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Increasingly, it is recognized that first-episode schizophrenia represents a critical stage of illness during which the effectiveness of therapeutic interventions can affect long-term outcome. In this regard, the advent of clozapine and subsequent atypical antipsychotic drugs held promise for improved outcomes in patients with first-episode schizophrenia, given the expectation of improved therapeutic efficacy and a more benign side effect burden compared with typical antipsychotic drugs. A growing number of large clinical trials have evaluated the merits of atypical antipsychotic drugs in the early stages of psychosis. A number of conclusions can be drawn from studies completed to date, with the caveat that data are either limited or unavailable for the antipsychotic drugs most recently approved by the US FDA. Studies of atypical antipsychotic drugs support data obtained with typical agents indicating that positive symptoms of psychosis are very treatment responsive and generally at lower doses than in chronic illness. It also appears that first-episode patients tend to stay on atypical antipsychotic drugs longer than on typical agents when all-cause discontinuation criteria are considered as the primary outcome measure. However, there are few differential advantages of clinical efficacy among the individual atypical antipsychotic drugs and there is little evidence to support distinct therapeutic advantages for negative symptoms or cognitive symptoms for atypical agents. Furthermore, while new-onset psychosis patients are particularly susceptible to extrapyramidal symptoms, they are also prone to gain weight and related metabolic adverse effects associated with many, but not all, atypical antipsychotic drugs. Recent data indicating that certain atypical antipsychotic drugs may have a sparing effect on cortical grey matter loss in first-episode schizophrenia is intriguing, given the potential long-term benefits. In summary, atypical antipsychotic drugs represent an incremental advance for patients in first-episode schizophrenia, especially in the area of neurological tolerability. However, metabolic concerns associated with many atypical agents along with limited benefits in cognition and negative symptom domains highlight the persistent therapeutic needs of these patients. [ABSTRACT FROM AUTHOR]

PURPOSE OF REVIEW: A role for apoptosis in schizophrenia has long been hypothesized, but only recently have studies begun to examine this issue. This paper will review studies of apoptotic regulatory proteins, DNA fragmentation, and gene microarrays to highlight the potential role of apoptosis in the pathophysiology and treatment of schizophrenia. RECENT FINDINGS: Although several studies indicate a possible increase in apoptotic susceptibility, accumulating evidence suggests that apoptotic activity may actually be downregulated in chronic schizophrenia. Furthermore, antipsychotics produce complex effects on apoptotic regulation in the central nervous system, activating both proapoptotic and antiapoptotic signaling pathways. SUMMARY: Somewhat paradoxically, apoptosis appears to be downregulated in cortex of patients with chronic schizophrenia. This could reflect either a pathophysiological failure to mount an effective response to an apoptotic insult or an appropriate compensatory response to an earlier insult. The former could account for evidence indicating reduced neuronal viability without large-scale neuronal death in schizophrenia. The latter could reflect an earlier period of increased apoptotic activity in response to one or more proapoptotic insults. Antipsychotic treatment can modify the apoptotic response. This suggests implications for treatment, especially if future studies indicate that gray matter loss occurs via apoptotic mechanisms. [ABSTRACT FROM AUTHOR]

