subtests from the BACS were examined to identify the best subset of tests to compose the short form measure. The Brief Assessment of Cognition-Short Form (BAC-SF) was evaluated for convergent validity in healthy and psychiatric samples (N = 3718). Verbal Memory, Digit Sequencing, and Symbol Coding subtests were found to best summarize the variance of composite scores in both Asian and US Norming samples (r = 0.91) indicating that BAC-SF is an appropriate approximation of cognitive deficits. Test re-test reliability of the BAC-SF was adequate (Intraclass Correlation Coefficient (ICC) = 0.73) and showed sufficient separation between healthy controls and schizophrenia (Average Predictive Accuracy = 79.9%; replication = 76.5%). Findings indicate that the BAC-SF an could be used as a cognitive screener for large-scale clinical and epidemiological studies. The short form does not replace the need for comprehensive neuropsychological batteries purposed for detailed neuropsychological and clinical investigation of cognitive function. Further replication of the construct might be necessary in other clinical populations.}, Doi = {10.1016/j.jpsychires.2017.05.006}, Key = {fds326635} } @article{fds330047, Author = {Cella, M and Stahl, D and Morris, S and Keefe, RSE and Bell, MD and Wykes, T}, Title = {Effects of cognitive remediation on negative symptoms dimensions: exploring the role of working memory.}, Journal = {Psychol Med}, Volume = {47}, Number = {15}, Pages = {2593-2601}, Year = {2017}, Month = {November}, url = {http://dx.doi.org/10.1017/S0033291717000757}, Abstract = {BACKGROUND: Recent theories suggest that poor working memory (WM) may be the cognitive underpinning of negative symptoms in people with schizophrenia. In this study, we first explore the effect of cognitive remediation (CR) on two clusters of negative symptoms (i.e. expressive and social amotivation), and then assess the relevance of WM gains as a possible mediator of symptom improvement. METHOD: Data were accessed for 309 people with schizophrenia from the NIMH Database of Cognitive Training and Remediation Studies and a separate study. Approximately half the participants received CR and the rest were allocated to a control condition. All participants were assessed before and after therapy and at follow-up. Expressive negative symptoms and social amotivation symptoms scores were calculated from the Positive and Negative Syndrome Scale. WM was assessed with digit span and letter-number span tests. RESULTS: Participants who received CR had a significant improvement in WM scores (d = 0.27) compared with those in the control condition. Improvements in social amotivation levels approached statistical significance (d = -0.19), but change in expressive negative symptoms did not differ between groups. WM change did not mediate the effect of CR on social amotivation. CONCLUSIONS: The results suggest that a course of CR may benefit behavioural negative symptoms. Despite hypotheses linking memory problems with negative symptoms, the current findings do not support the role of this cognitive domain as a significant mediator. The results indicate that WM improves independently from negative symptoms reduction.}, Doi = {10.1017/S0033291717000757}, Key = {fds330047} } @article{fds326113, Author = {Eum, S and Hill, SK and Rubin, LH and Carnahan, RM and Reilly, JL and Ivleva, EI and Keedy, SK and Tamminga, CA and Pearlson, GD and Clementz, BA and Gershon, ES and Keshavan, MS and Keefe, RSE and Sweeney, JA and Bishop, JR}, Title = {Cognitive burden of anticholinergic medications in psychotic disorders.}, Journal = {Schizophrenia Research}, Volume = {190}, Pages = {129-135}, Year = {2017}, Month = {December}, url = {http://dx.doi.org/10.1016/j.schres.2017.03.034}, Abstract = {BACKGROUND: Patients with psychotic disorders are often treated with numerous medications, many of which have anticholinergic activity. We assessed cognition in relation to the cumulative anticholinergic burden of multiple drugs included in treatment regimens of participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. METHOD: Clinically stable participants with schizophrenia (n=206), schizoaffective disorder (n=131), and psychotic bipolar disorder (n=146) were examined. Anticholinergic properties of all scheduled drugs were quantified using the Anticholinergic Drug Scale (ADS). ADS scores were summed across individual drugs to create a total ADS burden score for each participant and examined in relation to the Brief Assessment of Cognition in Schizophrenia (BACS). RESULTS: Anticholinergic burden aggregated across all medications was inversely related to cognitive performance starting at ADS scores of 4 in participants with schizophrenia. Those with ADS scores ≥4 had lower composite BACS scores compared to those with ADS<4 (p=0.004). Among BACS subtests, Verbal Memory was the most adversely affected by high anticholinergic burden. Despite similar anticholinergic burden scores across groups, a significant threshold effect of anticholinergic burden was not detected in schizoaffective or psychotic bipolar disorder. CONCLUSION: We identified an adverse effect threshold of anticholinergic burden on cognition in clinically stable participants with schizophrenia. This relationship was not identified in affective psychoses. Examination of other medications, doses, and clinical measures did not account for these findings. Patients with schizophrenia may have increased cognitive susceptibility to anticholinergic medications and the aggregate effects of one's medication regimen may be important to consider in clinical practice.}, Doi = {10.1016/j.schres.2017.03.034}, Key = {fds326113} } @article{fds330046, Author = {Ang, MS and Abdul Rashid and NA and Lam, M and Rapisarda, A and Kraus, M and Keefe, RSE and Lee, J}, Title = {The Impact of Medication Anticholinergic Burden on Cognitive Performance in People With Schizophrenia.}, Journal = {J Clin Psychopharmacol}, Volume = {37}, Number = {6}, Pages = {651-656}, Year = {2017}, Month = {December}, url = {http://dx.doi.org/10.1097/JCP.0000000000000790}, Abstract = {BACKGROUND: Cognitive deficits are prevalent in people with schizophrenia and associated with functional impairments. In addition to antipsychotics, pharmacotherapy in schizophrenia often includes other psychotropics, and some of these agents possess anticholinergic properties, which may impair cognition. The objective of this study was to explore the association between medication anticholinergic burden and cognition in schizophrenia. METHODS: Seven hundred five individuals with schizophrenia completed a neuropsychological battery comprising Judgment of Line Orientation Test, Wechsler Abbreviated Scale of Intelligence Matrix Reasoning, Continuous Performance Test-Identical Pairs Version, and the Brief Assessment of Cognition in Schizophrenia. Cognitive g and 3 cognitive factor scores that include executive function, memory/fluency, and speed of processing/vigilance, which were derived from a previously published analysis, were entered as cognitive variables. Anticholinergic burden was computed using 2 anticholinergic scales: Anticholinergic Burden Scale and Anticholinergic Drug Scale. Duration and severity of illness, antipsychotic dose, smoking status, age, and sex were included as covariates. RESULTS: Anticholinergic burden was associated with poorer cognitive performance in cognitive g, all 3 cognitive domains and most cognitive tasks in multivariate analyses. The associations were statistically significant, but the effect sizes were small (for Anticholinergic Burden Scale, Cohen f = 0.008; for Anticholinergic Drug Scale, Cohen f = 0.017). CONCLUSIONS: Although our results showed a statistically significant association between medications with anticholinergic properties and cognition in people with schizophrenia, the impact is of doubtful or minimal clinical significance.}, Doi = {10.1097/JCP.0000000000000790}, Key = {fds330046} } @article{fds332788, Author = {Khan, A and Liharska, L and Harvey, PD and Atkins, A and Ulshen, D and Keefe, RSE}, Title = {Negative Symptom Dimensions of the Positive and Negative Syndrome Scale Across Geographical Regions: Implications for Social, Linguistic, and Cultural Consistency.}, Journal = {Innovations in Clinical Neuroscience}, Volume = {14}, Number = {11-12}, Pages = {30-40}, Year = {2017}, Month = {December}, Abstract = {Objective: Recognizing the discrete dimensions that underlie negative symptoms in schizophrenia and how these dimensions are understood across localities might result in better understanding and treatment of these symptoms. To this end, the objectives of this study were to 1) identify the Positive and Negative Syndrome Scale negative symptom dimensions of expressive deficits and experiential deficits and 2) analyze performance on these dimensions over 15 geographical regions to determine whether the items defining them manifest similar reliability across these regions. Design: Data were obtained for the baseline Positive and Negative Syndrome Scale visits of 6,889 subjects across 15 geographical regions. Using confirmatory factor analysis, we examined whether a two-factor negative symptom structure that is found in schizophrenia (experiential deficits and expressive deficits) would be replicated in our sample, and using differential item functioning, we tested the degree to which specific items from each negative symptom subfactor performed across geographical regions in comparison with the United States. Results: The two-factor negative symptom solution was replicated in this sample. Most geographical regions showed moderate-to-large differential item functioning for Positive and Negative Syndrome Scale expressive deficit items, especially N3 Poor Rapport, as compared with Positive and Negative Syndrome Scale experiential deficit items, showing that these items might be interpreted or scored differently in different regions. Across countries, except for India, the differential item functioning values did not favor raters in the United States. Conclusion: These results suggest that the Positive and Negative Syndrome Scale negative symptom factor can be better represented by a two-factor model than by a single-factor model. Additionally, the results show significant differences in responses to items representing the Positive and Negative Syndrome Scale expressive factors, but not the experiential factors, across regions. This could be due to a lack of equivalence between the original and translated versions, cultural differences with the interpretation of items, dissimilarities in rater training, or diversity in the understanding of scoring anchors. Knowing which items are challenging for raters across regions can help to guide Positive and Negative Syndrome Scale training and improve the results of international clinical trials aimed at negative symptoms.}, Key = {fds332788} } @article{fds332789, Author = {Harvey, PD and Khan, A and Keefe, RSE}, Title = {Using the Positive and Negative Syndrome Scale (PANSS) to Define Different Domains of Negative Symptoms: Prediction of Everyday Functioning by Impairments in Emotional Expression and Emotional Experience.}, Journal = {Innovations in Clinical Neuroscience}, Volume = {14}, Number = {11-12}, Pages = {18-22}, Year = {2017}, Month = {December}, Abstract = {Background: Reduced emotional experience and expression are two domains of negative symptoms. The authors assessed these two domains of negative symptoms using previously developed Positive and Negative Syndrome Scale (PANSS) factors. Using an existing dataset, the authors predicted three different elements of everyday functioning (social, vocational, and everyday activities) with these two factors, as well as with performance on measures of functional capacity. Methods: A large (n=630) sample of people with schizophrenia was used as the data source of this study. Using regression analyses, the authors predicted the three different aspects of everyday functioning, first with just the two Positive and Negative Syndrome Scale factors and then with a global negative symptom factor. Finally, we added neurocognitive performance and functional capacity as predictors. Results: The Positive and Negative Syndrome Scale reduced emotional experience factor accounted for 21 percent of the variance in everyday social functioning, while reduced emotional expression accounted for no variance. The total Positive and Negative Syndrome Scale negative symptom factor accounted for less variance (19%) than the reduced experience factor alone. The Positive and Negative Syndrome Scale expression factor accounted for, at most, one percent of the variance in any of the functional outcomes, with or without the addition of other predictors. Implications: Reduced emotional experience measured with the Positive and Negative Syndrome Scale, often referred to as "avolition and anhedonia," specifically predicted impairments in social outcomes. Further, reduced experience predicted social impairments better than emotional expression or the total Positive and Negative Syndrome Scale negative symptom factor. In this cross-sectional study, reduced emotional experience was specifically related with social outcomes, accounting for essentially no variance in work or everyday activities, and being the sole meaningful predictor of impairment in social outcomes.}, Key = {fds332789} } @article{fds327060, Author = {Georgiades, A and Davis, VG and Atkins, AS and Khan, A and Walker, TW and Loebel, A and Haig, G and Hilt, DC and Dunayevich, E and Umbricht, D and Sand, M and Keefe, RSE}, Title = {Psychometric characteristics of the MATRICS Consensus Cognitive Battery in a large pooled cohort of stable schizophrenia patients.}, Journal = {Schizophrenia Research}, Volume = {190}, Pages = {172-179}, Year = {2017}, Month = {December}, url = {http://dx.doi.org/10.1016/j.schres.2017.03.040}, Abstract = {The MATRICS Consensus Cognitive Battery (MCCB) was developed to assess cognitive treatment effects in schizophrenia clinical trials, and is considered the FDA gold standard outcome measure for that purpose. The aim of the present study was to establish pre-treatment psychometric characteristics of the MCCB in a large pooled sample. The dataset included 2616 stable schizophrenia patients enrolled in 15 different clinical trials between 2007 and 2016 within the United States (94%) and Canada (6%). The MCCB was administered twice prior to the initiation of treatment in 1908 patients. Test-retest reliability and practice effects of the cognitive composite score, the neurocognitive composite score, which excludes the domain Social Cognition, and the subtests/domains were examined using Intra-Class Correlations (ICC) and Cohen's d. Simulated regression models explored which domains explained the greatest portion of variance in composite scores. Test-retest reliability was high (ICC=0.88) for both composite scores. Practice effects were small for the cognitive (d=0.15) and neurocognitive (d=0.17) composites. Simulated bootstrap regression analyses revealed that 3 of the 7 domains explained 86% of the variance for both composite scores. The domains that entered most frequently in the top 3 positions of the regression models were Speed of Processing, Working Memory, and Visual Learning. Findings provide definitive psychometric characteristics and a benchmark comparison for clinical trials using the MCCB. The test-retest reliability of the MCCB composite scores is considered excellent and the learning effects are small, fulfilling two of the key criteria for outcome measures in cognition clinical trials.}, Doi = {10.1016/j.schres.2017.03.040}, Key = {fds327060} } @article{fds339319, Author = {Atkins, AS and Khan, A and Ulshen, D and Vaughan, A and Balentin, D and Dickerson, H and Liharska, LE and Plassman, B and Welsh-Bohmer, K and Keefe, RSE}, Title = {Assessment of Instrumental Activities of Daily Living in Older Adults with Subjective Cognitive Decline Using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT).}, Journal = {J Prev Alzheimers Dis}, Volume = {5}, Number = {4}, Pages = {216-234}, Year = {2018}, url = {http://dx.doi.org/10.14283/jpad.2018.28}, Abstract = {BACKGROUND: Continuing advances in the understanding of Alzheimer's disease progression have inspired development of disease-modifying therapeutics intended for use in preclinical populations. However, identification of clinically meaningful cognitive and functional outcomes for individuals who are, by definition, asymptomatic remains a significant challenge. Clinical trials for prevention and early intervention require measures with increased sensitivity to subtle deficits in instrumental activities of daily living (IADL) that comprise the first functional declines in prodromal disease. Validation of potential endpoints is required to ensure measure sensitivity and reliability in the populations of interest. OBJECTIVES: The present research validates use of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) for performance-based assessment of IADL functioning in older adults (age 55+) with subjective cognitive decline. DESIGN: Cross-sectional validation study. SETTING: All participants were evaluated on-site at NeuroCog Trials, Durham, NC, USA. PARTICIPANTS: Participants included 245 healthy younger adults ages 20-54 (131 female), 247 healthy older adults ages 55-91 (151 female) and 61 older adults with subjective cognitive decline (SCD) ages 56-97 (45 female). MEASURES: Virtual Reality Functional Capacity Assessment Tool; Brief Assessment of Cognition App; Alzheimer's Disease Cooperative Study Prevention Instrument Project - Mail-In Cognitive Function Screening Instrument; Alzheimer's Disease Cooperative Study Instrumental Activities of Daily Living - Prevention Instrument, University of California, San Diego Performance-Based Skills Assessment - Validation of Intermediate Measures; Montreal Cognitive Assessment; Trail Making Test- Part B. RESULTS: Participants with SCD performed significantly worse than age-matched normative controls on all VRFCAT endpoints, including total completion time, errors and forced progressions (p≤0001 for all, after Bonferonni correction). Consistent with prior findings, both groups performed significantly worse than healthy younger adults (age 20-54). Participants with SCD also performed significantly worse than controls on objective cognitive measures. VRFCAT performance was strongly correlated with cognitive performance. In the SCD group, VRFCAT performance was strongly correlated with cognitive performance across nearly all tests with significant correlation coefficients ranging from 0.3 to 0.7; VRFCAT summary measures all had correlations greater than r=0.5 with MoCA performance and BAC App Verbal Memory (p<0.01 for all). CONCLUSIONS: Findings suggest the VRFCAT provides a sensitive tool for evaluation of IADL functioning in individuals with subjective cognitive decline. Strong correlations with cognition across groups suggest the VRFCAT may be uniquely suited for clinical trials in preclinical AD, as well as longitudinal investigations of the relationship between cognition and function.