Effects of Clozapine on Neurocognitive Functions in Schizophrenia: A Naturalistic Comparison to Non-clozapine Antipsychotics.

OBJECTIVE: While clozapine is recognized as the most effective antipsychotic for individuals with treatment-resistant schizophrenia, its effects on neurocognition remain unclear. This study aimed to compare the neurocognitive effects of clozapine treatment to those of non-clozapine antipsychotics in patients with schizophrenia and to examine the role of anticholinergic burden on cognitive impairments. DESIGN: This was a naturalistic study. Cross-sectional data were drawn from participants with chronic schizophrenia in two clinical trials assessing cognition. Cognition was evaluated using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). Anticholinergic burden was calculated for each medication using the Anticholinergic Cognitive Burden (ACB) scoring system. We stratified the participants treated with non-clozapine antipsychotics into high ACB score versus low ACB score groups. RESULTS: One hundred and seventy participants were enrolled and treated with clozapine (n=58) or non-clozapine antipsychotics (n=112). We observed no significant differences in the MCCB T-scores between the clozapine and the total non-clozapine groups for the cognitive composite score and the seven domain scores. However, the non-clozapine high ACB group showed significant impairments in processing speed and attention/vigilance, in contrast to the non-clozapine low ACB group (p<0.05). CONCLUSION: Our results show that cognitive effects of clozapine might be no different from other antipsychotics. Negative effects on neurocognition in participants treated with antipsychotics with a high ACB score were related to their total ACB score.

The psychometric properties of the Self-Evaluation of Negative Symptoms Scale (SNS) in treatment-resistant schizophrenia (TRS).

BACKGROUND: Clinician-administered measures of negative symptoms may not capture patients' subjective experiences. The Self-Evaluation of Negative Symptoms (SNS) has shown good psychometric properties when used in outpatients with higher-level functioning schizophrenia. We aimed to evaluate the psychometric properties of the SNS in low functioning participants with treatment-resistant schizophrenia (TRS). METHODS: Participants were assessed using the following measures at two time-points; time-point 1: SNS, Wide Range Achievement Test, 4th Edition Reading Subtest (WRAT-4), and Brief Assessment of Cognition in Schizophrenia (BACS). Time-point 2 (within a week of time-point 1): SNS, Negative Symptom Assessment 16 items (NSA-16), Scale to Assess Unawareness in Mental Disorder-Abbreviated (SUMD-A), Clinical Global Impression Severity Scale (CGI-S), Simpson Angus Scale (SAS), Calgary Depression Scale for Schizophrenia (CDSS), and the Patient Feasibility Questionnaire. RESULTS: Fifty participants with TRS were enrolled, a mean age of 43.8 years (SD = 11.19, min = 25, max = 64), a mean IQ of 80.62 (SD = 17.12, min = 65, max = 110), and a mean BACS Composite T-Score of 14.08 (SD = 17.16, min = -27, max = 49). Participants responded to SNS prompts with moderate consistency across two time-points. There were no significant correlations between the SNS and the NSA-16 Global Symptom score (Pearson r = 0.207, p = .150, Spearman r = 0.101, p = .483), NSA-16 Global Functioning score (Pearson r = 0.209, p = .145, Spearman r = 0.126, p = .384), nor the NSA-16 total score (Pearson r = 0.149, p = .302, Spearman r = 0.116, p = .421). However, when participants were stratified by BACS Composite T-score, there was a significant positive correlation between the SNS total and the NSA-16 Global Functioning score (Pearson r = 0.500, p = .048, Spearman r = 0.546, p = .029) among participants who demonstrated higher cognitive functioning. CONCLUSION: Participants with TRS and low functioning were able to respond to questions on the SNS regarding their subjective assessment of negative symptoms. However, self-reported and clinician-rated negative symptoms were not equivalent, except in a subgroup with higher cognitive functioning. This discrepant self-reporting appeared to relate to their low levels of insight and cognitive impairments.

Assessing instrumental activities of daily living (iADL) with a game-based assessment for individuals with schizophrenia.

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.

Does social cognition training augment response to computer-assisted cognitive remediation for schizophrenia?

OBJECTIVES: Cognitive remediation therapy (CRT) has shown significant improvement in cognition in schizophrenia. However, effect sizes of CRT have been reported to be modest raising the issue how to augment the effects of CRT on neurocognition and social cognition. Our aim was to examine whether the addition of computerized social cognition training would enhance the effects on neurocognition and social cognition as compared to CRT alone. METHODS: This is a 12-week, parallel group trial of 131 in- and out-patients with schizophrenia randomized to CRT (COGPACK or Brain Fitness) with computerized social cognition training (MRIGE), or CRT alone for 36 sessions. Participants were assessed at baseline and after 12 weeks of treatment. Assessments included neurocognition, social cognition, psychopathology, and functioning. RESULTS: The combined intervention, CRT + MRIGE, showed greater improvements in the MCCB indices of Visual Learning, Working Memory, Reasoning and Problem-Solving, and the neurocognitive composite score compared to CRT alone (Bonferroni adjusted p = 0.004, p = 0.005, p = 0.01, respectively), as did social cognition measures (Bonferroni adjusted p = 0.006, p = 0.005, respectively). CONCLUSIONS: Supplementing CRT with computerized social cognition training produced greater benefits in neurocognition, including visual learning, memory, executive functions, and social cognition relative to cognitive training alone. These findings favoring the combined training may be contributed to both the greater overall amount of cognitive practice, as well as the specific cognitive functions engaged by the social cognition training.

COMT genotype and response to cognitive remediation in schizophrenia.

BACKGROUND: A functional polymorphism of the catechol-O-methyltransferase (COMT) gene (Val158Met) partially appears to influence cognitive performance in schizophrenia subjects and healthy controls by modulating prefrontal dopaminergic activity. This study evaluated the association of the COMT Val108/158 Met genotype with response to computerized neurocognitive remediation (CRT). METHOD: 145 subjects with DSM-IV-TR schizophrenia or schizoaffective disorder were genotyped via saliva sampling. Subjects were evaluated on neurocognitive assessments (MATRICS) and clinical symptoms (PANSS) at baseline and endpoint after 12weeks of CRT. "Improvement" was defined as ≥67% of cognitive domains (≥4) showing performance increases. If ≤67% (≤2) of domains improved, the change was defined as "minimal improvement." A general linear model was conducted for change of each cognitive domain. RESULTS: Of 145 subjects, data from 138 subjects were usable. Distribution of COMT genotype: Met/Met: 28 (20.29%), Val/Met: 61 (44.20%), and Val/Val: 49 (35.51%). No significant differences were seen among genotype groups at baseline or across genotype group for "Improvement" vs. "Minimal Improvement." GLM analysis showed significant differences in Verbal Learning (p=0.003), Visual Learning (p=0.014) and Attention/Vigilance (p=0.011) favoring Met/Met and Val/Met groups. CONCLUSIONS: The low activity Met allele (Met/Met; Val/Met) was associated with significantly greater improvements in the MATRICS domains of Verbal Learning, Visual Learning and Attention/Vigilance after CRT.