Background: Exercise is beneficial for persons with schizophrenia; however, high dropout rates limit the impact of interventions. Virtual exercise programs have the potential to improve engagement; however, few intervention studies of virtual programs have been conducted in this population., Methods: This study examined qualitative data from 15 adults with schizophrenia who participated in a pilot randomized controlled trial of Virtual PACE-Life, a live, video-delivered group walking intervention guided by self-determination theory. Interviews elicited feedback on the intervention, barriers and facilitators to engagement, recommendations for intervention refinement, and preferences for exercise programming modality. Rapid qualitative analysis was used to explore similarities and differences between completers (i.e., those that attended ≥ 50% of virtual walking sessions; n = 9) and non-completers (i.e., those that attended < 50% of virtual walking sessions; n = 6)., Results: Both groups viewed Virtual PACE-Life positively but found the virtual exercise sessions challenging and inadequate for facilitating social interaction. Work obligations impacted completers' attendance whereas technological issues and forgetting impacted non-completers' attendance at virtual walking sessions. Completers preferred virtual exercise programs and non-completers preferred in-person exercise programs., Conclusions: These findings suggest that future virtual group-based walking programs should prioritize enhancing the social aspect, offering scheduling choices, and regularly assessing the perceived difficulty of exercise sessions. These modifications not only have the potential to improve intervention engagement but they also may increase participant autonomy and relatedness, core components of self-determination theory., Competing Interests: Declarations Ethics approval and consent to participate All participants provided written informed consent and the study was approved by the Institutional Review Board at the University of North Carolina at Chapel Hill. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Schizophrenia is a neurodevelopmental disorder associated with deficits in cognitive development and childhood psychopathology. Previous studies have focused on older children and the few studies of early childhood have yielded inconsistent findings. We studied cognitive development and psychopathology in children at familial high risk (FHR) of schizophrenia and matched controls from 1 to 6 years and hypothesized that FHR children would show consistent deficits across cognitive and behavioral measures in early childhood., Study Design: Cognitive development in children at high familial risk for schizophrenia or schizoaffective disorder (n = 33) and matched healthy controls (n = 66) was assessed at 1 and 2 years with the Mullen Scales of Early Learning, and at 4 and 6 years with the Stanford Binet Intelligence Scales, BRIEF-P/BRIEF and CANTAB. Psychopathology was assessed at 4 and 6 years with the BASC-2. General linear models were used to examine differences on outcome scores, and chi-square analyses were used to explore differences in the proportion of "at risk" or "below average" score profiles., Study Results: FHR children scored significantly lower than controls on Mullen Composite at age 2, and demonstrated broad deficits in IQ, executive function and working memory and 4 and 6 years. FHR children were also rated as significantly worse on most items of the BASC-2 at ages 4 and 6., Conclusions: Children at FHR for schizophrenia demonstrate abnormal cognitive development and psychopathology at younger ages than previously detected, suggesting that early detection and intervention needs to be targeted to very early childhood., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Previous research has suggested that demographic factors affect the likelihood of a patient with schizophrenia receiving a clozapine prescription. The authors aimed to determine the impact of race, social determinants of health, gender, rurality, and care patterns on clozapine prescription rates., Methods: This cross-sectional observational study used structured electronic health records data from 3,160 adult patients diagnosed as having schizophrenia between October 1, 2015, and November 30, 2021, in a multifacility health system. The social vulnerability index (SVI) was used to quantify social determinants of health. Descriptive data analysis, logistic regression, and sensitivity analysis were conducted to identify differences between patients with schizophrenia who received a clozapine prescription and those who received antipsychotic medications other than clozapine., Results: Overall, 401 patients with schizophrenia were given a clozapine prescription during the study period, and 2,456 received antipsychotics other than clozapine. Results of the logistic regression indicated that White race (OR=1.71, compared with Black race), community minority status and language SVI score (OR=2.97), and increased treatment duration (OR=1.36) were significantly associated with a higher likelihood of clozapine prescription; gender, rurality, age at first diagnosis, and ethnicity did not influence the likelihood of receiving clozapine., Conclusions: Black patients with schizophrenia had a lower likelihood of receiving a clozapine prescription compared with White patients, even after analyses accounted for demographic variables, social determinants of health, and care access patterns. Given the effectiveness of clozapine in managing treatment-resistant schizophrenia, it is crucial for future research to better understand the factors contributing to this treatment disparity., Competing Interests: Dr. Jarskog reports receiving research grant funding from Boehringer-Ingelheim, Corcept Therapeutics, and Otsuka and serving as a consultant to UpToDate and Signant Health. The other authors report no financial relationships with commercial interests.