}, Doi = {10.14283/jpad.2018.28}, Key = {fds339319} } @article{fds336079, Author = {Keefe, RSE and Harvey, PD and Khan, A and Saoud, JB and Staner, C and Davidson, M and Luthringer, R}, Title = {Cognitive Effects of MIN-101 in Patients With Schizophrenia and Negative Symptoms: Results From a Randomized Controlled Trial.}, Journal = {The Journal of Clinical Psychiatry}, Volume = {79}, Number = {3}, Year = {2018}, url = {http://dx.doi.org/10.4088/JCP.17m11753}, Abstract = {OBJECTIVE: Current dopamine-blocking antipsychotic drugs have little impact on the cognitive deficits associated with schizophrenia. We evaluated whether MIN-101, a molecule that combines sigma-2 antagonism and 5-HT2A antagonism, might improve cognitive deficits in individuals with moderate to severe negative symptoms in schizophrenia. METHODS: Individuals (N = 244) aged 18 to 60 years with stable symptoms of DSM-5-defined schizophrenia and moderate to severe negative symptoms were randomized to placebo (n = 83), MIN-101 32 mg (n = 78), or MIN-101 64 mg (n = 83) in a 12-week, phase 2b, prospective, double-blind, placebo-controlled, parallel-group trial between May 2015 and December 2015. In a post hoc analysis, mean z and T score changes from baseline at 12 weeks of treatment in the cognitive composite score and individual tests on the Brief Assessment of Cognition in Schizophrenia (BACS) Battery were compared between MIN-101 and placebo. RESULTS: A total of 79 patients (95.2%) from the placebo group, 76 (97.4%) from the MIN-101 32 mg group, and 79 (95.2%) from the MIN-101 64 mg group completed the BACS at baseline. The BACS token motor (P = .04), verbal fluency (P = .01), and composite z scores (P = .05) showed significant improvements in the MIN-101 32 mg group compared to the placebo group. At week 4, the clinical improvements from baseline in the Positive and Negative Syndrome Scale (PANSS) negative factor showed a significant correlation with improvements from baseline on the BACS composite in the 64 mg group (r = -0.292, P = .020). At week 12, improvement in the PANSS negative factor showed significant correlations with improvements in the BACS composite (r = -0.408, P = .002), Trail Making Test (r = -0.394, P = .003), and verbal memory (r = -0.322, P = .017) for the 64 mg group. CONCLUSIONS: Results suggest a possible benefit of MIN-101 on cognitive performance in individuals with schizophrenia with stable positive symptoms and concurrent clinically significant negative symptoms. TRIAL REGISTRATION: EU Clinical Trials Register identifier: 2014-004878-42.}, Doi = {10.4088/JCP.17m11753}, Key = {fds336079} } @article{fds337108, Author = {Romero, HR and Monsch, AU and Hayden, KM and Plassman, BL and Atkins, AS and Keefe, RSE and Brewster, S and Chiang, C and O'Neil, J and Runyan, G and Atkinson, MJ and Crawford, S and Budur, K and Burns, DK and Welsh-Bohmer, KA}, Title = {TOMMORROW neuropsychological battery: German language validation and normative study.}, Journal = {Alzheimer'S & Dementia (New York, N. Y.)}, Volume = {4}, Pages = {314-323}, Year = {2018}, url = {http://dx.doi.org/10.1016/j.trci.2018.06.009}, Abstract = {INTRODUCTION: Assessment of preclinical Alzheimer's disease (AD) requires reliable and validated methods to detect subtle cognitive changes. The battery of standardized cognitive assessments that is used for diagnostic criteria for mild cognitive impairment due to AD in the TOMMORROW study have only been fully validated in English-speaking countries. We conducted a validation and normative study of the German language version of the TOMMORROW neuropsychological test battery, which tests episodic memory, language, visuospatial ability, executive function, and attention. METHODS: German-speaking cognitively healthy controls (NCs) and subjects with AD were recruited from a memory clinic at a Swiss medical center. Construct validity, test-retest, and alternate form reliability were assessed in NCs. Criterion and discriminant validities of the cognitive measures were tested using logistic regression and discriminant analysis. Cross-cultural equivalency of performance of the German language tests was compared with English language tests. RESULTS: A total of 198 NCs and 25 subjects with AD (aged 65-88 years) were analyzed. All German language tests discriminated NCs from persons with AD. Episodic memory tests had the highest potential to discriminate with almost twice the predictive power of any other domain. Test-retest reliability of the test battery was adequate, and alternate form reliability for episodic memory tests was supported. For most tests, age was a significant predictor of group effect sizes; therefore, normative data were stratified by age. Validity and reliability results were similar to those in the published US cognitive testing literature. DISCUSSION: This study establishes the reliability and validity of the German language TOMMORROW test battery, which performed similarly to the English language tests. Some variations in test performance underscore the importance of regional normative values. The German language battery and normative data will improve the precision of measuring cognition and diagnosing incident mild cognitive impairment due to AD in clinical settings in German-speaking countries.}, Doi = {10.1016/j.trci.2018.06.009}, Key = {fds337108} } @article{fds326634, Author = {Hochberger, WC and Combs, T and Reilly, JL and Bishop, JR and Keefe, RSE and Clementz, BA and Keshavan, MS and Pearlson, GD and Tamminga, CA and Hill, SK and Sweeney, JA}, Title = {Deviation from expected cognitive ability across psychotic disorders.}, Journal = {Schizophrenia Research}, Volume = {192}, Pages = {300-307}, Year = {2018}, Month = {February}, url = {http://dx.doi.org/10.1016/j.schres.2017.05.019}, Abstract = {Patients with schizophrenia show a deficit in cognitive ability compared to estimated premorbid and familial intellectual abilities. However, the degree to which this pattern holds across psychotic disorders and is familial is unclear. The present study examined deviation from expected cognitive level in schizophrenia, schizoaffective disorder, and psychotic bipolar disorder probands and their first-degree relatives. Using a norm-based regression approach, parental education and WRAT-IV Reading scores (both significant predictors of cognitive level in the healthy control group) were used to predict global neuropsychological function as measured by the composite score from the Brief Assessment of Cognition in Schizophrenia (BACS) test in probands and relatives. When compared to healthy control group, psychotic probands showed a significant gap between observed and predicted BACS composite scores and a greater likelihood of robust cognitive decline. This effect was not seen in unaffected relatives. While BACS and WRAT-IV Reading scores were themselves highly familial, the decline in cognitive function from expectation had lower estimates of familiality. Thus, illness-related factors such as epigenetic, treatment, or pathophysiological factors may be important causes of illness related decline in cognitive abilities across psychotic disorders. This is consistent with the markedly greater level of cognitive impairment seen in affected individuals compared to their unaffected family members.}, Doi = {10.1016/j.schres.2017.05.019}, Key = {fds326634} } @article{fds337740, Author = {Healey, KM and Penn, DL and Perkins, D and Woods, SW and Keefe, RSE and Addington, J}, Title = {Latent Profile Analysis and Conversion to Psychosis: Characterizing Subgroups to Enhance Risk Prediction.}, Journal = {Schizophrenia Bulletin}, Volume = {44}, Number = {2}, Pages = {286-296}, Year = {2018}, Month = {February}, url = {http://dx.doi.org/10.1093/schbul/sbx080}, Abstract = {BACKGROUND: Groups at clinical high risk (CHR) of developing psychosis are heterogeneous, composed of individuals with different clusters of symptoms. It is likely that there exist subgroups, each associated with different symptom constellations and probabilities of conversion. METHOD: Present study used latent profile analysis (LPA) to ascertain subgroups in a combined sample of CHR (n = 171) and help-seeking controls (HSCs; n = 100; PREDICT study). Indicators in the LPA model included baseline Scale of Prodromal Symptoms (SOPS), Calgary Depression Scale for Schizophrenia (CDSS), and neurocognitive performance as measured by multiple instruments, including category instances (CAT). Subgroups were further characterized using covariates measuring demographic and clinical features. RESULTS: Three classes emerged: class 1 (mild, transition rate 5.6%), lowest SOPS and depression scores, intact neurocognitive performance; class 2 (paranoid-affective, transition rate 14.2%), highest suspiciousness, mild negative symptoms, moderate depression; and class 3 (negative-neurocognitive, transition rate 29.3%), highest negative symptoms, neurocognitive impairment, social cognitive impairment. Classes 2 and 3 evidenced poor social functioning. CONCLUSIONS: Results support a subgroup approach to research, assessment, and treatment of help-seeking individuals. Class 3 may be an early risk stage of developing schizophrenia.}, Doi = {10.1093/schbul/sbx080}, Key = {fds337740} } @article{fds327210, Author = {Xavier, RM and Pan, W and Dungan, JR and Keefe, RSE and Vorderstrasse, A}, Title = {Unraveling interrelationships among psychopathology symptoms, cognitive domains and insight dimensions in chronic schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {193}, Pages = {83-90}, Year = {2018}, Month = {March}, url = {http://dx.doi.org/10.1016/j.schres.2017.07.002}, Abstract = {INTRODUCTION: Insight in schizophrenia is long known to have a complex relationship with psychopathology symptoms and cognition. However, very few studies have examined models that explain these interrelationships. METHODS: In a large sample derived from the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial (N=1391), we interrogated these interrelationships for potential causal pathways using structural equation modeling. Using the NIMH consensus model, latent variables were constructed for psychopathology symptom dimensions, including positive, negative, disorganized, excited and depressed from the Positive and Negative Syndrome Scale (PANSS) items. Neurocognitive variables were created from five predefined domains of working memory, verbal memory, reasoning, vigilance and processing speed. Illness insight and treatment insight were tested using latent variables constructed from the Illness and Treatment Attitude Questionnaire (ITAQ). RESULTS: Disorganized symptoms had the strongest effect on insight. Illness insight mediated the relationship of positive, depressed, and disorganized symptoms with treatment insight. Neurocognition mediated the relationship between disorganized and treatment insight and depressed symptoms and treatment insight. There was no effect of negative symptoms on either illness insight or treatment insight. Taken together, our results indicate overlapping and unique relational paths for illness and treatment insight dimensions, which could suggest differences in causal mechanisms and potential interventions to improve insight.}, Doi = {10.1016/j.schres.2017.07.002}, Key = {fds327210} } @article{fds370730, Author = {Ventura, J and Welikson, T and Subotnik, KL and Ered, A and Keefe, R and Hellemann, GH and Nuechterlein, KH}, Title = {T59. VIRTUAL REALTY ASSESSMENT OF FUNCTIONAL CAPACITY IN EARLY SCHIZOPHRENIA: ASSOCIATIONS WITH NEUROCOGNITION, FUNCTIONAL CAPACITY PERFORMANCE, AND DAILY FUNCTIONING}, Journal = {Schizophrenia Bulletin}, Volume = {44}, Number = {suppl_1}, Pages = {S136-S137}, Publisher = {Oxford University Press (OUP)}, Year = {2018}, Month = {April}, url = {http://dx.doi.org/10.1093/schbul/sby016.335}, Doi = {10.1093/schbul/sby016.335}, Key = {fds370730} } @article{fds370731, Author = {Seccomandi, B and Agbedjro, D and Bell, M and Keefe, R and Keshavan, M and Galderisi, S and Medalia, A and Fiszdon, J and Maj, M and Mucci, A and Cavallato, R and Wykes, T and Cella, M}, Title = {T206. DOES AGE INFLUENCE RESPONSE TO COGNITIVE REMEDIATION?}, Journal = {Schizophrenia Bulletin}, Volume = {44}, Number = {suppl_1}, Pages = {S196-S197}, Publisher = {Oxford University Press (OUP)}, Year = {2018}, Month = {April}, url = {http://dx.doi.org/10.1093/schbul/sby016.482}, Doi = {10.1093/schbul/sby016.482}, Key = {fds370731} } @article{fds327061, Author = {Kendler, KS and Ohlsson, H and Keefe, RSE and Sundquist, K and Sundquist, J}, Title = {The joint impact of cognitive performance in adolescence and familial cognitive aptitude on risk for major psychiatric disorders: a delineation of four potential pathways to illness.}, Journal = {Mol Psychiatry}, Volume = {23}, Number = {4}, Pages = {1076-1083}, Year = {2018}, Month = {April}, url = {http://dx.doi.org/10.1038/mp.2017.78}, Abstract = {How do joint measures of premorbid cognitive ability and familial cognitive aptitude (FCA) reflect risk for a diversity of psychiatric and substance use disorders? To address this question, we examined, using Cox models, the predictive effects of school achievement (SA) measured at age 16 and FCA-assessed from SA in siblings and cousins, and educational attainment in parents-on risk for 12 major psychiatric syndromes in 1 140 608 Swedes born 1972-1990. Four developmental patterns emerged. In the first, risk was predicted jointly by low levels of SA and high levels of FCA-that is a level of SA lower than would be predicted from the FCA. This pattern was strongest in autism spectrum disorders and schizophrenia, and weakest in bipolar illness. In these disorders, a pathologic process seems to have caused cognitive functioning to fall substantially short of familial potential. In the second pattern, seen in the internalizing conditions of major depression and anxiety disorders, risk was associated with low SA but was unrelated to FCA. Externalizing disorders-drug abuse and alcohol use disorders-demonstrated the third pattern, in which risk was predicted jointly by low SA and low FCA. The fourth pattern, seen in eating disorders, was directly opposite of that observed in externalizing disorders with risk associated with high SA and high FCA. When measured together, adolescent cognitive ability and FCA identified four developmental patterns leading to diverse psychiatric disorders. The value of cognitive assessments in psychiatric research can be substantially increased by also evaluating familial cognitive potential.}, Doi = {10.1038/mp.2017.78}, Key = {fds327061} } @article{fds336080, Author = {Shafee, R and Nanda, P and Padmanabhan, JL and Tandon, N and Alliey-Rodriguez, N and Kalapurakkel, S and Weiner, DJ and Gur, RE and Keefe, RSE and Hill, SK and Bishop, JR and Clementz, BA and Tamminga, CA and Gershon, ES and Pearlson, GD and Keshavan, MS and Sweeney, JA and McCarroll, SA and Robinson, EB}, Title = {Polygenic risk for schizophrenia and measured domains of cognition in individuals with psychosis and controls.}, Journal = {Translational Psychiatry}, Volume = {8}, Number = {1}, Pages = {78}, Year = {2018}, Month = {April}, url = {http://dx.doi.org/10.1038/s41398-018-0124-8}, Abstract = {Psychotic disorders including schizophrenia are commonly accompanied by cognitive deficits. Recent studies have reported negative genetic correlations between schizophrenia and indicators of cognitive ability such as general intelligence and processing speed. Here we compare the effect of polygenetic risk for schizophrenia (PRSSCZ) on measures that differ in their relationships with psychosis onset: a measure of current cognitive abilities (the Brief Assessment of Cognition in Schizophrenia, BACS) that is greatly reduced in psychotic disorder patients, a measure of premorbid intelligence that is minimally affected by psychosis onset (the Wide-Range Achievement Test, WRAT); and educational attainment (EY), which covaries with both BACS and WRAT. Using genome-wide single nucleotide polymorphism (SNP) data from 314 psychotic and 423 healthy research participants in the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) Consortium, we investigated the association of PRSSCZ with BACS, WRAT, and EY. Among apparently healthy individuals, greater genetic risk for schizophrenia (PRSSCZ) was significantly associated with lower BACS scores (r = -0.17, p = 6.6 × 10-4 at PT = 1 × 10-4), but not with WRAT or EY. Among individuals with psychosis, PRSSCZ did not associate with variations in any of these three phenotypes. We further investigated the association between PRSSCZ and WRAT in more than 4500 healthy subjects from the Philadelphia Neurodevelopmental Cohort. The association was again null (p > 0.3, N = 4511), suggesting that different cognitive phenotypes vary in their etiologic relationship with schizophrenia.}, Doi = {10.1038/s41398-018-0124-8}, Key = {fds336080} } @article{fds371748, Author = {Sand, M and Nakagome, K and Cordes, J and Brenner, R and Gründer, G and Keefe, R and Riesenberg, R and Walling, D and Daniels, K and Wang, L and Carter, K and Brown, D}, Title = {T205. Effect of BI 409306 on Positive and Negative Syndrome Scale in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial}, Journal = {Biological Psychiatry}, Volume = {83}, Number = {9}, Pages = {S207-S208}, Publisher = {Elsevier BV}, Year = {2018}, Month = {May}, url = {http://dx.doi.org/10.1016/j.biopsych.2018.02.542}, Doi = {10.1016/j.biopsych.2018.02.542}, Key = {fds371748} } @article{fds329375, Author = {Blokland, GAM and Del Re and EC and Mesholam-Gately, RI and Jovicich, J and Trampush, JW and Keshavan, MS and DeLisi, LE and Walters, JTR and Turner, JA and Malhotra, AK and Lencz, T and Shenton, ME and Voineskos, AN and Rujescu, D and Giegling, I and Kahn, RS and Roffman, JL and Holt, DJ and Ehrlich, S and Kikinis, Z and Dazzan, P and Murray, RM and Di Forti, M and Lee, J and Sim, K and Lam, M and Wolthusen, RPF and de Zwarte, SMC and Walton, E and Cosgrove, D and Kelly, S and Maleki, N and Osiecki, L and Picchioni, MM and Bramon, E and Russo, M and David, AS and Mondelli, V and Reinders, AATS and Falcone, MA and Hartmann, AM and Konte, B and Morris, DW and Gill, M and Corvin, AP and Cahn, W and Ho, NF and Liu, JJ and Keefe, RSE and Gollub, RL and Manoach, DS and Calhoun, VD and Schulz, SC and Sponheim, SR and Goff, DC and Buka, SL and Cherkerzian, S and Thermenos, HW and Kubicki, M and Nestor, PG and Dickie, EW and Vassos, E and Ciufolini, S and Reis Marques and T and Crossley, NA and Purcell, SM and Smoller, JW and van Haren, NEM and Toulopoulou, T and Donohoe, G and Goldstein, JM and Seidman, LJ and McCarley, RW and Petryshen, TL}, Title = {The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.}, Journal = {Schizophrenia Research}, Volume = {195}, Pages = {306-317}, Year = {2018}, Month = {May}, url = {http://dx.doi.org/10.1016/j.schres.2017.09.024}, Abstract = {BACKGROUND: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10-10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. CONCLUSIONS: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.}, Doi = {10.1016/j.schres.2017.09.024}, Key = {fds329375} } @article{fds336078, Author = {Keefe, RSE and Nomikos, G and Zhong, W and Christensen, MC and Jacobson, W}, Title = {A Subgroup Analysis of the Impact of Vortioxetine on Functional Capacity, as Measured by UPSA, in Patients with Major Depressive Disorder and Subjective Cognitive Dysfunction.}, Journal = {The International Journal of Neuropsychopharmacology}, Volume = {21}, Number = {5}, Pages = {442-447}, Year = {2018}, Month = {May}, url = {http://dx.doi.org/10.1093/ijnp/pyy020}, Abstract = {BACKGROUND: We evaluated vortioxetine's effects on functional capacity in demographic and clinical subgroups of patients with major depressive disorder. METHODS: This was an exploratory analysis of the CONNECT study (NCT01564862) that evaluated changes in functional capacity using University of California San Diego Performance-based Skills Assessment data, categorized by sex, age, education, employment status, and baseline disease severity (Montgomery-Åsberg Depression Rating Scale, Clinical Global Impressions-Severity of Illness). RESULTS: Greater changes in University of California San Diego Performance-based Skills Assessment composite scores were observed with vortioxetine vs placebo in specific subgroups: males (∆+3.2), females (∆+2.9), 45-54 or ≥55 years (∆+5.6, ∆+3.4), working (∆+2.8), high school or greater education (∆+2.7, ∆+2.8), disease severity (Montgomery-Åsberg Depression Rating Scale, <30, ∆+3.5; ≥30, ∆+2.5; Clinical Global Impressions-Severity of Illness ≤4, ∆+2.8; >4, ∆+3.0), major depressive episodes (≤2, >2 [∆+2.7,+3.3]), and episode duration (≤22, >22 weeks [∆+3.7,+2.4]). CONCLUSIONS: Our findings support the need for additional studies to assess whether vortioxetine improves functional capacity within specific patient subgroups. CLINICAL TRIAL REGISTRY: clinicaltrials.gov: NCT01564862.}, Doi = {10.1093/ijnp/pyy020}, Key = {fds336078} } @article{fds329482, Author = {Xavier, RM and Vorderstrasse, A and Keefe, RSE and Dungan, JR}, Title = {Genetic correlates of insight in schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {195}, Pages = {290-297}, Year = {2018}, Month = {May}, url = {http://dx.doi.org/10.1016/j.schres.2017.10.021}, Abstract = {UNLABELLED: Insight in schizophrenia is clinically important as it is associated with several adverse outcomes. Genetic contributions to insight are unknown. We examined genetic contributions to insight by investigating if polygenic risk scores (PRS) and candidate regions were associated with insight. METHOD: Schizophrenia case-only analysis of the Clinical Antipsychotics Trials of Intervention Effectiveness trial. Schizophrenia PRS was constructed using Psychiatric Genomics Consortium (PGC) leave-one out GWAS as discovery data set. For candidate regions, we selected 105 schizophrenia-associated autosomal loci and 11 schizophrenia-related oligodendrocyte genes. We used regressions to examine PRS associations and set-based testing for candidate analysis. RESULTS: We examined data from 730 subjects. Best-fit PRS at p-threshold of 1e-07 was associated with total insight (R2=0.005, P=0.05, empirical P=0.054) and treatment insight (R2=0.005, P=0.048, empirical P=0.048). For models that controlled for neurocognition, PRS significantly predicted treatment insight but at higher p-thresholds (0.1 to 0.5) but did not survive correction. Patients with highest polygenic burden had 5.9 times increased risk for poor insight compared to patients with lowest burden. PRS explained 3.2% (P=0.002, empirical P=0.011) of variance in poor insight. Set-based analyses identified two variants associated with poor insight- rs320703, an intergenic variant (within-set P=6e-04, FDR P=0.046) and rs1479165 in SOX2-OT (within-set P=9e-04, FDR P=0.046). CONCLUSION: To the best of our knowledge, this is the first study examining genetic basis of insight. We provide evidence for genetic contributions to impaired insight. Relevance of findings and necessity for replication are discussed.}, Doi = {10.1016/j.schres.2017.10.021}, Key = {fds329482} } @article{fds332787, Author = {Xavier, RM and Dungan, JR and Keefe, RSE and Vorderstrasse, A}, Title = {Polygenic signal for symptom dimensions and cognitive performance in patients with chronic schizophrenia.}, Journal = {Schizophrenia Research. Cognition}, Volume = {12}, Pages = {11-19}, Year = {2018}, Month = {June}, url = {http://dx.doi.org/10.1016/j.scog.2018.01.001}, Abstract = {Genetic etiology of psychopathology symptoms and cognitive performance in schizophrenia is supported by candidate gene and polygenic risk score (PRS) association studies. Such associations are reported to be dependent on several factors - sample characteristics, illness phase, illness severity etc. We aimed to examine if schizophrenia PRS predicted psychopathology symptoms and cognitive performance in patients with chronic schizophrenia. We also examined if schizophrenia associated autosomal loci were associated with specific symptoms or cognitive domains. Case-only analysis using data from the Clinical Antipsychotics Trials of Intervention Effectiveness-Schizophrenia trials (n = 730). PRS was constructed using Psychiatric Genomics Consortium (PGC) leave one out genome wide association analysis as the discovery data set. For candidate region analysis, we selected 105-schizophrenia associated autosomal loci from the PGC study. We found a significant effect of PRS on positive symptoms at p-threshold (PT ) of 0.5 (R2 = 0.007, p = 0.029, empirical p = 0.029) and negative symptoms at PT of 1e-07 (R2 = 0.005, p = 0.047, empirical p = 0.048). For models that additionally controlled for neurocognition, best fit PRS predicted positive (p-threshold 0.01, R2 = 0.007, p = 0.013, empirical p = 0.167) and negative symptoms (p-threshold 0.1, R2 = 0.012, p = 0.004, empirical p = 0.329). No associations were seen for overall neurocognitive and social cognitive performance tests. Post-hoc analyses revealed that PRS predicted working memory and vigilance performance but did not survive correction. No candidate regions that survived multiple testing corrections were associated with either symptoms or cognitive performance. Our findings point to potentially distinct pathogenic mechanisms for schizophrenia symptoms.}, Doi = {10.1016/j.scog.2018.01.001}, Key = {fds332787} } @article{fds346907, Author = {Fava, M and Mahableshwarkar, AR and Jacobson, W and Zhong, W and Keefe, RS and Olsen, CK and Jaeger, J}, Title = {What is the overlap between subjective and objective cognitive impairments in MDD?}, Journal = {Ann Clin Psychiatry}, Volume = {30}, Number = {3}, Pages = {176-184}, Year = {2018}, Month = {August}, Abstract = {BACKGROUND: Cognitive impairments, such as memory deficits and executive impairment, are common among patients with major depressive disorder (MDD) and can be captured with objective or subjective assessments. The aim of this post-hoc analysis of the CONNECT study was to assess the degree of overlap between subjective and objective cognitive impairment among MDD patients, and to evaluate associated clinical characteristics. METHODS: The study was conducted from April 2012 to February 2014 and enrolled a total of 602 patients with MDD who reported subjective cognitive impairment. Efficacy was assessed using a battery of objective tests of cognitive function representing multiple domains: Digit Symbol Substitution Test performance, Trail Making Test A, Trail Making Test B, Congruent and Incongruent Stroop Test, Groton Maze Learning Test, Detection Task, Identification Task, and One-Back Task. The Cognitive and Physical Functioning Questionnaire (CPFQ) was used to capture patient-reported assessments of cognitive function. RESULTS: Although 48% of patients with MDD met our conservative criteria for subjectively defined marked cognitive impairment, 64% of patients with MDD met our conservative criteria for objectively defined cognitive impairment. Therefore, the proportion of patients defined as having impaired cognition was somewhat similar regardless of methodology. Overall, 80% of patients with MDD in this study reported either subjective or objective cognitive impairment per subjective and objective scales. However, the proportion of patients meeting criteria for both subjectively and objectively defined cognitive impairment was only 31%. This could be explained by the fact that the CPFQ total score was only modestly-although significantly-correlated with all but one of the objective tests. CONCLUSIONS: This post-hoc study shows that approximately 80% of patients with MDD participating in an antidepressant trial reported either subjective or objective cognitive impairment.}, Key = {fds346907} } @article{fds337700, Author = {Lam, M and Lee, J and Rapisarda, A and See, YM and Yang, Z and Lee, S-A and Abdul-Rashid, NA and Kraus, M and Subramaniam, M and Chong, S-A and Keefe, RSE}, Title = {Longitudinal Cognitive Changes in Young Individuals at Ultrahigh Risk for Psychosis.}, Journal = {Jama Psychiatry}, Volume = {75}, Number = {9}, Pages = {929-939}, Year = {2018}, Month = {September}, url = {http://dx.doi.org/10.1001/jamapsychiatry.2018.1668}, Abstract = {IMPORTANCE: Cognitive deficits are a key feature of risk for psychosis. Longitudinal changes in cognitive architecture may be associated with the social and occupational functioning in young people. OBJECTIVES: To examine longitudinal profiles of cognition in individuals at ultrahigh risk (UHR) for psychosis, compared with healthy controls, and to investigate the association of cognition with functioning. DESIGN, SETTING, AND PARTICIPANTS: This study has a multiple-group prospective design completed in 24 months and was conducted from January 1, 2009, to November 11, 2012, as part of the Longitudinal Youth at-Risk Study conducted in Singapore. Participants either were recruited from psychiatric outpatient clinics, educational institutions, and community mental health agencies or self-referred. Follow-up assessments were performed every 6 months for 2 years or until conversion to psychosis. Individuals with medical causes for psychosis, current illicit substance use, or color blindness were excluded. Data analysis was conducted from June 2014 to May 2018. MAIN OUTCOMES AND MEASURES: Neuropsychological, perceptual, and social cognitive tasks; semi-structured interviews, and the Structured Clinical Interview for DSM-IV Axis I disorders were administered every 6 months. The UHR status of nonconverters, converters, remitters, and nonremitters was monitored. Cognitive domain scores and functioning were investigated longitudinally. RESULTS: In total, 384 healthy controls and 173 UHR individuals between ages 14 and 29 years were evaluated prospectively. Of the 384 healthy controls, 153 (39.8%) were female and 231 (60.2%) were male with a mean (SD) age of 21.69 (3.26) years. Of the 173 individuals at UHR for psychosis, 56 (32.4%) were female and 117 (67.6%) were male with a mean (SD) age of 21.27 (3.52) years). After 24 months of follow-up, 383 healthy controls (99.7%) and 122 individuals at UHR for psychosis (70.5%) remained. Baseline cognitive deficits were associated with psychosis conversion later (mean odds ratio [OR], 1.66; combined 95% CI, 1.08-2.83; P = .04) and nonremission of UHR status (mean OR, 1.67; combined 95% CI, 1.09-2.95; P = .04). Five cognitive components-social cognition, attention, verbal fluency, general cognitive function, and perception-were obtained from principal components analysis. Longitudinal component structure change was observed in general cognitive function (maximum vertical deviation = 0.59; χ2 = 8.03; P = .01). Group-by-time interaction on general cognitive function (F = 12.23; η2 = 0.047; P < .001) and perception (F = 8.33; η2 = 0.032; P < .001) was present. Changes in attention (F = 5.65; η2 = 0.013; P = .02) and general cognitive function (F = 7.18; η2 = 0.014; P = .01) accounted for longitudinal changes in social and occupational functioning. CONCLUSIONS AND RELEVANCE: Individuals in this study who met the UHR criteria appeared to demonstrate cognitive deficits, and those whose UHR status remitted were seen to recover cognitively. Cognition appeared as poor in nonremitters and appeared to be associated with poor functional outcome. This study suggests that cognitive dimensions are sensitive to the identification of young individuals at risk for psychosis and to the longitudinal course of those at highest risk.}, Doi = {10.1001/jamapsychiatry.2018.1668}, Key = {fds337700} } @article{fds336077, Author = {Yang, Z and Lim, K and Lam, M and Keefe, R and Lee, J}, Title = {Factor structure of the positive and negative syndrome scale (PANSS) in people at ultra high risk (UHR) for psychosis.}, Journal = {Schizophrenia Research}, Volume = {201}, Pages = {85-90}, Year = {2018}, Month = {November}, url = {http://dx.doi.org/10.1016/j.schres.2018.05.024}, Abstract = {INTRODUCTION: The Positive and Negative Syndrome Scale (PANSS), a comprehensive psychopathology assessment scale used in the evaluation of psychopathology in schizophrenia, is also often used in the Ultra-High-Risk (UHR) population. This paper examined the dimensional structure of the PANSS in a UHR sample. METHODS: A total of 168 individuals assessed to be at UHR for psychosis on the Comprehensive Assessment of At-Risk Mental States (CAARMS) were evaluated on the PANSS, Calgary Depression Scale for Schizophrenia (CDSS), Beck Anxiety Inventory (BAI), Brief Assessment of Cognition in Schizophrenia (BACS), and Global Assessment of Functioning (GAF). Exploratory factor analysis (EFA) of the PANSS was performed to identify the factorial structure. Convergent validity was explored with the CAARMS, CDSS, BAI and BACS. RESULTS: EFA of the PANSS yielded five symptom factors - Positive, Negative, Cognition/Disorganization, Anxiety/Depression, and Hostility. This 5-factor solution showed good convergent validity with the CAARMS composite score, CDSS, BAI, and BACS. Positive, Negative and Anxiety/Depression factors were associated with functioning. CONCLUSION: The reported PANSS factor structure may serve to improve the understanding and measurement of clinical symptom dimensions manifested in people with UHR for future research and clinical setting.}, Doi = {10.1016/j.schres.2018.05.024}, Key = {fds336077} } @article{fds339669, Author = {Keefe, RSE and Pani, L}, Title = {Take This Cognitive Training Efficacy Bar Fight Outside (to a Regulatory Agency).}, Journal = {Biological Psychiatry. Cognitive Neuroscience and Neuroimaging}, Volume = {3}, Number = {11}, Pages = {900-902}, Year = {2018}, Month = {November}, url = {http://dx.doi.org/10.1016/j.bpsc.2018.09.002}, Doi = {10.1016/j.bpsc.2018.09.002}, Key = {fds339669} } @article{fds339773, Author = {Wang, C and Lee, J and Ho, NF and Lim, JKW and Poh, JS and Rekhi, G and Krishnan, R and Keefe, RSE and Adcock, RA and Wood, SJ and Fornito, A and Chee, MWL and Zhou, J}, Title = {Large-Scale Network Topology Reveals Heterogeneity in Individuals With at Risk Mental State for Psychosis: Findings From the Longitudinal Youth-at-Risk Study.}, Journal = {Cerebral Cortex}, Volume = {28}, Number = {12}, Pages = {4234-4243}, Year = {2018}, Month = {December}, url = {http://dx.doi.org/10.1093/cercor/bhx278}, Abstract = {Emerging evidence demonstrates heterogeneity in clinical outcomes of prodromal psychosis that only a small percentage of at-risk individuals eventually progress to full-blown psychosis. To examine the neurobiological underpinnings of this heterogeneity from a network perspective, we tested whether the early patterns of large-scale brain network topology were associated with risk of developing clinical psychosis. Task-free functional MRI data were acquired from subjects with At Risk Mental State (ARMS) for psychosis and healthy controls (HC). All individuals had no history of drug abuse and were not on antipsychotics. We performed functional connectomics analysis to identify patterns of system-level functional brain dysconnectivity associated with ARMS individuals with different outcomes. In comparison to HC and ARMS who did not transition to psychosis at follow-up (ARMS-NT), ARMS individuals who did (ARMS-T) showed marked brain functional dysconnectivity, characterized by loss of network segregation and disruption of network communities, especially the salience, default, dorsal attention, sensorimotor and limbic networks (P < 0.05 FWE-corrected, Cohen's d > 1.00), and was associated with baseline symptom severity. In contrast, we did not observe connectivity differences between ARMS-NT and HC individuals. Taken together, these results suggest a possible large-scale functional brain network topology phenotype related to risk of psychosis transition in ARMS individuals.}, Doi = {10.1093/cercor/bhx278}, Key = {fds339773} } @article{fds348865, Author = {Krystal, AD and Pizzagalli, DA and Mathew, SJ and Sanacora, G and Keefe, R and Song, A and Calabrese, J and Goddard, A and Goodman, W and Lisanby, SH and Smoski, M and Weiner, R and Iosifescu, D and Nurnberger, J and Szabo, S and Murrough, J and Shekhar, A and Potter, W}, Title = {The first implementation of the NIMH FAST-FAIL approach to psychiatric drug development.}, Journal = {Nat Rev Drug Discov}, Volume = {18}, Number = {1}, Pages = {82-84}, Year = {2018}, Month = {December}, url = {http://dx.doi.org/10.1038/nrd.2018.222}, Doi = {10.1038/nrd.2018.222}, Key = {fds348865} } @article{fds371764, Author = {Keefe, R and Canadas, E and Song, D and Farlow, D}, Title = {A Randomized, Double-Blind, Controlled, 6-Week Trial to Assess a Novel Digital Intervention Designed to Improve Cognitive Dysfunction as Adjunct Therapy to Antidepressant Medication in Adults With Major Depressive Disorder}, Journal = {Neuropsychopharmacology}, Volume = {44}, Number = {SUPPL 1}, Pages = {425-425}, Year = {2019}, Key = {fds371764} } @article{fds338438, Author = {Kraus, MS and Walker, TM and Jarskog, LF and Millet, RA and Keefe, RSE}, Title = {Basic auditory processing deficits and their association with auditory emotion recognition in schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {204}, Pages = {155-161}, Year = {2019}, Month = {February}, url = {http://dx.doi.org/10.1016/j.schres.2018.08.031}, Abstract = {BACKGROUND: Individuals with schizophrenia are impaired in their ability to recognize emotions based on vocal cues and these impairments are associated with poor global outcome. Basic perceptual processes, such as auditory pitch processing, are impaired in schizophrenia and contribute to difficulty identifying emotions. However, previous work has focused on a relatively narrow assessment of auditory deficits and their relation to emotion recognition impairment in schizophrenia. METHODS: We have assessed 87 patients with schizophrenia and 73 healthy controls on a comprehensive battery of tasks spanning the five empirically derived domains of auditory function. We also explored the relationship between basic auditory processing and auditory emotion recognition within the patient group using correlational analysis. RESULTS: Patients exhibited widespread auditory impairments across multiple domains of auditory function, with mostly medium effect sizes. Performance on all of the basic auditory tests correlated with auditory emotion recognition at the p < .01 level in the patient group, with 9 out of 13 tests correlating with emotion recognition at r = 0.40 or greater. After controlling for cognition, many of the largest correlations involved spectral processing within the phase-locking range and discrimination of vocally based stimuli. CONCLUSIONS: While many auditory skills contribute to this impairment, deficient formant discrimination appears to be a key skill contributing to impaired emotion recognition as this was the only basic auditory skill to enter a step-wise multiple regression after first entering a measure of cognitive impairment, and formant discrimination accounted for significant unique variance in emotion recognition performance after accounting for deficits in pitch processing.