Schizophrenia is characterized by persistent cognitive deficits that significantly impact functional outcomes. Despite the current available treatments, these deficits remain inadequately addressed, highlighting the need to explore the effect of more novel treatments on cognition. The current study examined the effect of intranasal oxytocin on cognitive functioning in people with schizophrenia by utilizing data from a 12-week, randomized controlled trial. Sixty-seven participants with schizophrenia or schizoaffective disorder were randomized to receive placebo or intranasal oxytocin. Participants completed a comprehensive neuropsychological battery at baseline and 12 weeks. The results demonstrated that intranasal oxytocin did not significantly improve cognition in people with schizophrenia compared to placebo. These findings suggest that oxytocin does not worsen or enhance cognition in people with schizophrenia. Yet, the current intervention did not standardize the timing of cognitive assessments relative to the timing of oxytocin administration, which may explain our findings. Future studies attempting to clarify this relationship would benefit from employing a more controlled approach to the timing of treatment and assessments., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Persons with schizophrenia have reduced cardiorespiratory fitness (CRF), a predictor of all-cause mortality. Exercise is effective for improving CRF; however, motivational challenges affecting those with schizophrenia impact exercise engagement and maintenance. Virtual Physical Activity Can Enhance Life (Virtual PACE-Life), a multicomponent walking intervention guided by self-determination theory (SDT), was developed to target CRF in this population while addressing motivational difficulties. Virtual PACE-Life includes live video-delivered group walking sessions, Fitbit activity tracking, recommendations for home-based walking sessions, goal setting, and if-then plans. The present study was a 16-week pilot randomized controlled trial that evaluated the impact of Virtual PACE-Life against Fitbit Alone in a sample of 37 participants with schizophrenia on intermediate targets (competence, autonomy, and relatedness satisfaction, autonomous motivation), proximal outcomes (Fitbit-measured steps/day and minutes spent walking), and the primary outcome (CRF using the 6-minute walk test). Blinded research staff completed assessments at baseline, midpoint, posttest, and one-month follow-up. Analysis of covariance and hierarchical linear regression analyses were used to evaluate group differences at each timepoint controlling for baseline. Attendance at Virtual PACE-Life groups was 58% and Fitbit adherence was above 70% in both conditions. Intent-to-treat results indicated greater competence and autonomy satisfaction for Virtual PACE-Life but not in relatedness satisfaction or autonomous motivation. There were no group differences in proximal or primary outcomes during the intervention period. Completer analyses showed improvements in steps/day and autonomous motivation favoring Virtual PACE-Life. Future research is needed to maximize the exercise and CRF benefits of virtual group-based exercise for persons with schizophrenia.

Black Americans are diagnosed with schizophrenia spectrum disorders at more than twice the rate of White individuals and experience significantly worse outcomes following diagnosis. Little research has examined specific factors that may contribute to worse functional outcomes among Black Americans diagnosed with schizophrenia. One approach to understanding why racial disparities emerge is to examine established predictors of functioning in this population: neurocognition, social cognition, and symptom severity. The present study aims to broaden existing literature on racial differences within these domains by (a) examining racial differences in functioning and these established predictors of functioning (i.e., neurocognition, social, and symptom severity) and (b) investigating whether cognition and symptom domains similarly predict functioning between Black and White Americans with schizophrenia. Sixty-six participants' baseline neurocognition, social cognition, symptom severity, and functioning were assessed. Black participants demonstrated lower neurocognition scores and higher levels of disorganized symptoms relative to White participants. No racial differences in functioning or social cognition were observed. Further, race did not moderate the relationship between any of these established predictors and functioning outcomes. The largely nonsignificant differences in known predictors of functioning highlight the need to explore further domains that may be more relevant for understanding racial disparities in schizophrenia. Considering that psychosocial treatments for schizophrenia spectrum disorders often focus on cognition, these results underscore the importance of identifying whether these domains or other treatment targets may be better in addressing racial disparities in functioning. Possible areas of exploration for future work (e.g., structural factors, racism-related stress) are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

People with schizophrenia exhibit reduced alpha oscillations and frontotemporal coordination of brain activity. Alpha oscillations are associated with top-down inhibition. Reduced alpha oscillations may fail to censor spurious endogenous activity, leading to auditory hallucinations. Transcranial alternating current stimulation (tACS) at the alpha frequency was shown to enhance alpha oscillations in people with schizophrenia and may thus be a network-based treatment for auditory hallucinations. We conducted a double-blind, randomized, placebo-controlled pilot clinical trial to examine the efficacy of 10-Hz tACS in treating auditory hallucinations in people with schizophrenia. 10-Hz tACS was administered in phase at the dorsolateral prefrontal cortex and the temporoparietal junction with a return current at Cz. Patients were randomized to receive tACS or sham for five consecutive days during the treatment week (40 min/day), followed by a maintenance period, during which participants received weekly tACS (40 min/visit) or sham. tACS treatment reduced general psychopathology (p < 0.05, Cohen's d = -0.690), especially depression (p < 0.005, Cohen's d = -0.806), but not auditory hallucinations. tACS treatment increased alpha power in the target region (p < 0.05), increased the frequency of peak global functional connectivity towards 10 Hz (p < 0.05), and reduced left-right frontal functional connectivity (p < 0.005). Importantly, changes in brain functional connectivity significantly correlated with symptom improvement (p < 0.05). Daily 10 Hz-tACS increased alpha power and altered alpha-band functional connectivity. Successful target engagement reduced depression and other general psychopathology symptoms, but not auditory hallucinations. Considering existing research of 10Hz tACS as a treatment for major depressive disorder, our study demonstrates its transdiagnostic potential for treating depression., (© 2022. The Author(s).)

Background: Premature mortality in individuals with schizophrenia spectrum disorders (SSDs) is largely due to high rates of chronic health conditions. Although exercise has been shown to improve health in this population, scalable and accessible interventions are limited., Aim: To examine the impact of Physical Activity Can Enhance Life (PACE-Life), a novel walking intervention, on physical activity, and on secondary outcomes of cardiorespiratory fitness (CRF), physical health, autonomous motivation, social support, and quality of life., Method: Sixteen individuals with SSDs were enrolled in a 10-week open trial. The intervention included walking groups, home-based walks, Fitbit use, and goal-setting and if-then plans. Within-group effect sizes were calculated to represent changes from baseline to post-test and 1-month follow-up., Results: Participants increased self-reported weekly walking minutes and decreased daily hours spent sitting; however, Fitbit-recorded exercise behavior changed only minimally. There were also improvements in secondary outcomes including autonomous motivation and hip circumference. CRF improved only minimally, and findings were relatively unchanged with outliers removed from the full sample., Conclusions: This open trial demonstrates modest improvements in key parameters of exercise behavior and physical health from participating in PACE-Life. Future research should assess the efficacy of this intervention in a randomized controlled trial.

Objective: The authors sought to increase the rate of cardiometabolic monitoring for patients receiving antipsychotic drugs in an academic outpatient psychiatric clinic serving people with serious mental illness., Methods: Using a prospective quasi-experimental, interrupted time-series design with data from the electronic health record (EHR), the authors determined metabolic monitoring rates before, during, and after implementation of prespecified quality improvement (QI) measures between August 2016 and July 2017. QI measures included a combination of provider, patient, and staff education; systematic barrier reduction; and an EHR-based reminder system., Results: After 1 year of QI implementation, the rate of metabolic monitoring had increased from 33% to 49% (p<0.01) for the primary outcome measure (hemoglobin A1C and lipid panel). This increased monitoring rate was sustained for 27 months beyond the end of the QI intervention. More than 75% of providers did not find the QI reminders burdensome., Conclusions: Significant improvement in the rate of metabolic monitoring for people taking antipsychotic drugs can be achieved with little added burden on providers. Future research needs to assess the full range of patient, provider, and system barriers that prevent cardiometabolic monitoring for all individuals receiving antipsychotic drugs.

The COVID-19 pandemic has presented a formidable challenge to care continuity for community mental health clients with serious mental illness and for providers who have had to quickly pivot the modes of delivering critical services. Despite these challenges, many of the changes implemented during the pandemic can and should be maintained. These include offering a spectrum of options for remote and in-person care, greater integration of behavioral and physical healthcare, prevention of viral exposure, increased collaborative decision-making related to long-acting injectable and clozapine use, modifying safety plans and psychiatric advance directives to include new technologies and broader support systems, leveraging natural supports, and integration of digital health interventions. This paper represents the authors' collaborative attempt to both reflect the changes to clinical practice we have observed in CMHCs across the US during this pandemic and to suggest how these changes can align with best practices identified in the empirical literature.