}, Doi = {10.1016/j.schres.2018.08.031}, Key = {fds338438} } @article{fds342181, Author = {Brown, D and Nakagome, K and Cordes, J and Brenner, R and Gründer, G and Keefe, RSE and Riesenberg, R and Walling, DP and Daniels, K and Wang, L and McGinniss, J and Sand, M}, Title = {Evaluation of the Efficacy, Safety, and Tolerability of BI 409306, a Novel Phosphodiesterase 9 Inhibitor, in Cognitive Impairment in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial.}, Journal = {Schizophrenia Bulletin}, Volume = {45}, Number = {2}, Pages = {350-359}, Year = {2019}, Month = {March}, url = {http://dx.doi.org/10.1093/schbul/sby049}, Abstract = {BACKGROUND: Patients with cognitive impairment associated with schizophrenia may benefit from treatments targeting dysfunctional glutamatergic neurotransmission. BI 409306, a potent and selective phosphodiesterase 9 inhibitor, was assessed in patients with schizophrenia using a learn-and-confirm adaptive trial design. METHODS: This double-blind, parallel-group trial randomized patients 2:1:1:1:1 to once-daily placebo or BI 409306 (10, 25, 50, or 100 mg) for 12 weeks. Stage 1 (learn) assessed change from baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) scores (week 12) to identify ≥1 meaningful endpoints for stage 2 (confirm). If no domains showed efficacy, change from baseline in Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) composite scores (week 12) was the primary endpoint. The key secondary endpoint was change from baseline in Schizophrenia Cognition Rating Scale (SCoRS) total score. Safety was monitored. RESULTS: Five hundred eighteen patients were randomized. In stage 1, CANTAB did not differentiate between BI 409306 and placebo (n = 120), so the primary endpoint of change from baseline in MCCB composite score was analyzed in 450 patients in stage 2. There was no significant difference between BI 409306 (1.2-2.8) and placebo (2.5) in MCCB composite score change. BI 409306 did not significantly improve change from baseline in SCoRS total score (-3.1 to -2.0) vs placebo (-2.5). Adverse events were dose-dependent, increasing from 33.3% (10 mg) to 53.5% (100 mg), vs 36.4% for placebo. CONCLUSION: The primary endpoint of cognitive function improvement was not met. BI 409306 was well-tolerated, with an acceptable safety profile.}, Doi = {10.1093/schbul/sby049}, Key = {fds342181} } @article{fds370535, Author = {Kraus, M and Walker, T and Perkins, D and Keefe, R}, Title = {T32. INTACT AUDITORY PERCEPTION IN INDIVIDUALS AT CLINICAL HIGH RISK FOR PSYCHOSIS}, Journal = {Schizophrenia Bulletin}, Volume = {45}, Number = {Supplement_2}, Pages = {S215-S215}, Publisher = {Oxford University Press (OUP)}, Year = {2019}, Month = {April}, url = {http://dx.doi.org/10.1093/schbul/sbz019.312}, Doi = {10.1093/schbul/sbz019.312}, Key = {fds370535} } @article{fds370728, Author = {Harvey, P and Khan, A and Atkins, A and Keefe, R}, Title = {O5.7. VIRTUAL REALITY FUNCTIONAL CAPACITY ASSESSMENT IN PATIENTS WITH SCHIZOPHRENIA: CORRELATES OF PERFORMANCE OF SOLITARY AND SOCIALLY RELEVANT TASKS}, Journal = {Schizophrenia Bulletin}, Volume = {45}, Number = {Supplement_2}, Pages = {S175-S175}, Publisher = {Oxford University Press (OUP)}, Year = {2019}, Month = {April}, url = {http://dx.doi.org/10.1093/schbul/sbz021.216}, Doi = {10.1093/schbul/sbz021.216}, Key = {fds370728} } @article{fds370729, Author = {Podhorna, J and Hake, S and Groeschl, M and Pollentier, S and Atkins, A and Keefe, R}, Title = {S27. EFFICACY, SAFETY, AND PHARMACOKINETICS OF BI 425809 ONCE DAILY IN PATIENTS WITH SCHIZOPHRENIA: METHODOLOGY OF A RANDOMIZED TRIAL}, Journal = {Schizophrenia Bulletin}, Volume = {45}, Number = {Supplement_2}, Pages = {S315-S316}, Publisher = {Oxford University Press (OUP)}, Year = {2019}, Month = {April}, url = {http://dx.doi.org/10.1093/schbul/sbz020.572}, Doi = {10.1093/schbul/sbz020.572}, Key = {fds370729} } @article{fds371921, Author = {Krystal, A and Pizzagalli, D and Smoski, M and Mathew, S and Nurnberger, J and Lisanby, S and Iosifescu, D and Murrough, J and Weiner, R and Calabrese, J and Sanacora, G and Keefe, R and Song, A and Goodman, W and Szabo, S and Whitten, A and Gao, K and Potter, W}, Title = {116. Results of the NIMH FAST-MAS Phase IIa Proof of Mechanism Study of the Effects of the Selective κ Opioid Antagonist JNJ-67953964 on fMRI Ventral Striatal Activity in Anhedonic Patients}, Journal = {Biological Psychiatry}, Volume = {85}, Number = {10}, Pages = {S48-S49}, Publisher = {Elsevier BV}, Year = {2019}, Month = {May}, url = {http://dx.doi.org/10.1016/j.biopsych.2019.03.130}, Doi = {10.1016/j.biopsych.2019.03.130}, Key = {fds371921} } @article{fds342388, Author = {Mahncke, HW and Kim, S-J and Rose, A and Stasio, C and Buckley, P and Caroff, S and Duncan, E and Yasmin, S and Jarskog, LF and Lamberti, JS and Nuechterlein, K and Strassnig, M and Velligan, D and Ventura, J and Walker, T and Stroup, TS and Keefe, RSE}, Title = {Evaluation of a plasticity-based cognitive training program in schizophrenia: Results from the eCaesar trial.}, Journal = {Schizophrenia Research}, Volume = {208}, Pages = {182-189}, Year = {2019}, Month = {June}, url = {http://dx.doi.org/10.1016/j.schres.2019.03.006}, Abstract = {OBJECTIVE: Cognitive impairment in schizophrenia is a core feature of the disorder. Computerized cognitive training has shown promise in pilot studies. A 26-week randomized blinded placebo-controlled trial was conducted to investigate the effect of a novel computerized cognitive training program on cognitive and functional capacity outcomes. METHOD: The study followed MATRICS guidelines for the evaluation of interventions designed to improve cognitive function in schizophrenia. Participants (N = 150) were randomized to experimental (computerized cognitive training in a game-like format) or active control (computer games) groups. Training was conducted in-clinic, with an intended training schedule of 5 days per week, 1 h per day, for 26 weeks. Co-primary outcome measures were the MATRICS Consensus Cognitive Battery (MCCB) composite score and the UCSD Performance-Based Skills Assessment (UPSA-2) total score, secondary outcome measures included the Cognitive Assessment Interview (CAI) and the Short-Form-12 Mental Composite Score (SF-12 MCS). Target engagement was assessed with task-learning based assessment. RESULTS: At baseline, the groups were well matched. No significant effect of the experimental treatment was seen on the primary or secondary outcome measures compared to the active control. Review of the task learning/target engagement data suggested inadequate target engagement. CONCLUSIONS: Results do not support a cognitive or functional capacity benefit from this implementation of a computerized cognitive training program in people with schizophrenia. In future trials, careful consideration is merited of the assessment of task learning/target engagement, the effects of making the cognitive training game-like on motivation, and the implicit effects of trial requirements on participant selection.}, Doi = {10.1016/j.schres.2019.03.006}, Key = {fds342388} } @article{fds343406, Author = {Keefe, RSE}, Title = {Why are there no approved treatments for cognitive impairment in schizophrenia?}, Journal = {World Psychiatry : Official Journal of the World Psychiatric Association (Wpa)}, Volume = {18}, Number = {2}, Pages = {167-168}, Year = {2019}, Month = {June}, url = {http://dx.doi.org/10.1002/wps.20648}, Doi = {10.1002/wps.20648}, Key = {fds343406} } @article{fds341562, Author = {Harvey, PD and Khan, A and Atkins, A and Keefe, RS}, Title = {Virtual reality assessment of functional capacity in people with Schizophrenia: Associations with reduced emotional experience and prediction of functional outcomes.}, Journal = {Psychiatry Research}, Volume = {277}, Pages = {58-63}, Year = {2019}, Month = {July}, url = {http://dx.doi.org/10.1016/j.psychres.2019.01.045}, Abstract = {Virtual Reality (VR) approaches have had considerable success in measurement of functional capacity. However, it is not clear if factors other than cognitive impairment influence performance on VR measures. Many people with schizophrenia have significant negative symptoms and they could reduce engagement in assessment. 158 patients with schizophrenia performed the VRFCAT, were tested with the MCCB, were rated with the PANSS, and were rated on everyday functioning. Scores for reduced emotional experience and reduced expression were derived. Reduced emotional experience, but not reduced expression, was correlated with socially relevant VRFCAT subtasks and real-world social functioning. Performance on the socially relevant subtasks, but not the solitary subtasks, shared variance with work outcomes. MCCB performance was associated with both subdomains, but socially relevant subtasks shared more variance. Patients with higher reduced emotional experience validly engaged in socially relevant VR simulations, as indexed by correlations with outcome measures. These patients had poorer performance on socially relevant tasks than on solitary tasks. The differential validity of solitary vs. socially relevant simulations was supported by differences in correlates, suggesting that assessments with a focus on performance of simulated socially relevant tasks could be developed.}, Doi = {10.1016/j.psychres.2019.01.045}, Key = {fds341562} } @article{fds343768, Author = {Harvey, PD and Khan, A and Atkins, A and Walker, TM and Keefe, RSE}, Title = {Comprehensive review of the research employing the schizophrenia cognition rating scale (SCoRS).}, Journal = {Schizophrenia Research}, Volume = {210}, Pages = {30-38}, Year = {2019}, Month = {August}, url = {http://dx.doi.org/10.1016/j.schres.2019.05.040}, Abstract = {This review of research utilizing the Schizophrenia Cognition Rating Scale (SCoRS) outlines the development, evaluation, validation, and implementation of the SCoRS to assess whether the scale meets the criteria as a functional co-primary as defined by the MATRICS-CT initiative. Interview-based co-primary assessments should be: 1) practical and easy to administer for a clinician or researcher; 2) validated in individuals with schizophrenia; 3) contain the relevant areas of cognition and functioning applicable to schizophrenia; 4) able to assess all phases and severity levels of schizophrenia; 5) capable of monitoring disease progression; 6) minimal burden to patients; and 7) sensitive to assess treatment effects. A review of the literature was conducted to present information on the development, psychometric properties and usage of the SCoRS. Review of the development of the SCoRS followed the parameters outlined for scale development on content expert validation and feedback. The SCoRS shows good psychometric properties in various studies, and demonstrates low burden on clinicians and patients. The items measure global concepts that do not require notable cultural modification, making international use feasible. While multiple performance-based tests in cognition and functional outcomes are available, there is a need for a multi-domain, interview-based assessment of cognitive progression and treatment response in clinical trials. The SCoRS appears to meet many of the criteria for an optimal co-primary measure for schizophrenia cognition clinical trials as defined in the MATRICS-CT initiative.}, Doi = {10.1016/j.schres.2019.05.040}, Key = {fds343768} } @article{fds372050, Author = {Podhorna, J and Hake, S and Zhao, Y and Groeschl, M and Pollentier, S and Atkins, A and Keefe, R}, Title = {P.244 Novel endpoints of motivation and reinforcement learning in a large interventional clinical trial of BI 425809 in patients with schizophrenia}, Journal = {European Neuropsychopharmacology}, Volume = {29}, Pages = {S187-S188}, Publisher = {Elsevier BV}, Year = {2019}, Month = {December}, url = {http://dx.doi.org/10.1016/j.euroneuro.2019.09.286}, Doi = {10.1016/j.euroneuro.2019.09.286}, Key = {fds372050} } @article{fds343766, Author = {Pani, L and Keefe, RSE}, Title = {Approaches to attenuated psychosis syndrome treatments: A perspective on the regulatory issues.}, Journal = {Schizophrenia Research. Cognition}, Volume = {18}, Pages = {100155}, Year = {2019}, Month = {December}, url = {http://dx.doi.org/10.1016/j.scog.2019.100155}, Doi = {10.1016/j.scog.2019.100155}, Key = {fds343766} } @article{fds370726, Author = {Horan, B and Hake, S and Huang, S and Zhao, Y and Keefe, R and Atkins, A and Podhorna, J}, Title = {BI 425809 Once Daily in Patients With Schizophrenia: Feasibility of Novel Endpoints to Assess Motivation}, Journal = {Neuropsychopharmacology}, Volume = {45}, Number = {SUPPL 1}, Pages = {131-132}, Year = {2020}, Key = {fds370726} } @article{fds370727, Author = {Lindenmayer, J-P and Khan, A and Harvey, P and Keefe, R and Liharska, L and Yavorsky, C and Seddo, M}, Title = {IMPAIRED CLINICAL INSIGHT AS A PREDICTOR OF RELAPSE IN SCHIZOPHRENIA}, Journal = {Schizophrenia Bulletin}, Volume = {46}, Pages = {S180-S181}, Year = {2020}, Key = {fds370727} } @article{fds371763, Author = {Nuechterlein, K and Tishler, T and Ellingson, B and Ventura, J and Williamson, D and Turkoz, I and Keefe, R and O'Donnell, A and Alphs, L}, Title = {Frontal Intracortical Myelin Volume is Related to Speed of Processing in Patients With First-Episode Schizophrenia Assessed With the MATRICS Consensus Cognitive Battery (MCCB)}, Journal = {Neuropsychopharmacology}, Volume = {45}, Number = {SUPPL 1}, Pages = {336-337}, Year = {2020}, Key = {fds371763} } @article{fds349932, Author = {Goldberg, TE and Harvey, PD and Devanand, DP and Keefe, RSE and Gomar, JJ}, Title = {Development of an UPSA Short Form for Use in Longitudinal Studies in the Early Alzheimer's Disease Spectrum.}, Journal = {The Journal of Prevention of Alzheimer'S Disease}, Volume = {7}, Number = {3}, Pages = {179-183}, Year = {2020}, Month = {January}, url = {http://dx.doi.org/10.14283/jpad.2019.51}, Abstract = {<h4>Background</h4>In individuals with only mild or very mild cognitive attenuations (i.e., so-called pre-clinical AD), performance-based measures of function may be superior to informant-based measures because of increased sensitivity, greater reliability, and fewer ceiling effects.<h4>Objective</h4>We sought to determine if a performance-based measure of everyday function would demonstrate adequate psychometric properties and validity in the context of serial assessment over a one-year period in patients with Mild Cognitive Impairment (MCI) and early stage Alzheimer's disease (AD).<h4>Design</h4>Participants were assessed with the performance-based measure at baseline, six weeks, and one year.<h4>Setting</h4>A specialized center for the assessment and treatment of AD.<h4>Participants</h4>Three groups of subjects participated: a healthy subjects (HS) older cognitively intact group (N=43), an MCI group (N=20), and an AD group (N=26).<h4>Measurements</h4>A three subtest short form of the UCSD Performance-Based Skills Assessment (UPSA) (called the UPSA-3) was the measure of interest. It consisted of the Communication, Planning, and Finance subtests.<h4>Results</h4>Mixed model repeated measures were used to assess performance over time. Large group effects were present (HS>MCI>AD). Additionally, the AD and MCI groups demonstrated declines over one year, while the HS group remained stable (group x time interaction p=.11). The MCI/AD group demonstrated adequate test-retest reliability and did not demonstrate ceiling or floor effects.<h4>Conclusion</h4>Our data indicate that the UPSA-3 is suitable for clinical trials in that it has adequate ecological coverage and reasonable psychometric properties, and perhaps most importantly, demonstrates validity in serial assessments.}, Doi = {10.14283/jpad.2019.51}, Key = {fds349932} } @article{fds343767, Author = {Ventura, J and Welikson, T and Ered, A and Subotnik, KL and Keefe, RSE and Hellemann, GS and Nuechterlein, KH}, Title = {Virtual reality assessment of functional capacity in the early course of schizophrenia: Associations with cognitive performance and daily functioning.}, Journal = {Early Interv Psychiatry}, Volume = {14}, Number = {1}, Pages = {106-114}, Year = {2020}, Month = {February}, url = {http://dx.doi.org/10.1111/eip.12831}, Abstract = {AIM: Computer-based virtual reality assessments of functional capacity have shown promise as a reliable and valid way to assess individuals with multi-episode schizophrenia. However, there has been little research utilizing this innovative approach with young patients who are in the early phase of schizophrenia. METHODS: Outpatients in the early course of schizophrenia (n = 42) were compared to controls (n = 13) at cross-sectional study points. Patients were within 2 years of their first psychotic episode, were an average of 22.2 years old and had an average of 12.3 years of education. We used the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) and the University of California, San Diego (UCSD) Performance-Based Skills Assessment-2 (UPSA-2) to assess functional capacity. The MATRICS Consensus Cognitive Battery (MCCB) and the Cognitive Assessment Interview (CAI) were the measures of cognitive functioning. The Global Functioning Scale: Role (GFS-R) and Social (GFS-S), and the Role Functioning Scale (RFS) were the measures of daily functioning. RESULTS: Early course patients vs controls were slower (patient M = 830.41 seconds vs control M = 716.84 seconds; t = 3.0, P < .01) and committed more errors (patient M = 3.2 vs control M = 1.7 seconds, t = 2.9, P < .01) on the VRFCAT. Total time was significantly correlated with the UPSA (r = -0.66, P < .01), MCCB (r = -0.70, P < .01), CAI (r = -0.51, P < .01), and GFS role (r = -0.52, P <. 01) and social functioning (r = -0.43, P = .03). CONCLUSIONS: We extend previous findings to patients with first-episode schizophrenia. Virtual-reality-based performance was correlated with a standard test of functional capacity, indicating VRFCAT validity. Furthermore, correlations with cognitive functioning and occupational/school and social functioning indicate promise as a co-primary measure to track changes in response to treatment.}, Doi = {10.1111/eip.12831}, Key = {fds343767} } @article{fds347052, Author = {Kraus, MS and Gold, JM and Barch, DM and Walker, TM and Chun, CA and Buchanan, RW and Csernansky, JG and Goff, DC and Green, MF and Jarskog, LF and Javitt, DC and Kimhy, D and Lieberman, JA and McEvoy, JP and Mesholam-Gately, RI and Seidman, LJ and Ball, MP and Kern, RS and McMahon, RP and Robinson, J and Marder, SR and Keefe, RSE}, Title = {The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.}, Journal = {Schizophrenia Research. Cognition}, Volume = {19}, Pages = {100161}, Year = {2020}, Month = {March}, url = {http://dx.doi.org/10.1016/j.scog.2019.100161}, Abstract = {In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests.}, Doi = {10.1016/j.scog.2019.100161}, Key = {fds347052} } @article{fds349057, Author = {Rakesh, G and Mischel, NA and Luber, B and Keefe, RSE and Emory, S and Lisanby, SH and Szabo, ST}, Title = {Theta Burst for Cognitive Remediation in Schizophrenia: A Case Series and Feasibility Study.}, Journal = {J Ect}, Volume = {36}, Number = {1}, Pages = {72-74}, Year = {2020}, Month = {March}, url = {http://dx.doi.org/10.1097/YCT.0000000000000625}, Doi = {10.1097/YCT.0000000000000625}, Key = {fds349057} } @article{fds349213, Author = {Kollins, SH and DeLoss, DJ and Cañadas, E and Lutz, J and Findling, RL and Keefe, RSE and Epstein, JN and Cutler, AJ and Faraone, SV}, Title = {A novel digital intervention for actively reducing severity of paediatric ADHD (STARS-ADHD): a randomised controlled trial.}, Journal = {The Lancet Digital Health}, Volume = {2}, Number = {4}, Pages = {e168-e178}, Year = {2020}, Month = {April}, url = {http://dx.doi.org/10.1016/S2589-7500(20)30017-0}, Abstract = {BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a common paediatric neurodevelopmental disorder with substantial effect on families and society. Alternatives to traditional care, including novel digital therapeutics, have shown promise to remediate cognitive deficits associated with this disorder and may address barriers to standard therapies, such as pharmacological interventions and behavioural therapy. AKL-T01 is an investigational digital therapeutic designed to target attention and cognitive control delivered through a video game-like interface via at-home play for 25 min per day, 5 days per week for 4 weeks. This study aimed to assess whether AKL-T01 improved attentional performance in paediatric patients with ADHD. METHODS: The Software Treatment for Actively Reducing Severity of ADHD (STARS-ADHD) was a randomised, double-blind, parallel-group, controlled trial of paediatric patients (aged 8-12 years, without disorder-related medications) with confirmed ADHD and Test of Variables of Attention (TOVA) Attention Performance Index (API) scores of -1·8 and below done by 20 research institutions in the USA. Patients were randomly assigned 1:1 to AKL-T01 or a digital control intervention. The primary outcome was mean change in TOVA API from pre-intervention to post-intervention. Safety, tolerability, and compliance were also assessed. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02674633 and is completed. FINDINGS: Between July 15, 2016, and Nov 30, 2017, 857 patients were evaluated and 348 were randomly assigned to receive AKL-T01 or control. Among patients who received AKL-T01 (n=180 [52%]; mean [SD] age, 9·7 [1·3] years) or control (n=168 [48%]; mean [SD] age, 9·6 [1·3] years), the non-parametric estimate of the population median change from baseline TOVA API was 0·88 (95% CI 0·24-1·49; p=0·0060). The mean (SD) change from baseline on the TOVA API was 0·93 (3·15) in the AKL-T01 group and 0·03 (3·16) in the control group. There were no serious adverse events or discontinuations. Treatment-related adverse events were mild and included frustration (5 [3%] of 180) and headache (3 [2%] of 180). Patient compliance was a mean of 83 (83%) of 100 expected sessions played (SD, 29·2 sessions). INTERPRETATION: Although future research is needed for this digital intervention, this study provides evidence that AKL-T01 might be used to improve objectively measured inattention in paediatric patients with ADHD, while presenting minimal adverse events. FUNDING: Sponsored by Akili Interactive Labs.}, Doi = {10.1016/S2589-7500(20)30017-0}, Key = {fds349213} } @article{fds349715, Author = {Ho, NF and Lee, BJH and Tng, JXJ and Lam, MZY and Chen, G and Wang, M and Zhou, J and Keefe, RSE and Sim, K}, Title = {Corticolimbic brain anomalies are associated with cognitive subtypes in psychosis: A longitudinal study.}, Journal = {Eur Psychiatry}, Volume = {63}, Number = {1}, Pages = {e40}, Year = {2020}, Month = {April}, url = {http://dx.doi.org/10.1192/j.eurpsy.2020.36}, Abstract = {BACKGROUND: Earlier studies examining structural brain abnormalities associated with cognitively derived subgroups were mainly cross-sectional in design and had mixed findings. Thus, we obtained cross-sectional and longitudinal data to characterize the extent and trajectory of brain structure abnormalities underlying distinct cognitive subtypes ("preserved," "deteriorated," and "compromised") seen in psychotic spectrum disorders. METHODS: Data from 364 subjects (225 patients with psychotic conditions and 139 healthy controls) were first used to determine the relationship of cognitive subtypes with cross-sectional measures of subcortical volume and cortical thickness. To probe neurodevelopmental abnormalities, brain structure laterality was examined. To examine whether neuroprogressive abnormalities persist, longitudinal brain structural changes over 5 years were examined within a subset of 101 subjects. Subsequent discriminant analysis using the identified brain measures was performed on an independent subject group. RESULTS: Cross-sectional comparisons showed that cortical thinning and limbic volume reductions were most widespread in "deteriorated" cognitive subtype. Laterality comparisons showed more rightward amygdala lateralization in "compromised" than "preserved" subtype. Longitudinal comparisons revealed progressive hippocampal shrinkage in "deteriorated" compared with healthy controls and "preserved" subtype, which correlated with worse negative symptoms, cognitive and psychosocial functioning. Post-hoc discrimination analysis on an independent group of 52 subjects using the identified brain structures found an overall accuracy of 71% for classification of cognitive subtypes. CONCLUSION: These findings point toward distinct extent and trajectory of corticolimbic abnormalities associated with cognitive subtypes in psychosis, which can allow further understanding of the biological course of cognitive functioning over illness course and with treatment.}, Doi = {10.1192/j.eurpsy.2020.36}, Key = {fds349715} } @article{fds349352, Author = {Krystal, AD and Pizzagalli, DA and Smoski, M and Mathew, SJ and Nurnberger, J and Lisanby, SH and Iosifescu, D and Murrough, JW and Yang, H and Weiner, RD and Calabrese, JR and Sanacora, G and Hermes, G and Keefe, RSE and Song, A and Goodman, W and Szabo, ST and Whitton, AE and Gao, K and Potter, WZ}, Title = {A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia.}, Journal = {Nat Med}, Volume = {26}, Number = {5}, Pages = {760-768}, Year = {2020}, Month = {May}, url = {http://dx.doi.org/10.1038/s41591-020-0806-7}, Abstract = {The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.}, Doi = {10.1038/s41591-020-0806-7}, Key = {fds349352} } @article{fds350570, Author = {Chaturvedi, R and Kraus, M and Keefe, RSE}, Title = {A new measure of authentic auditory emotion recognition: Application to patients with schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {222}, Pages = {450-454}, Year = {2020}, Month = {August}, url = {http://dx.doi.org/10.1016/j.schres.2019.11.043}, Abstract = {BACKGROUND: Many social processes such as emotion recognition are severely impaired in patients with schizophrenia. While basic auditory processing seems to play a key role in identifying emotions, research in this field is limited due to the lack of proper assessment batteries. Many of the widely accepted tests utilize actors to portray certain emotions-these batteries are less ecologically and face valid. METHODS: This study utilized a newly developed auditory emotion recognition test that contained natural stimuli from spontaneous displays of emotions to assess 28 patients with schizophrenia and 16 healthy controls. RESULTS: The results indicate that the newly developed test, referred to as the INTONATION Test, is more sensitive to the emotion recognition deficits in patients with schizophrenia than previously used measures. The correlations of the INTONATION Test measures with basic auditory processes were similar to established tests of auditory emotion. Particular emotion sub scores from the INTONTATION test, such as happiness, demonstrated the strongest correlations with specific auditory processing skills, such as formant discrimination and sinusoidal amplitude modulation detection (SAM60). CONCLUSIONS: The results from this study indicate that auditory emotion recognition impairments are more pronounced in patients with schizophrenia when perceiving authentic displays of emotion. Understanding these deficits could help specify the nature of auditory emotion recognition deficits in patients with schizophrenia and those at risk.}, Doi = {10.1016/j.schres.2019.11.043}, Key = {fds350570} } @article{fds350817, Author = {Lindenmayer, J-P and Goldring, A and Borne, S and Khan, A and Keefe, RSE and Insel, BJ and Thanju, A and Ljuri, I and Foreman, B}, Title = {Assessing instrumental activities of daily living (iADL) with a game-based assessment for individuals with schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {223}, Pages = {166-172}, Year = {2020}, Month = {September}, url = {http://dx.doi.org/10.1016/j.schres.2020.07.001}, Abstract = {BACKGROUND: The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is an "applied" game-based assessment that uses a multi-level functional task to assess instrumental activities of daily living (iADL). This study examines the feasibility, convergent validity, and predictive ability of the VRFCAT in a sample of inpatients with chronic schizophrenia. METHODS: Inpatients with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder, completed the VRFCAT prior to discharge. The UPSA-B, SLOF, and PSP were administered, both at baseline and after four-weeks in the community. VRFCAT performance scores were compared to published data from the VRFCAT validation study. RESULTS: All 62 participants completed the VRFCAT. Compared to the performance of stable outpatients, participants performed 1.50 SDs below the VRFCAT mean adjusted total time (ATT) (Validation study: Mean T Score = 32.5, SD = 16.59) with more errors. The VRFCAT ATT T-score was significantly correlated with baseline UPSA-B total score (p = 0.005) and PSP Global score (p = 0.010). 34 participants completed the follow-up period (55%), and 28 were lost to follow-up. There were no statistically significant differences in VRFCAT scores between these two groups (all p > 0.29). The VRFCAT composite score at baseline was significantly associated with the UPSA-B total score (p = 0.010) and the PSP total score (p = 0.008) at four-weeks, as was the PSP Socially Useful Activities subscale score (p = 0.006). CONCLUSION: The VRFCAT is a valid measure of iADLs in inpatients with chronic schizophrenia. The VRFCAT predicted instrumental functioning four-weeks post-discharge. Future studies should examine other moderators of measures of functional capacity pre-discharge, predicting function later in the community.}, Doi = {10.1016/j.schres.2020.07.001}, Key = {fds350817} } @article{fds349351, Author = {Kilciksiz, CM and Keefe, R and Benoit, J and Öngür, D and Torous, J}, Title = {Verbal memory measurement towards digital perspectives in first-episode psychosis: A review.}, Journal = {Schizophrenia Research. Cognition}, Volume = {21}, Pages = {100177}, Year = {2020}, Month = {September}, url = {http://dx.doi.org/10.1016/j.scog.2020.100177}, Abstract = {BACKGROUND: Even in the early phases of psychotic spectrum illnesses such as schizophrenia, patients can experience cognitive decline or deficits prior to the onset of psychotic symptoms such as delusions and hallucinations. In this systematic review, we assessed which verbal memory assessments are most widely used in first-episode psychosis and may be applied via digital technologies (smartphone applications, etc.) for use in early detection. METHODS: In November 2019, we searched for studies measuring verbal memory in first episode psychosis or schizophrenia over the past 10 years on PubMed and PsycINFO. We screened abstracts of these studies and excluded review studies. Full-texts of included studies were used to identify the verbal memory measurement tests, follow-up frequencies, and sample sizes. RESULTS: We screened 233 reports and found that 120 original research studies measured verbal memory in first episode psychosis over the past 10 years. Four of these studies specified using a computer, 24 (20%) used a paper-pen format, 1(1%) used both, and 91 (76%) studies did not specify their administration tools or suggest there were offered in digital formats. Thirty-five (30%) studies had follow-up measurements of verbal memory, while 85 (70%) had only a single verbal memory measurement. DISCUSSION: While many scales are commonly used to measure verbal memory in first episode psychosis, they are not often administered via digital technology. There is an emerging opportunity to administer these and other tests via digital technologies for expanding access to early detection of cognitive decline in clinical high risk and first-episode psychosis.}, Doi = {10.1016/j.scog.2020.100177}, Key = {fds349351} } @article{fds352555, Author = {Harvey, PD and Horan, WP and Atkins, AS and Stevens, H and Welch, M and Yuan, J and Patterson, TL and Narasimhan, M and Keefe, RSE}, Title = {Factor structure of cognitive performance and functional capacity in schizophrenia: Evidence for differences across functional capacity measures.}, Journal = {Schizophrenia Research}, Volume = {223}, Pages = {297-304}, Year = {2020}, Month = {September}, url = {http://dx.doi.org/10.1016/j.schres.2020.08.010}, Abstract = {BACKGROUND: Cognition and functional capacity predict functional outcomes in mental illness. Traditional approaches conceptualize cognition as comprised of domains, but many studies support a unifactorial structure. Some functional capacity measures may share a single-factor structure with cognition. In this study, we examined the factor structure of two measures of functional capacity, a conventional assessment and a newer computerized assessment, testing for a shared factor structure with cognition. METHODS: Patients with schizophrenia and healthy controls were examined with the MATRICS Consensus Cognitive Battery (MCCB), the UCSD Performance Based Skills Assessment (UPSA), and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). Models of the factor structures of the MCCB, UPSA, and VRFCAT were calculated, as were correlations between MCCB scores and individual VRFCAT objectives. RESULTS: The MCCB, VRFCAT, and UPSA all had unifactorial structures. The best fitting model of the correlations between MCCB and UPSA was a shared single factor, while the best fit for the relationship between MCCB and VRFCAT had two factors. Correlations between the MCCB domain and composite scores and the VRFCAT objectives suggested global rather than specific patterns of correlation. DISCUSSION: The relationship between cognitive performance and functional capacity was found to vary across functional capacity assessments. The UPSA and MCCB were not differentiated into separate factors, suggesting that the UPSA may overlap with neurocognitive performance. However, the VRFCAT appears to measure functional abilities that are separable from, yet correlated with, neurocognitive performance. It may provide a more distinctive assessment of the functional capacity construct.}, Doi = {10.1016/j.schres.2020.08.010}, Key = {fds352555} } @article{fds350818, Author = {Keefe, RSE and Green, MF and Harvey, PD}, Title = {Requisite Skills and the Meaningful Measurement of Cognition.}, Journal = {Jama Psychiatry}, Volume = {77}, Number = {11}, Pages = {1103-1104}, Year = {2020}, Month = {November}, url = {http://dx.doi.org/10.1001/jamapsychiatry.2020.1618}, Doi = {10.1001/jamapsychiatry.2020.1618}, Key = {fds350818} } @article{fds359635, Author = {Turner, TH and Atkins, A and Keefe, RSE}, Title = {Virtual Reality Functional Capacity Assessment Tool (VRFCAT-SL) in Parkinson's Disease.}, Journal = {J Parkinsons Dis}, Volume = {11}, Number = {4}, Pages = {1917-1925}, Year = {2021}, url = {http://dx.doi.org/10.3233/JPD-212688}, Abstract = {BACKGROUND: Cognitive impairment is common in Parkinson's disease (PD) and highly associated with loss of independence, caregiver burden, and assisted living placement. The need for cognitive functional capacity tools validated for use in PD clinical and research applications has thus been emphasized in the literature. The Virtual Reality Functional Capacity Assessment Tool (VRFCAT-SL) is a tablet-based instrument that assesses proficiency for performing real world tasks in a highly realistic environment. OBJECTIVE: The present study explored application of the VRFCAT-SL in clinical assessments of patients with PD. Specifically, we examined associations between VRFCAT-SL performance and measures of cognition, motor severity, and self-reported cognitive functioning. METHODS: The VRFCAT-SL was completed by a sample of 29 PD patients seen in clinic for a comprehensive neuropsychological evaluation. Fifteen patients met Movement Disorders Society Task Force criteria for mild cognitive impairment (PD-MCI); no patients were diagnosed with dementia. Non-parametric correlations between VRFCAT-SL performance and standardized neuropsychological tests and clinical measures were examined. RESULTS: VRFCAT-SL performance was moderately associated with global rank on neuropsychological testing and discriminated PD-MCI. Follow-up analyses found completion time was associated with visual memory, sustained attention, and set-switching, while errors were associated with psychomotor inhibition. No clinical or motor measures were associated with VRFCAT-SL performance. Self-report was not associated with VRFCAT-SL or neuropsychological test performance. CONCLUSION: The VRFCAT-SL appears to provide a useful measure of cognitive functional capacity that is not confounded by PD motor symptoms. Future studies will examine utility in PD dementia.}, Doi = {10.3233/JPD-212688}, Key = {fds359635} } @article{fds354357, Author = {Seccomandi, B and Agbedjro, D and Bell, M and Keefe, RSE and Keshavan, M and Galderisi, S and Fiszdon, J and Mucci, A and Cavallaro, R and Bechi, M and Ojeda, N and Peña, J and Wykes, T and Cella, M}, Title = {Can IQ moderate the response to cognitive remediation in people with schizophrenia?