Background: Challenges in employment are highly prevalent among people with schizophrenia regardless of their employment history. Although supportive employment can be effective, few participants sustain meaningful competitive employment. Our goal was to identify the correlates of developing sustained unemployment., Methods: We examined employment outcomes by comparing clinical, neurocognitive, and social cognitive features in 234 participants with Schizophrenia Spectrum Disorders across t competitive employment outcomes: currently employed, participants who had never worked for a year, and those who had been employed but developed long-term unemployment. We examined social cognition and neurocognition, as well as positive and negative schizophrenia symptoms, and premorbid functioning and demographic factors., Results: We found significant differences in age, race, premorbid functioning, cognitive performance, and social cognition between currently and formerly employed patients. When individual tasks were examined, emotion recognition and verbal working memory performance were the domains differentiating the groups. Older African Americans were over-represented in the formerly employed group., Conclusions: There were minimal differences other than age and race between formerly employed patients and those who had never worked. These data suggest the possibility that deterioration in employment outcomes may also co-occur with declines in other abilities. Opportunities and disparities may also be a contributor to re-entering the work force.

Poor health and low cardiorespiratory fitness (CRF) contribute substantially to the shortened lifespan of individuals with schizophrenia spectrum disorders (SSDs). Increasing physical activity has demonstrated value; however, there are limited interventions that are accessible and adequately address motivational challenges. This paper reports on an open trial of Physical Activity Can Enhance Life (PACE-Life), a motivational theory-based manualized multicomponent walking intervention. The primary aim was to examine the feasibility of implementing PACE-Life through meeting the recruitment target (n=14), attendance and adherence rates, and participant feedback. The secondary aim was to assess the impact of PACE-Life on intermediate targets (autonomous motivation and satisfaction of autonomy, relatedness, and competence needs), proximal outcomes (Fitbit steps/day and minutes spent walking), the primary outcome (CRF), and secondary outcomes (loneliness, symptoms, resting heart rate, blood pressure, weight, body mass index, and hip and waist circumference). Seventeen participants with SSDs enrolled in a 24-week open trial. Assessments occurred at baseline, midpoint, post-test, and one-month follow-up. The recruitment target was exceeded, the group attendance rate was 34%, Fitbit adherence rate was 54%, and participant feedback indicated satisfaction with the intervention as well as a positive group environment. There was a large improvement in the primary outcome of CRF with 77% of participants achieving clinically significant improvement at post-test. Small and medium effect size increases were observed in autonomous motivation and satisfaction of autonomy, relatedness, and competence needs. Fitbit data and secondary outcomes generally remained unchanged or worsened during the intervention. Results from this open trial indicate that PACE-Life leads to meaningful changes in CRF among people with SSDs., Competing Interests: Conflicts of Interest Given her role as Associate Editor, Ana M. Abrantes had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to Adrian Taylor. The additional authors declare no conflicts of interest relevant to the subject of this article.

Background: Suicide risk among individuals with schizophrenia (SZ) is intractably high, with over 40% of individuals attempting to take their own lives during their lifetime and an estimated 5-10% completing suicide. At present, available pharmacological and psychotherapeutic treatments offer limited risk reduction benefits, and thus, there remains an urgent need to explore novel interventions that will ameliorate this risk. Aerobic exercise (AE) has been shown to improve a number of predictors of suicide risk (e.g., depressed mood, sleeping difficulties). As individuals with SZ display a highly sedentary lifestyle, AE may reduce suicide risk., Methods: Employing a multi-site, single-blind, randomized clinical trial design, we will examine the impact of AE on risk for suicide and related variables in individuals with SZ. Participants will be randomized to one of two 12-week exercise interventions: AE or a stretching and toning (ST) control intervention. Primary outcome measures will include suicide risk (Columbia Suicide Severity Rating Scale, C-SSRS) and aerobic fitness (VO 2 max), along with additional measures of suicide risk, mood, emotion regulation, sleep, cognition, and physical activity, with assessments completed at baseline and after 6 and 12 weeks of interventions., Discussion: It is hypothesized that AE will reduce suicide risk among individuals with SZ. This study may offer support for a more efficacious treatment method for this population in addition to the pre-existing pharmacological and psychotherapeutic treatment regimens., Trial Registration: Clinicaltrials.gov, NCT03270098 . Registered on September 1, 2017.