}, Journal = {J Psychiatr Res}, Volume = {133}, Pages = {38-45}, Year = {2021}, Month = {January}, url = {http://dx.doi.org/10.1016/j.jpsychires.2020.12.013}, Abstract = {BACKGROUND: IQ and IQ decline are considered risk factors for poor prognosis in people with a diagnosis of schizophrenia. However, it is still not clear if, at least in part, IQ and IQ decline influence long-term outcomes via a negative effect on interventions. AIM: To identify whether current IQ, estimated premorbid IQ, or IQ decline moderate the response to cognitive remediation (CR). METHOD: Individual participant data from twelve randomised controlled trials of CR were considered. Hierarchical and k-means analyses were carried out to identify different IQ clusters. The moderating effect of estimated premorbid IQ, current IQ, and different IQ clusters (preserved, deteriorated and compromised trajectories) on cognitive outcomes at post-therapy and follow-up were evaluated using multiple linear regression. RESULTS: Data from 984 participants (CR = 544, control = 440) with schizophrenia and schizoaffective disorders were considered. The sample had a mean current IQ of 84.16 (SD 15.61) and estimated premorbid IQ of 95.82 (SD 10.63). Current IQ moderated working memory outcomes: people with higher IQ had larger working memory gains after therapy compared to those with a lower IQ. Those with a preserved IQ had better cognitive outcomes compared to either the deteriorated or compromised IQ groups, and those with a deteriorated IQ had better outcomes compared to those in the compromised IQ group. CONCLUSION: Current IQ is a significant moderator of cognitive gains after CR. These findings highlight the need to evaluate whether therapy adaptations (e.g. offering more sessions) can attenuate this effect so that those with lower IQ may derive benefit similar to those with higher IQ.}, Doi = {10.1016/j.jpsychires.2020.12.013}, Key = {fds354357} } @article{fds355040, Author = {Seccomandi, B and Agbedjro, D and Bell, M and Keefe, RSE and Keshavan, M and Galderisi, S and Fiszdon, J and Mucci, A and Cavallaro, R and Ojeda, N and Peña, J and Müller, D and Roder, V and Wykes, T and Cella, M}, Title = {Exploring the role of age as a moderator of cognitive remediation for people with schizophrenia.}, Journal = {Schizophrenia Research}, Volume = {228}, Pages = {29-35}, Year = {2021}, Month = {February}, url = {http://dx.doi.org/10.1016/j.schres.2020.11.060}, Abstract = {BACKGROUND: While Cognitive Remediation (CR) is effective in reducing cognitive and functioning difficulties in people with schizophrenia, there is variability in treatment response. Previous research suggested that participants' age may be a significant moderator of CR response. AIM: To examine the impact of participants' age on CR outcomes. METHOD: Individual participant data were accessed from fourteen CR randomised controlled trials. We tested the moderating effect of participants' age on cognitive and functioning outcomes using multivariate linear models. RESULTS: Data from 1084 people with a diagnosis of schizophrenia were considered. Participants had a mean age of 36.6 years (SD 11), with 11.6 years of education (SD 2.8), and an average duration of illness of 13.5 years (SD 10.7). Multivariate models showed that participants' age, when considered as a continuous variable, was not a significant moderator of treatment effect for cognitive and functioning outcomes. However, when participants were split by median age, younger participants showed higher gains in executive functions following CR compared to older participants (p=0.02). CONCLUSION: These results suggest that participants' age does not moderate most CR outcomes. However, larger age differences may influence the effect of CR on executive function. This may suggest some adaptation of CR practice according to participants' age. These findings inform the CR personalisation agenda.}, Doi = {10.1016/j.schres.2020.11.060}, Key = {fds355040} } @article{fds355504, Author = {Keefe, RSE}, Title = {Where do we cut the bell-shaped curve of CIAS?}, Journal = {Schizophrenia Research}, Volume = {228}, Pages = {633-634}, Year = {2021}, Month = {February}, url = {http://dx.doi.org/10.1016/j.schres.2021.01.013}, Doi = {10.1016/j.schres.2021.01.013}, Key = {fds355504} } @article{fds353538, Author = {Cohen, EA and Hassman, HH and Ereshefsky, L and Walling, DP and Grindell, VM and Keefe, RSE and Wyka, K and Horan, WP}, Title = {Placebo response mitigation with a participant-focused psychoeducational procedure: a randomized, single-blind, all placebo study in major depressive and psychotic disorders.}, Journal = {Neuropsychopharmacology}, Volume = {46}, Number = {4}, Pages = {844-850}, Year = {2021}, Month = {March}, url = {http://dx.doi.org/10.1038/s41386-020-00911-5}, Abstract = {The remarkably high and growing placebo response rates in clinical trials for CNS indications, such as depression and schizophrenia, constitute a major challenge for the drug development enterprise. Despite extensive literature on participant expectancies and other potent psychosocial factors that perpetuate placebo response, no empirically validated participant-focused strategies to mitigate this phenomenon have been available. This study evaluated the efficacy of the Placebo-Control Reminder Script (PCRS), a brief interactive procedure that educates participants about factors known to cause placebo response, which was administered prior to the primary outcome assessments to subjects with major depressive or psychotic disorders who had at least moderate depression. Participants were informed they would participate in a 2-week randomized clinical trial with a 50% chance of receiving either an experimental antidepressant medication or placebo. In actuality, all participants received placebo. Participants randomly assigned to receive the PCRS (n = 70) reported significantly smaller reductions (i.e., less placebo response) in depression than those who did not receive the PCRS (n = 67). The magnitude of this effect was medium (Cohen's d = 0.40) and was not significantly impacted by diagnostic status. The number of adverse events (i.e., nocebo effect) was also lower in the PCRS group, particularly in the first week of the study. These findings suggest that briefly educating participants about placebo response factors can help mitigate the large placebo response rates that are increasingly seen in failed CNS drug development programs.}, Doi = {10.1038/s41386-020-00911-5}, Key = {fds353538} } @article{fds355910, Author = {Fleischhacker, WW and Podhorna, J and Gröschl, M and Hake, S and Zhao, Y and Huang, S and Keefe, RSE and Desch, M and Brenner, R and Walling, DP and Mantero-Atienza, E and Nakagome, K and Pollentier, S}, Title = {Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomised, placebo-controlled phase 2 study.}, Journal = {Lancet Psychiatry}, Volume = {8}, Number = {3}, Pages = {191-201}, Year = {2021}, Month = {March}, url = {http://dx.doi.org/10.1016/S2215-0366(20)30513-7}, Abstract = {BACKGROUND: Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no approved pharmacotherapy is available. This study investigated whether the glycine transporter-1 inhibitor BI 425809 improves cognition in patients with schizophrenia. METHODS: This phase 2, randomised, double-blind, placebo-controlled, parallel-group trial (81 centres, 11 countries), randomly assigned outpatients (aged 18-50 years) with schizophrenia on stable treatment to add-on once-daily oral BI 425809 2 mg, 5 mg, 10 mg, or 25 mg or placebo (1:1:1:1:2) for 12 weeks. Treatment was assigned in blocks using interactive response technology; patients, investigators, and all trial personnel were masked to group assignment. The primary endpoint was change from baseline in MATRICS Consensus Cognitive Battery (MCCB) overall composite T-score at week 12. Six predefined dose-response models were evaluated using a multiple comparison procedure and modelling approach with mixed model repeated measures to assess evidence for a non-flat dose-response relationship for cognitive improvements with BI 425809. Adverse events were monitored. Safety analyses included all randomly allocated patients who received one or more doses of trial medication; efficacy analyses included patients from this set who also had available baseline data and at least one post-baseline on-treatment measurement for the primary or secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02832037. FINDINGS: 509 patients were randomly assigned between April 25, 2018, and Oct 4, 2019 (BI 425809 2 mg, n=85; 5 mg, n=84; 10 mg, n=85; 25 mg, n=85; placebo, n=170 444 (87%) completed the 12-week treatment. Five of six dose-response models showed a statistically significant benefit of BI 425809 over placebo (linear [t=2·55, p=0·015], linear in log [t=2·56, p=0·015]; Emax [t=2·75, p=0·0089], sigmoid Emax [t=2·98, p=0·0038], logistic [t=2·77, p=0·0085]). Pairwise comparisons showed greater mean improvement from baseline in MCCB overall composite T-score at week 12 with BI 425809 10 mg and 25 mg versus placebo (adjusted mean difference 1·98 [95% CI 0·43-3·53] for 10 mg and 1·73 [0·18-3·28] for 25 mg; standardised effect size 0·34 for 10 mg and 0·30 for 25 mg). Adverse events were balanced across groups, reported in 50 (59%) of 85 patients on BI 425809 2 mg, 44 (52%) of 84 on 5 mg, 35 (41%) of 85 on 10 mg, 36 (42%) of 85 on 25 mg, and 74 (44%) of 170 on placebo. INTERPRETATION: BI 425809 improved cognition after 12 weeks in patients with schizophrenia; doses of 10 mg and 25 mg showed the largest separation from placebo. If these encouraging results are confirmed in phase 3 trials, BI 425809 could provide an effective treatment for cognitive impairment associated with schizophrenia. FUNDING: Boehringer Ingelheim.}, Doi = {10.1016/S2215-0366(20)30513-7}, Key = {fds355910} } @article{fds354388, Author = {Lim, K and Smucny, J and Barch, DM and Lam, M and Keefe, RSE and Lee, J}, Title = {Cognitive Subtyping in Schizophrenia: A Latent Profile Analysis.}, Journal = {Schizophrenia Bulletin}, Volume = {47}, Number = {3}, Pages = {712-721}, Year = {2021}, Month = {April}, url = {http://dx.doi.org/10.1093/schbul/sbaa157}, Abstract = {Cognitive dysfunction is a core feature of schizophrenia. The subtyping of cognitive performance in schizophrenia may aid the refinement of disease heterogeneity. The literature on cognitive subtyping in schizophrenia, however, is limited by variable methodologies and neuropsychological tasks, lack of validation, and paucity of studies examining longitudinal stability of profiles. It is also unclear if cognitive profiles represent a single linear severity continuum or unique cognitive subtypes. Cognitive performance measured with the Brief Assessment of Cognition in Schizophrenia was analyzed in schizophrenia patients (n = 767). Healthy controls (n = 1012) were included as reference group. Latent profile analysis was performed in a schizophrenia discovery cohort (n = 659) and replicated in an independent cohort (n = 108). Longitudinal stability of cognitive profiles was evaluated with latent transition analysis in a 10-week follow-up cohort. Confirmatory factor analysis (CFA) was carried out to investigate if cognitive profiles represent a unidimensional structure. A 4-profile solution was obtained from the discovery cohort and replicated in an independent cohort. It comprised of a "less-impaired" cognitive subtype, 2 subtypes with "intermediate cognitive impairment" differentiated by executive function performance, and a "globally impaired" cognitive subtype. This solution showed relative stability across time. CFA revealed that cognitive profiles are better explained by distinct meaningful profiles than a severity linear continuum. Associations between profiles and negative symptoms were observed. The subtyping of schizophrenia patients based on cognitive performance and its associations with symptomatology may aid phenotype refinement, mapping of specific biological mechanisms, and tailored clinical treatments.}, Doi = {10.1093/schbul/sbaa157}, Key = {fds354388} } @article{fds366331, Author = {Eum, S and Hill, SK and Alliey-Rodriguez, N and Stevenson, JM and Rubin, LH and Lee, AM and Mills, LJ and Reilly, JL and Lencer, R and Keedy, SK and Ivleva, E and Keefe, RSE and Pearlson, GD and Clementz, BA and Tamminga, CA and Keshavan, MS and Gershon, ES and Sweeney, JA and Bishop, JR}, Title = {Genome-wide association study accounting for anticholinergic burden to examine cognitive dysfunction in psychotic disorders.}, Journal = {Neuropsychopharmacology}, Volume = {46}, Number = {10}, Pages = {1802-1810}, Year = {2021}, Month = {September}, url = {http://dx.doi.org/10.1038/s41386-021-01057-8}, Abstract = {Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E-9). The inclusion of anticholinergic burden improved association models (P < 0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research.}, Doi = {10.1038/s41386-021-01057-8}, Key = {fds366331} } @article{fds358788, Author = {Eskridge, CLM and Hochberger, WC and Kaseda, ET and Lencer, R and Reilly, JL and Keedy, SK and Keefe, RSE and Pearlson, GD and Keshavan, MS and Tamminga, CA and Sweeney, JA and Hill, SK}, Title = {Deficits in generalized cognitive ability, visual sensorimotor function, and inhibitory control represent discrete domains of neurobehavioral deficit in psychotic disorders.}, Journal = {Schizophrenia Research}, Volume = {236}, Pages = {54-60}, Year = {2021}, Month = {October}, url = {http://dx.doi.org/10.1016/j.schres.2021.07.036}, Abstract = {Psychotic disorders are characterized by impaired cognition, yet some reports indicate specific deficits extend beyond reduced general cognitive ability. This study utilized exploratory and confirmatory factor analytic methods to evaluate the latent structure of a broad neurocognitive battery used in the Bipolar-Schizophrenia Network of Intermediate Phenotypes (B-SNIP) study, which included neuropsychological and neurophysiological measures in psychotic disorder probands and their unaffected first-degree relatives. Findings indicate that the factor structure of data from this set of assessments is more complex than the unitary factor of global cognitive ability underlying the Brief Assessment of Cognition in Schizophrenia (BACS). In addition to assessing generalized cognitive ability, two other factors were identified: visual sensorimotor function and inhibitory behavioral control. This complex cognitive architecture, derived in controls, generalized to patients across the psychosis spectrum and to their unaffected relatives. These findings highlight the need for a more differentiated assessment of neurobehavioral functions in studies designed to test for diagnostically specific biomarkers, endophenotypes for gene discovery and beneficial effects of therapeutics on cognitive function.}, Doi = {10.1016/j.schres.2021.07.036}, Key = {fds358788} } @article{fds354288, Author = {Keefe, RSE and Woods, SW and Cannon, TD and Ruhrmann, S and Mathalon, DH and McGuire, P and Rosenbrock, H and Daniels, K and Cotton, D and Roy, D and Pollentier, S and Sand, M}, Title = {A randomized Phase II trial evaluating efficacy, safety, and tolerability of oral BI 409306 in attenuated psychosis syndrome: Design and rationale.}, Journal = {Early Interv Psychiatry}, Volume = {15}, Number = {5}, Pages = {1315-1325}, Year = {2021}, Month = {October}, url = {http://dx.doi.org/10.1111/eip.13083}, Abstract = {AIM: Attenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first-episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase-9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated. METHODS: In this Phase II, multinational, double-blind, parallel-group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout. CONCLUSIONS: This trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence-based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers.}, Doi = {10.1111/eip.13083}, Key = {fds354288} } @article{fds371761, Author = {Zhang, L and Lizano, P and Xu, Y and Rubin, L and Lee, A and Lencer, R and Reilly, J and Keefe, R and Keedy, S and Pearlson, G and Clementz, B and Keshavan, M and Gershon, E and Tamminga, C and Sweeney, JA and Hill, S and Bishop, J}, Title = {Peripheral Inflammation is Associated With Impairments of Inhibitory Behavioral Control and Visual Sensorimotor Function in Psychotic Disorders}, Journal = {Neuropsychopharmacology}, Volume = {47}, Pages = {380-381}, Year = {2022}, Key = {fds371761} } @article{fds371760, Author = {Brady, L and Eremenc, S and Keefe, R and Trivedi, M and Sand, M and Koblan, K and Stafford, E and Streiff, R and Lisanby, S}, Title = {Developing Novel Clinical Outcome Assessments (COAs) for Psychiatric Illnesses}, Journal = {Neuropsychopharmacology}, Volume = {47}, Pages = {2-3}, Year = {2022}, Key = {fds371760} } @article{fds371762, Author = {Horan, B and Depp, C and Hurst, S and Klein, H and Harvey, P and Keefe, R}, Title = {Content Validation of a Functional Co-Primary Measure for Clinical Trials Targeting Cognitive Impairment Associated With Schizophrenia (CIAS): An FDA-Funded Study}, Journal = {Neuropsychopharmacology}, Volume = {47}, Pages = {383-384}, Year = {2022}, Key = {fds371762} } @article{fds366684, Author = {Atkins, AS and Kraus, MS and Welch, M and Yuan, Z and Stevens, H and Welsh-Bohmer, KA and Keefe, RSE}, Title = {Remote self-administration of digital cognitive tests using the Brief Assessment of Cognition: Feasibility, reliability, and sensitivity to subjective cognitive decline.}, Journal = {Frontiers in Psychiatry}, Volume = {13}, Pages = {910896}, Year = {2022}, url = {http://dx.doi.org/10.3389/fpsyt.2022.910896}, Abstract = {Cognitive impairment is a common and pervasive feature of etiologically diverse disorders of the central nervous system, and a target indication for a growing number of symptomatic and disease modifying drugs. Remotely acquired digital endpoints have been recognized for their potential in providing frequent, real-time monitoring of cognition, but their ultimate value will be determined by the reliability and sensitivity of measurement in the populations of interest. To this end, we describe initial validation of remote self-administration of cognitive tests within a regulatorily compliant tablet-based platform. Participants were 61 older adults (age 55+), including 20 individuals with subjective cognitive decline (SCD). To allow comparison between remote (in-home) and site-based testing, participants completed 2 testing sessions 1 week apart. Results for three of four cognitive domains assessed demonstrated equivalence between remote and site-based tests, with high cross-modality ICCs (absolute agreement) for Symbol Coding (ICC = 0.75), Visuospatial Working Memory (ICC = 0.70) and Verbal Fluency (ICC > 0.73). Group differences in these domains were significant and reflected sensitivity to objective cognitive impairment in the SCD group for both remote and site-based testing (p < 0.05). In contrast, performance on tests of verbal episodic memory suggested inflated performance during unmonitored testing and indicate reliable use of remote cognitive assessments may depend on the construct, as well as the population being tested.}, Doi = {10.3389/fpsyt.2022.910896}, Key = {fds366684} } @article{fds362559, Author = {Kraus, MS and Walker, TM and Perkins, D and Keefe, RSE}, Title = {Basic auditory processing and emotion recognition in individuals at clinical high risk for psychosis.}, Journal = {Schizophrenia Research. Cognition}, Volume = {27}, Pages = {100225}, Year = {2022}, Month = {March}, url = {http://dx.doi.org/10.1016/j.scog.2021.100225}, Doi = {10.1016/j.scog.2021.100225}, Key = {fds362559} } @article{fds362794, Author = {Lim, K and Rapisarda, A and Keefe, RSE and Lee, J}, Title = {Social skills, negative symptoms and real-world functioning in individuals at ultra-high risk of psychosis.}, Journal = {Asian J Psychiatr}, Volume = {69}, Pages = {102996}, Year = {2022}, Month = {March}, url = {http://dx.doi.org/10.1016/j.ajp.2021.102996}, Abstract = {BACKGROUND: Impairment in real-world social functioning is observed in individuals at Ultra-High Risk (UHR) of psychosis. Both social skills and negative symptoms appear to influence real-world functioning. This study aims to examine the psychometric properties of a social skills measure, the High-Risk Social Challenge task (HiSoC), and evaluate the relationship between social skills, negative symptoms, and real-world functioning in UHR individuals. METHODS: HiSoC data was analysed in 87 UHR individuals and 358 healthy controls. Exploratory factor analysis (EFA) was used to evaluate the factor structure of the HiSoC task. Convergent and divergent validity were assessed. Negative symptoms were assessed on the Positive and Negative Syndrome Scale (PANSS) and real-world functioning was indexed by the Global Assessment of Functioning (GAF). Commonality analysis was used to partition unique and shared variance of HiSoC and negative symptoms with real-world functioning. RESULTS: EFA yielded a three-factor structure of HiSoC consisting of Affect, Odd behaviour and language, and Social-interpersonal. The HiSoC task discriminated UHR and healthy controls (p < 0.001, Cohen's d = 0.437-0.598). Commonality analysis revealed that the unique variance of the social amotivation subdomain of negative symptoms was the strongest predictor of GAF (p < .001, R2 = .480). Shared variance of 3.7% between HiSoC Social-interpersonal and social amotivation was observed in relation to functioning. CONCLUSION: The HiSoC is a psychometrically valid task that is sensitive to identify social skill deficits in UHR. While social skills are related to functioning, experiential negative symptoms appear to be an important target for improving real-world functional outcomes.}, Doi = {10.1016/j.ajp.2021.102996}, Key = {fds362794} } @article{fds362558, Author = {Zhang, L and Hill, SK and Guo, B and Wu, B and Alliey-Rodriguez, N and Eum, S and Lizano, P and Ivleva, EI and Reilly, JL and Keefe, RSE and Keedy, SK and Tamminga, CA and Pearlson, GD and Clementz, BA and Keshavan, MS and Gershon, ES and Sweeney, JA and Bishop, JR}, Title = {Impact of polygenic risk for coronary artery disease and cardiovascular medication burden on cognitive impairment in psychotic disorders.}, Journal = {Prog Neuropsychopharmacol Biol Psychiatry}, Volume = {113}, Pages = {110464}, Year = {2022}, Month = {March}, url = {http://dx.doi.org/10.1016/j.pnpbp.2021.110464}, Abstract = {BACKGROUND: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established. METHODS: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRSCAD) were quantified for each participant across 13 p-value thresholds (PT 0.5-5e-8). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRSCAD was examined in relation to the BACS and the optimized PT was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRSCAD-cognition associations. Multiple regression analyses examined PRSCAD under the optimal PT and medication burden in relation to the BACS composite and subtest scores. RESULTS: Higher PRSCAD was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p < 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRSCAD. After controlling for PRSCAD, a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029). CONCLUSIONS: Higher PRSCAD and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders.}, Doi = {10.1016/j.pnpbp.2021.110464}, Key = {fds362558} } @article{fds363085, Author = {Keefe, RSE and Cañadas, E and Farlow, D and Etkin, A}, Title = {Digital Intervention for Cognitive Deficits in Major Depression: A Randomized Controlled Trial to Assess Efficacy and Safety in Adults.}, Journal = {American Journal of Psychiatry}, Volume = {179}, Number = {7}, Pages = {482-489}, Year = {2022}, Month = {July}, url = {http://dx.doi.org/10.1176/appi.ajp.21020125}, Abstract = {OBJECTIVE: The authors evaluated AKL-T03, an investigational digital intervention delivered through a video game-based interface, designed to target the fronto-parietal network to enhance functional domains for attentional control. AKL-T03 was tested in adult patients with major depressive disorder and a demonstrated cognitive impairment at baseline. METHODS: Adults ages 25-55 years on a stable antidepressant medication regimen with residual mild to moderate depression and an objective impairment in cognition (as measured using the symbol coding test) were enrolled in a double-blind randomized controlled study. Participants were randomized either to AKL-T03 or to an expectation-matched digital control intervention. Participants were assessed at baseline and after completion of their 6-week at-home intervention. The primary outcome measure was improvement in sustained attention, as measured by the Test of Variables of Attention (TOVA). RESULTS: AKL-T03 (N=37) showed a statistically significant medium-effect-size improvement in sustained attention compared with the control intervention on the TOVA primary outcome (N=37) (partial eta-squared=0.11). Additionally, a composite score derived from all cognitive measures demonstrated significant improvement with AKL-T03 over the control intervention. Individual secondary and exploratory endpoints did not demonstrate statistically significant between-group differences. No serious adverse events were reported, and two patients (5.5%) in the AKL-T03 group reported an intervention-related adverse event (headache). CONCLUSIONS: Treatment with AKL-T03 resulted in significant improvement in sustained attention, as well as in cognitive functioning as a whole, compared with a control intervention. AKL-T03 is a safe digital intervention that is effective in the treatment of cognitive impairment associated with major depression. Further research will be needed to understand the clinical consequences of this treatment-induced change.}, Doi = {10.1176/appi.ajp.21020125}, Key = {fds363085} } @article{fds366161, Author = {Seccomandi, B and Agbedjro, D and Keefe, RSE and Galderisi, S and Fiszdon, J and Mucci, A and Wykes, T and Cella, M}, Title = {Evaluating how treatment adherence influences cognitive remediation outcomes.}, Journal = {Behav Res Ther}, Volume = {158}, Pages = {104186}, Year = {2022}, Month = {November}, url = {http://dx.doi.org/10.1016/j.brat.2022.104186}, Abstract = {BACKGROUND: There is evidence that Cognitive Remediation (CR) is an efficacious approach to reduce cognitive and functioning difficulties in people with schizophrenia. However, there is still a limited understanding of what influences different treatment responses. Treatment adherence has been suggested as one factor but has not been investigated systematically. AIM: To investigate how the number of CR sessions completed influences treatment outcomes. METHOD: This study used data from six randomised controlled trials comparing CR to a control condition. Instrumental variable analysis was used to evaluate the effect of number of treatment sessions on cognitive and functional outcomes. Logistic regression analysis was conducted to identify significant predictors of session attendance. RESULTS: A total of 440 participants with schizophrenia spectrum diagnosis were considered. Participants were mostly men (71.6%) and had a mean age of 39.6 (SD 10.69). A higher number of CR sessions led to larger improvements in executive function and processing speed at end of therapy. However, number of sessions did not influence outcomes for working memory and functioning. Younger age and higher levels of negative symptoms at baseline were associated with higher treatment attendance. CONCLUSION: These findings highlight the importance of treatment adherence and underscore the importance of massed practice, at least for some cognitive outcomes. While it may be complex to assess a single session's contribution to outcome in a dose-response fashion, accessing more sessions seems associated with some cognitive benefits. Observing a relationship to functioning may require longer therapy.}, Doi = {10.1016/j.brat.2022.104186}, Key = {fds366161} } @article{fds366160, Author = {Williamson, DJ and Nuechterlein, KH and Tishler, T and Ventura, J and Ellingson, BM and Turkoz, I and Keefe, RSE and Alphs, L}, Title = {Dispersion of cognitive performance test scores on the MATRICS Consensus Cognitive Battery: A different perspective.}, Journal = {Schizophrenia Research. Cognition}, Volume = {30}, Pages = {100270}, Year = {2022}, Month = {December}, url = {http://dx.doi.org/10.1016/j.scog.2022.100270}, Abstract = {OBJECTIVE: Persons with schizophrenia exhibit greater neurocognitive test score dispersion. Here, we seek to characterize dispersion on the Neurocognitive Composite subtests of the Measurement of Treatment Research to Improve Cognition in Schizophrena Consensus Cognitive Battery (MCCB) and determine the relative effects of different antipsychotic formulations on dispersion and mean performance. METHOD: In this post hoc analysis of the DREaM study (NCT02431702), which compared treatment with paliperidone palmitate (PP) long-acting injectable with oral antipsychotic (OAP) treatment over 18 months, dispersion in MCCB neurocognitive subtest performance was calculated for each participant by visit (test occasion). RESULTS: Over 18 months, mean neurocognitive performance improved in a manner consistent with the expected effects of practice in both groups (p < 0.05); this improvement was observed during the first 9 months (PP: p < 0.05, OAP: p < 0.001), followed by stable performance over the second 9 months (PP: p = 0.821, OAP: p = 0.375). Rates of change did not differ between groups (treatment-by-visit interaction: p = 0.548). In contrast, analyses of dispersion focusing on contrasts between baselines and end points of the first and second 9 months revealed different patterns. Over the first 9 months, dispersion in both groups lessened to a similar extent. However, over the second 9 months, dispersion remained stable in the PP group, whereas neurocognitive performance became significantly more variable in the OAP group (p < 0.01). CONCLUSION: Dispersion of neurocognitive test scores provides a different index of cognitive change than that provided by composite scores. Long-term maintenance of therapeutic levels provided by PP over time may limit (relative to oral AP) the extent to which cognitive performance becomes more variable.}, Doi = {10.1016/j.scog.2022.100270}, Key = {fds366160} } @article{fds374580, Author = {Horan, WP and Depp, CA and Hurst, S and Linthicum, J and Vargas, G and Klein, H and Keefe, RSE and Harvey, PD}, Title = {Qualitative Analysis of the Content Validity of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) in Schizophrenia: A Multi-Stakeholder Perspective}, Journal = {Schizophrenia Bulletin Open}, Volume = {4}, Number = {1}, Year = {2023}, Month = {January}, url = {http://dx.doi.org/10.1093/schizbullopen/sgad012}, Abstract = {The US Food and Drug Agency (FDA) requires clinical trials targeting cognitive impairment associated with schizophrenia (CIAS) to demonstrate the functional relevance of cognitive improvements by employing a functional co-primary measure. Although quantitative evidence supports the suitability of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) for this purpose, FDA guidelines for qualification of clinical outcome assessments require evidence of content validity, defined as qualitative evidence that key stakeholders view the measure as relevant and important. To collect this important qualitative data, semi-structured interviews were conducted with outpatients with schizophrenia (n = 24), caregivers (n = 12), and professional peer support specialists (n = 12) to elicit their views about the definition and importance of functional independence, the importance of the functional domains assessed by the VRFCAT (meal planning, using transportation, handling money, shopping), and the relevance of the VRFCAT tasks to these domains. Qualitative thematic analyses revealed consistent themes across groups in defining functional independence, including performing instrumental self-care, financial, and social tasks; making decisions autonomously; and not depending on others to carry out daily activities. There were, however, notable differences in their views regarding the importance of and barriers to functional independence. All groups viewed the VRFCAT as assessing skill domains that are central to independent functioning and, with some minor differences, the VRFCAT tasks were viewed as relevant and meaningful examples of the domains. These qualitative results provide converging evidence that key stakeholders view the VRFCAT as a content-valid measure.}, Doi = {10.1093/schizbullopen/sgad012}, Key = {fds374580} } @article{fds371563, Author = {Rekhi, G and Saw, YE and Lim, K and Keefe, RSE and Lee, J}, Title = {Impact of Cognitive Impairments on Health-Related Quality of Life in Schizophrenia.}, Journal = {Brain Sciences}, Volume = {13}, Number = {2}, Year = {2023}, Month = {January}, url = {http://dx.doi.org/10.3390/brainsci13020215}, Abstract = {The impact of cognitive impairments on the health-related quality of life (HRQoL) in individuals with schizophrenia is unclear. The aim of this study was to examine the association between cognitive impairments and HRQoL in individuals with schizophrenia. A total of 609 individuals with schizophrenia were assessed on the Positive and Negative Syndrome Scale (PANSS) and a neurocognitive battery which comprised of the Wechsler Abbreviated Scale of Intelligence matrix reasoning, the Benton Judgment of Line Orientation Test, Continuous Performance Tests-Identical Pairs, and the Brief Assessment of Cognition in Schizophrenia. A cognitive factor g was derived from the neurocognitive battery. EuroQol five-dimensional (EQ-5D-5L) utility scores were derived from PANSS scores via a previously validated algorithm and used as a measure of HRQoL. Hierarchical multiple regression was conducted to examine the association between cognitive factor g and the EQ-5D-5L. Cognitive factor g (β = 0.189, t = 4.956, p < 0.001) was found to be significantly associated with EQ-5D-5L scores. Age (β = -0.258, t = -6.776, p < 0.001), sex (β = 0.081, t = 2.117, p = 0.035), and being employed (β = 0.091, t = 2.317, p = 0.021) were also significant predictors of EQ-5D-5L. Our results add to the extant literature on the burden cognitive impairments exact in individuals with schizophrenia. More research is needed to develop effective interventions for cognitive impairments in schizophrenia.}, Doi = {10.3390/brainsci13020215}, Key = {fds371563} } @article{fds370725, Author = {Kendler, KS and Keefe, RSE and Ohlsson, H and Sundquist, J and Sundquist, K}, Title = {Risk for psychiatric and substance use disorders as a function of transitions in Sweden's public educational system: a national study.}, Journal = {Psychol Med}, Pages = {1-8}, Year = {2023}, Month = {March}, url = {http://dx.doi.org/10.1017/S003329172300048X}, Abstract = {BACKGROUND: To clarify, in a national sample, associations between risk for seven psychiatric and substance use disorders and five key transitions in Sweden's public educational system. METHODS: Swedish-born individuals (1972-1995, N = 1 997 910) were followed through 12-31-2018, at mean age 34.9. We predicted, from these educational transitions, risk for major depression (MD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), anorexia nervosa (AN), alcohol use disorder (AUD), and drug use disorder (DUD), assessed from Swedish national registers, by Cox regression, censoring individuals with onsets ⩽17. We also predicted risk from the deviation of grades from family-genetic expectations (deviation 1) and from changes in grades from ages 16 to 19 (deviation 2). RESULTS: We observed four major risk patterns across transitions in our disorders: (i) MD and BD, (ii) OCD and SZ, (iii) AUD and DUD, and (iv) AN. Failing early educational transitions had the greatest impact on risk for OCD and SZ while for other disorders, not progressing from basic to upper high school had the largest effect. Completing vocational v. college-prep upper high school was strongly associated with risk for AUD and DUD, had little relation with MD, OCD, BD, and SZ risk, and was protective for AN. Deviation 1 predicted risk most strongly for SZ, AN, and MD. Deviation 2 predicted risk most strongly for SZ, AUD, and DUD. CONCLUSIONS: The pattern of educational transitions and within family and within person development deviations are strongly and relatively specifically associated with future risk for seven psychiatric and substance-use disorders.}, Doi = {10.1017/S003329172300048X}, Key = {fds370725} } @article{fds370724, Author = {Feber, L and Peter, N and Schneider-Thoma, J and Siafis, S and Bighelli, I and Hansen, W-P and Prates Baldez and D and Salanti, G and Keefe, RSE and Engel, RR and Leucht, S}, Title = {Antipsychotic drugs and their effects on cognitive function: protocol for a systematic review, pairwise, and network meta-analysis.}, Journal = {Systematic Reviews}, Volume = {12}, Number = {1}, Pages = {54}, Year = {2023}, Month = {March}, url = {http://dx.doi.org/10.1186/s13643-023-02213-5}, Abstract = {BACKGROUND: There is evidence that antipsychotic drugs differ in their effect on the cognitive symptoms of schizophrenia. So far, there is no comprehensive systematic review available that would enable providers and patients to make informed choices regarding this important aspect of treatment. With a large number of substances available, conventional pairwise meta-analyses will not be sufficient to inform this choice. To fill this gap, we will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomized controlled trials (RCTs) to rank antipsychotics according to their effect on cognitive functioning. METHODS: In our NMA, we will include RCTs in patients with schizophrenia or schizophrenia-like psychoses comparing one antipsychotic agent with another antipsychotic agent or placebo that measures cognitive function. We will include studies on patients of every age group, in any phase of illness (e.g., acute or stable, first episode or chronic schizophrenia, in- or outpatients) with an intervention time of at least 3 weeks. The primary outcome will be the composite score of cognitive functioning, preferentially measured with the test battery developed by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. The secondary outcomes include the seven cognitive domains that the composite score is composed of, as well as functioning and quality of life. Study selection and data extraction will be conducted by at least two independent reviewers. We will use the Cochrane Risk of Bias tool 2 to determine the risk of bias in studies, and we will evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). We will perform NMA using R (package netmeta). We will conduct subgroup and sensitivity analyses to explore the heterogeneity and assess the robustness of our findings. DISCUSSION: This systematic review and network meta-analysis aims to inform evidence-based antipsychotic treatment choice for cognitive deficits in schizophrenia patients by analyzing existing RCTs on this subject. The results have the potential to support patients' and physicians' decision-making processes based on the latest available evidence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022312483.