Black Americans are disproportionately diagnosed with schizophrenia and experience worse objective functional outcomes (e.g., hospitalizations) than their White counterparts. However, we have a limited understanding of the psychological pathways through which Black Americans with schizophrenia reach worse outcomes. This study assessed race and domains of functioning (e.g., neurocognition, functional capacity) known to be associated with objective outcomes in a sample of 108 non-Hispanic Black and 61 non-Hispanic White individuals with schizophrenia-spectrum disorders from the Social Cognition Psychometric Evaluation (SCOPE) study. Three primary findings emerged: First, Black participants showed lower scores than White participants on measures of neurocognition(NC), social cognition(SC), and everyday living skills, but not social skills or community functioning. Second, neighborhood socioeconomic status (SES) explained 21% of the relationship between race and NC but did not mediate the relationship between race and SC or everyday living skills. Finally, prior research has established that NC, SC, social skills, and everyday living skills predict community functioning in individuals. Finally, prior research has established that NC, SC, social skills, and everyday living skills predict community functioning in individuals with schizophrenia. In our sample, after controlling for neighborhood SES, race did not moderate the relationships of NC, SC, social skills, or everyday living skills to community functioning. This indicates that relationships between these domains are comparably strong across Black and White Americans. Taken together, these findings show that NC, SC, and everyday living skills may be important areas to explore in regards to racial disparities in schizophrenia. More research, especially incorporating nuanced race- and SES-related variables, is needed to understand how to best intervene and improve real-world outcomes for Black Americans with schizophrenia., Competing Interests: Declaration of competing interest Dr. Harvey serves as a consultant/advisory board member for Boeheringer Ingelheim, Lundbeck, Otsuka Digital Heath, Roche, Sanofi, Sunovion, and Takeda. The other authors report no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Persons diagnosed with schizophrenia spectrum disorders (SSDs) often experience pervasive feelings of loneliness, which are considered a significant barrier to treatment and recovery., Aim: As impaired social cognition may contribute to increased loneliness and less skillful social interactions, this study examines the relationships between loneliness and measures of social cognition and functional outcome from the Social Cognition Psychometric Evaluation (SCOPE) study., Methods: This study evaluated the relationship between loneliness, social cognitive ability, and social functioning in the context of a large-scale psychometric investigation. We also explored the associations of select demographic characteristics and clinical variables on the endorsement of loneliness in persons diagnosed with a psychotic disorder., Results: Seventy-four stable outpatients with SSDs and 58 healthy controls completed the UCLA Loneliness Scale in addition to the standard SCOPE battery. Our findings support prior research indicating persons diagnosed with a psychotic disorder experience greater levels of loneliness than normative groups. However, the results also indicate that self-reported loneliness is not associated with social cognitive abilities or functional outcome in psychosis. Regression analyses indicate that roughly half the variance in loneliness endorsed by persons with SSDs is accounted for by clinical variables, with loneliness most strongly associated with guilt and self-esteem., Conclusion: These findings suggest that treatments aiming to reduce perceived social isolation in psychosis should incorporate techniques to bolster selfesteem, reduce guilt, and improve depressive symptoms.