}, Doi = {10.1186/s13643-023-02213-5}, Key = {fds370724} } @article{fds371818, Author = {Cecchi, M and Adachi, M and Basile, A and Buhl, DL and Chadchankar, H and Christensen, S and Christian, E and Doherty, J and Fadem, KC and Farley, B and Forman, MS and Honda, S and Johannesen, J and Kinon, BJ and Klamer, D and Marino, MJ and Missling, C and O'Donnell, P and Piser, T and Puryear, CB and Quirk, MC and Rotte, M and Sanchez, C and Smith, DG and Uslaner, JM and Javitt, DC and Keefe, RSE and Mathalon, D and Potter, WZ and Walling, DP and Ereshefsky, L}, Title = {Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.}, Journal = {Schizophrenia Research}, Volume = {254}, Pages = {178-189}, Year = {2023}, Month = {April}, url = {http://dx.doi.org/10.1016/j.schres.2023.02.018}, Abstract = {OBJECTIVE: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline. METHODS: 81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT). RESULTS: Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects. CONCLUSIONS: With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.}, Doi = {10.1016/j.schres.2023.02.018}, Key = {fds371818} } @article{fds371571, Author = {McCutcheon, RA and Keefe, RSE and McGuire, PK}, Title = {Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment.}, Journal = {Mol Psychiatry}, Volume = {28}, Number = {5}, Pages = {1902-1918}, Year = {2023}, Month = {May}, url = {http://dx.doi.org/10.1038/s41380-023-01949-9}, Abstract = {Cognitive deficits are a core feature of schizophrenia, account for much of the impaired functioning associated with the disorder and are not responsive to existing treatments. In this review, we first describe the clinical presentation and natural history of these deficits. We then consider aetiological factors, highlighting how a range of similar genetic and environmental factors are associated with both cognitive function and schizophrenia. We then review the pathophysiological mechanisms thought to underlie cognitive symptoms, including the role of dopamine, cholinergic signalling and the balance between GABAergic interneurons and glutamatergic pyramidal cells. Finally, we review the clinical management of cognitive impairments and candidate novel treatments.}, Doi = {10.1038/s41380-023-01949-9}, Key = {fds371571} } @article{fds371570, Author = {McCutcheon, RA and Keefe, RSE and McGuire, PK}, Title = {Correction: Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment.}, Journal = {Mol Psychiatry}, Volume = {28}, Number = {5}, Pages = {1919}, Year = {2023}, Month = {May}, url = {http://dx.doi.org/10.1038/s41380-023-01984-6}, Doi = {10.1038/s41380-023-01984-6}, Key = {fds371570} } @article{fds371747, Author = {Zhang, L and Lizano, P and Xu, Y and Rubin, LH and Lee, AM and Lencer, R and Reilly, JL and Keefe, RSE and Keedy, SK and Pearlson, GD and Clementz, BA and Keshavan, MS and Gershon, ES and Tamminga, CA and Sweeney, JA and Hill, SK and Bishop, JR}, Title = {Peripheral inflammation is associated with impairments of inhibitory behavioral control and visual sensorimotor function in psychotic disorders.}, Journal = {Schizophrenia Research}, Volume = {255}, Pages = {69-78}, Year = {2023}, Month = {May}, url = {http://dx.doi.org/10.1016/j.schres.2023.03.030}, Abstract = {Elevated markers of peripheral inflammation are common in psychosis spectrum disorders and have been associated with brain anatomy, pathology, and physiology as well as clinical outcomes. Preliminary evidence suggests a link between inflammatory cytokines and C-reactive protein (CRP) with generalized cognitive impairments in a subgroup of individuals with psychosis. Whether these patients with elevated peripheral inflammation demonstrate deficits in specific cognitive domains remains unclear. To examine this, seventeen neuropsychological and sensorimotor tasks and thirteen peripheral inflammatory and microvascular markers were quantified in a subset of B-SNIP consortium participants (129 psychosis, 55 healthy controls). Principal component analysis was conducted across the inflammatory markers, resulting in five inflammation factors. Three discrete latent cognitive domains (Visual Sensorimotor, General Cognitive Ability, and Inhibitory Behavioral Control) were characterized based on the neurobehavioral battery and examined in association with inflammation factors. Hierarchical clustering analysis identified cognition-sensitive high/low inflammation subgroups. Among persons with psychotic disorders but not healthy controls, higher inflammation scores had significant associations with impairments of Inhibitory Control (R2 = 0.100, p-value = 2.69e-4, q-value = 0.004) and suggestive associations with Visual Sensorimotor function (R2 = 0.039, p-value = 0.024, q-value = 0.180), but not with General Cognitive Ability (R2 = 0.015, p-value = 0.162). Greater deficits in Inhibitory Control were observed in the high inflammation patient subgroup, which represented 30.2 % of persons with psychotic disorders, as compared to the low inflammation psychosis subgroup. These findings indicate that inflammation dysregulation may differentially impact specific neurobehavioral domains across psychotic disorders, particularly performance on tasks requiring ongoing behavioral monitoring and control.}, Doi = {10.1016/j.schres.2023.03.030}, Key = {fds371747} } @article{fds374358, Author = {Lutz, J and Pratap, A and Lenze, EJ and Bestha, D and Lipschitz, JM and Karantzoulis, S and Vaidyanathan, U and Robin, J and Horan, W and Brannan, S and Mittoux, A and Davis, MC and Lakhan, SE and Keefe, R}, Title = {Innovative Technologies in CNS Trials: Promises and Pitfalls for Recruitment, Retention, and Representativeness}, Journal = {Innovations in Clinical Neuroscience}, Volume = {20}, Number = {7-9}, Pages = {40-46}, Year = {2023}, Month = {July}, Abstract = {Objective: Recruitment of a sufficiently large and representative patient sample and its retention during central nervous system (CNS) trials presents major challenges for study sponsors. Technological advances are reshaping clinical trial operations to meet these challenges, and the COVID-19 pandemic further accelerated this development. Method of Research: The International Society for CNS Clinical Trials and Methodology (ISCTM; www.isctm.org) Innovative Technologies for CNS Trials Working Group surveyed the state of technological innovations for improved recruitment and retention and assessed their promises and pitfalls. Results: Online advertisement and electronic patient registries can enhance recruitment, but challenges with sample representativeness, conversion rates from eligible prescreening to enrolled patients, data privacy and security, and patient identification remain hurdles for optimal use of these technologies. Electronic medical records (EMR) mining with artificial intelligence (AI)/machine learning (ML) methods is promising but awaits translation into trials. During the study treatment phase, technological innovations increasingly support participant retention, including adherence with the investigational treatment. Digital tools for adherence and retention support take many forms, including patient-centric communication channels between researchers and participants, real-time study reminders, and digital behavioral interventions to increase study compliance. However, such tools add technical complexities to trials, and their impact on the generalizability of results are largely unknown. Conclusion: Overall, the group found a scarcity of systematic data directly assessing the impact of technological innovations on study recruitment and retention in CNS trials, even for strategies with already high adoption, such as online recruitment. Given the added complexity and costs associated with most technological innovations, such data is needed to fully harness technologies for CNS trials and drive further adoption.}, Key = {fds374358} } @article{fds372237, Author = {Darrow, SM and Pizzagalli, DA and Smoski, M and Mathew, SJ and Nurnberger, J and Lisanby, SH and Iosifescu, D and Murrough, JW and Yang, H and Weiner, RD and Sanacora, G and Keefe, RSE and Song, A and Goodman, W and Whitton, AE and Potter, WZ and Krystal, AD}, Title = {Using latent profile analyses to classify subjects with anhedonia based on reward-related measures obtained in the FAST-MAS study.}, Journal = {J Affect Disord}, Volume = {339}, Pages = {584-592}, Year = {2023}, Month = {October}, url = {http://dx.doi.org/10.1016/j.jad.2023.07.081}, Abstract = {BACKGROUND: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments. METHODS: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures. RESULTS: Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures. LIMITATIONS: The main limitations include the small sample size and exploratory nature of analyses. CONCLUSIONS: Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity.}, Doi = {10.1016/j.jad.2023.07.081}, Key = {fds372237} } %% Papers Published @article{fds135040, Title = {Keefe, R.S.E., Mohs, R.C., Losonczy, M.F., Davidson, M., Silverman, J.M., Kendler, K.S., Nora, R., Horvath, T.B., and Davis, K.L. Characteristics of very poor outcome schizophrenia. American Journal of Psychiatry 1987; 144:889-895.}, Year = {1987}, Key = {fds135040} } @article{fds135031, Title = {Kahn, R.S., Harvey P.D., Davidson, M., Keefe, R.S.E., Apter, S., Neale, J.M., Mohs, R.C., and Davis, K.L. Neuropsychological functioning correlates of central monoamine function in chronic schizophrenia. Schizophrenia Research. 1994; 11:217-224.}, Year = {1994}, Key = {fds135031} } @article{fds135041, Title = {Keefe, R.S.E., Silverman, J.M., Lees Roitman, S.E., Harvey, P.D., Duncan, A., Alroy, D., Siever, L.J, Mohs, R.C., and Davis, K.L. Performance of nonpsychotic relatives of schizophrenic patients on cognitive tests. Psychiatry Research 1994; 53:1-12.}, Year = {1994}, Key = {fds135041} } @article{fds135043, Title = {Siever, L.J., Freidman, L., Moskowitz, J., Mitropoulou, V., Keefe, R.S.E., Lees Roitman, S, Merhige, D., Trestman, R., Silverman, J.M., and Mohs, R.C. Eye movement impairment and schizotypal psychopathology. American Journal of Psychiatry 1994; 151:1209-1216.}, Year = {1994}, Key = {fds135043} } @article{fds135044, Title = {Keefe, R.S.E., and Harvey P.D. (1994) Understanding Schizophrenia: A Guide to the New Research on Causes and Treatment, New York: The Free Press (Division of Simon and Schuster), 283 pp.}, Year = {1994}, Key = {fds135044} } @article{fds135030, Title = {Keefe, R.S.E., Lees Roitman, S.E., Harvey, P.D. Blum, C., DuPre, R.L., Davidson, M., and Davis, K.L. A pen-and-paper human analogue of a monkey prefrontal cortex activation task: spatial working memory in patients with schizophrenia. Schizophrenia Research, 1995; 17:25-33.}, Year = {1995}, Key = {fds135030} } @article{fds135032, Title = {Keefe, R.S.E. The contribution of neuropsychology to psychiatry. American Journal of Psychiatry 1995; 152:6-15.}, Year = {1995}, Key = {fds135032} } @article{fds135033, Title = {Siever, L.J., Bergman, A.J., and Keefe, R.S.E. The schizophrenia spectrum personality disorders. In: Schizophrenia, S.R. Hirsch and D.R. Weinberger, eds., pp. 87-105, Oxford: Blackwell University Press, 1995.}, Year = {1995}, Key = {fds135033} } @article{fds135034, Title = {Keefe R.S.E., and Cornblatt, B.A. Neuropsychology of Schizophrenia, edited by A.S. David and J.C. Cutting. Contemporary Psychology (in press).}, Year = {1995}, Key = {fds135034} } @article{fds135045, Title = {Yehuda R., Keefe, R.S.E., Harvey, P.D., Levengood, R.A., Gerber D.K., Geni J., and Siever, L.J. Learning and memory deficits in combat veterans with post-traumatic stress disorder. American Journal of Psychiatry 1995; 152:137-139.}, Year = {1995}, Key = {fds135045} } @article{fds135046, Title = {Davidson, M., Harvey, P.D., Powchik, P., Parrella, M., White, L., Knobler, H.Y., Losonczy, M.F., Keefe, R.S.E., Katz, S., and Frecska, E. Severity of symptoms in geriatric schizophrenic patients. American Journal of Psychiatry 1995; 152:197-207.}, Year = {1995}, Key = {fds135046} } @article{fds135047, Title = {Wainberg, M.L. Keefe, R.S.E., Siever L.J. The neuropsychiatry of schizotypal personality disorder. In: Neuropsychiatry of Behavior Disorders, J.J. Ratey, ed., pp. 210-229, Oxford: Blackwell University Press, 1995.}, Year = {1995}, Key = {fds135047} } @article{fds135048, Title = {Davidson, M., and Keefe, R.S.E. Cognitive impairment as a target for pharmacological treatment in schizophrenia. Schizophrenia Research 1995; 17:123-129.}, Year = {1995}, Key = {fds135048} } @article{fds135049, Title = {Keefe, R. Progress in Experimental Personality and Psychopathology Research, vol. 15, edited by E.F. Walker, R.H. Dworkin, and B.A. Cornblatt. American Journal of Psychiatry 1995;152:288-289.}, Year = {1995}, Key = {fds135049} } @article{fds135050, Title = {Trestman, R.L., Keefe, R.S.E., Mitropoulou, V., Harvey, P.D. deVegvar M.L., Lees Roitman, S.E., Davidson, M., Aaronson, A., Silverman, J.M., and Siever, L.J. Cognitive function and biological correlates of cognitive performance in schizotypal personality disorder. Psychiatry Research 1995; 59:127-136.}, Year = {1995}, Key = {fds135050} } @article{fds135035, Title = {Keefe, R.S.E., Practical applications of neuropsychology in clinical psychiatry. Directions in Psychiatry 1996; 16(4):1-8.}, Year = {1996}, Key = {fds135035} } @article{fds135036, Title = {Vocisano, C., Klein, D.N., Keefe, R.S.E., Dienst, E.R., Kincaid, M.M. Demographics, family history, premorbid functioning, developmental characteristics, and course of patients with deteriorated affective disorder. American Journal of Psychiatry 1996:153:248-255.}, Year = {1996}, Key = {fds135036} } @article{fds135037, Title = {Harvey, P.D., Keefe, R.S.E., Mitropolou, V., DuPre, R.L., Lees Roitman, S.E., Mohs, R.C., and Siever, L.J. Information processing and vulnerability to schizophrenia: Performance of patients with schizotypal and nonschizotypal personality disorders. Psychiatry Research 1996;60:49-56.}, Year = {1996}, Key = {fds135037} } @article{fds135038, Title = {Keefe R.S.E., and Cornblatt, B.A. Neuropsychology of Schizophrenia, edited by A.S. David and J.C. Cutting. Contemporary Psychology (in press).}, Year = {1996}, Key = {fds135038} } @article{fds135051, Title = {Epstein, J.I., Keefe, R.S.E., Lees Roitman, S.E., Harvey, P.D., and Mohs, R.C. Impact of neuroleptic medications on continuous performance test measures in schizophrenia. Biological Psychiatry 1996;39:902-905.}, Year = {1996}, Key = {fds135051} } @article{fds135052, Title = {Harvey, P.D., Davidson, M., White, L., Keefe, R.S.E., Hirschowitz, J., Mohs, R.C., and Davis, K.L. Empirical evaluation of the factorial structure of clinical symptoms in schizophrenia: Effects of typical neuroleptics on the BPRS. Biological Psychiatry 1996;40:755-761.}, Year = {1996}, Key = {fds135052} } @article{fds135053, Title = {Keefe, R.S.E., Frecska, E., Apter, S., Davidson, M., Hirschowitz, J., and Davis, K.L. Clinical characteristics of kraepelinian schizophrenia: Replication and extension of previous findings. American Journal of Psychiatry 1996; 153: 806-811.}, Year = {1996}, Key = {fds135053} } @article{fds135054, Title = {Keefe, R.S.E. Neuropsychological assessment of patients with schizophrenia. Clinical Advances in the Treatment of Psychiatric Disorders 1996; 10(5):16, 11-13.}, Year = {1996}, Key = {fds135054} } @article{fds135042, Title = {Keefe, R.S.E., Silverman, J., Mohs, R.C., Siever, L.J, Harvey, P.D., Friedman, L., Lees Roitman S.E., DuPre R.L., Smith C.J., Schmeidler, J., and Davis, K.L. Eye tracking, attention, and schizotypal personality symptoms in nonpsychotic relatives of schizophrenic patients. Archives of General Psychiatry 54: 169-177, 1997.}, Year = {1997}, Key = {fds135042} } @article{fds135039, Title = {McEvoy, J.P., and Keefe, R.S.E. Informing subjects of risks and benefits. 1999: pp. 129-157. In: Ethics in Psychiatric Research, H.A. Pincus, J.A. Lieberman, and S. Ferris, eds., Washington, DC: American Psychiatric Association}, Year = {1998}, Key = {fds135039} } @article{fds135055, Title = {Keefe, R.S.E. The neurobiology of disturbances of the self: Autonoetic agnosia in schizophrenia. 1998: pp. 142-173. In: Insight and Psychosis, X.F. Amador and A. David, eds., New York: Oxford University Press.}, Year = {1998}, Key = {fds135055} } @article{fds135056, Title = {Harvey, P.D., and Keefe, R.S.E. Cognition and the new antipsychotics. Journal of Advances in Schizophrenia and Brain Research 1998;1:2-8.}, Year = {1998}, Key = {fds135056} } @article{fds135057, Title = {Davis, K.L., Buchsbaum, M.S., Shihabuddin, L., Spiegel-Cohen, J., Metzger, M., Frecska, E., Keefe, R.S., and Powchik, P. Ventricular enlargement in poor-outcome schizophrenia. Biological Psychiatry 1998;43:783-793.}, Year = {1998}, Key = {fds135057} } @article{fds135058, Title = {Keefe, R.S.E. and Harvey, P.D. Schizophrenia. In: McGraw Hill Encyclopedia of Science & Technology, 9th edition (2001).}, Year = {2001}, Key = {fds135058} } @article{fds135059, Title = {Harvey, P.D., and Keefe, R.S.E. Studies of cognitive change with treatment in schizophrenia. American Journal of Psychiatry, 2001; 158: 176-184.}, Year = {2001}, Key = {fds135059} } @article{fds135060, Title = {Keefe, R.S.E. Neurocognition. 2001: pp. 192-205, In Current Issues in the Psychopharmacology of Schizophrenia, Breier, A., et al, eds. Lippincott, Williams & Wilkins: Philadelphia.}, Year = {2001}, Key = {fds135060} } %% Chapters in Books @misc{fds366162, Author = {Harvey, PD and Keefe, RSE}, Title = {The importance of treating cognition in schizophrenia and other severe mental illnesses: background, strategies, and findings to date}, Pages = {177-191}, Booktitle = {ESSENTIAL CNS DRUG DEVELOPMENT}, Year = {2012}, Key = {fds366162} } @misc{fds326114, Author = {Vance, M and Pappadopulos, E and Keefe, R and Kalali, A}, Title = {Conceptual issues in cultural adaptation and the role of culture in assessment of health-related quality of life in schizophrenia}, Pages = {53-62}, Booktitle = {Beyond Assessment of Quality of Life in Schizophrenia}, Publisher = {Springer International Publishing}, Year = {2016}, Month = {January}, ISBN = {9783319300597}, url = {http://dx.doi.org/10.1007/978-3-319-30061-0_4}, Abstract = {Before we begin a discussion about the role of culture in evaluating health-related quality of life in schizophrenia, let’s clarify some terms used in connection with measurement of psychiatric states and samples of behavior across clinical disciplines and related industries. For conceptual consistency of the discussion in this chapter, it’s important to understand how terminology from other scientific disciplines is used across healthcare and pharmaceutical industries that describes, or simply refers to, psychometric measurement and the tools that are used for such purpose.}, Doi = {10.1007/978-3-319-30061-0_4}, Key = {fds326114} } | |
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