Individuals with schizophrenia spectrum disorders (SSD) consistently show deficits in social cognition (SC) which is associated with real world outcomes. Psychosocial treatments have demonstrated reliable improvements in SC abilities, highlighting the need for accurate identification of SC deficits for efficient and individualized treatment planning. To this end, the Observable Social Cognition Rating Scale (OSCARS) is an 8-item scale with both self and informant versions. This study investigated psychometric properties of the OSCARS as both a self and informant-reported scale in a large sample of SSD (n = 382) and individuals without a psychiatric diagnosis (n = 289). A two-factor structure (Social Cognitive Bias and Social Cognitive Ability) of the OSCARS demonstrated acceptable model fit with good internal consistency for both self- and informant-report. The OSCARS had adequate convergent, external, and predictive validity. Area Under the Curve (AUC) values suggest the OSCARS has some value in identifying individuals with impaired SC and social competence, although stronger AUC values were demonstrated when identifying individuals with impaired real-world functioning. Overall, psychometric properties indicate the OSCARS may be a useful first-step tool for clinicians to detect functioning deficits in SSD and efficiently identify individuals in need of additional assessment or psychosocial interventions., Competing Interests: Declaration of Competing interest MH received a fee from Lundbeck as a speaker at an education grant conference and travel support from Angelini. In the last year, AEP received consulting fees and travel reimbursement from Roche. PDH reports the following conflicts of interest within the past year: consulting fees or travel reimbursements from Alkermes, Boehringer Ingelheim, Intra-Cellular Therapies, Minerva Pharma, Otsuka America, Regeneron Pharma, Roche Pharma, Sunovion Pharma, Takeda Pharma, and Teva; Royalties from the Brief Assessment of Cognition in Schizophrenia; He is chief scientific officer of i-Function, Inc.; Research grants from Takeda and from the Stanley Medical Research Foundation. LFJ has received grant support from Auspex/Teva, Boehringer Ingelheim, Otsuka, NIH and has served as a consultant for Bracket and UpToDate. TFH, LN, and DLP report no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Face perception is a highly developed function of the human visual system. Previous studies of event-related potentials (ERPs) have identified a face-selective ERP component (negative peak at about 170 ms after stimulus onset, N170) in healthy participants. In contrast, patients with schizophrenia exhibit reduced amplitude of the N170, which may represent a pathological deficit in the neurophysiology of face perception. Interestingly, healthy humans with schizophrenia-like experiences (schizotypy) also exhibit abnormal processing of face perception. Yet, it has remained unknown how schizotypy in healthy humans is associated with the neurophysiological substrates of face perception. Here, we recruited 35 healthy participants and assessed their schizotypy by the magical ideation rating scale. We used high-density electroencephalography to obtain ERPs elicited by a set of Mooney faces (face and non-face visual stimuli). We investigated median and mean reaction times and visual ERP components in response to the stimuli. We observed a significant difference in N170 amplitude between the two face-stimulus conditions and found that the measured schizotypy scores were significantly correlated with both reaction times and N170 amplitude in response to the face stimuli across all participants. Our results thus support the model of schizotypy as a manifestation of a continuum between healthy individuals and patients with schizophrenia, where the N170 impairment serves as a biomarker for the degree of pathology along this continuum., Competing Interests: Declaration of competing interest S.A., C.L., L.F.J., and F.F. have no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Impairments in social functioning are central to Schizophrenia (SCZ). Patients with SCZ have challenges in the ability to evaluate their functioning. A correlate of self-assessments in SCZ is depression, wherein negligible depression predicts overestimation. Healthy individuals misestimate their functioning, but mild dysthymia predicts accuracy. We examined depression, gender, and schizophrenia as predictors of self-reported everyday functioning., Methods: 218 people with SCZ and 154 healthy controls self-reported their social functioning. They self-reported their depression with the Beck Depression Inventory (BDI) and their social cognitive ability on the Observable Social Cognition Rating Scale (OSCARS)., Results: 64% of subjects were male. Schizophrenia patients reported more depression, poorer social functioning, and worse social cognition. Linear regression analyses revealed significant correlations between self-reported social functioning and BDI scores, which also predicted self-reported social cognition. There was no significant effect of sex on self-reports of social functioning or social cognition. Finally, when BDI and OSCARS were directly compared to diagnosis and sex for prediction of self-reported social functioning, there was no impact of diagnosis or sex., Implications: Self-reported interpersonal functioning is determined by current depression. Both healthy people and people with schizophrenia index their social functioning and their social cognitive by their level of depression., Competing Interests: Declaration of Competing Interest In the last three years, Dr. Harvey has received consulting fees or travel reimbursements from Allergan, Alkermes, Akili, Biogen, Boehringer Ingelheim, Forum Pharma, Genentech (Roche Pharma), Intra-Cellular Therapies, Jazz Pharma, Lundbeck Pharma, Minerva Pharma, Otsuka America (Otsuka Digital Health), Roche Parma, Sanofi Pharma, Sunovion Pharma, Takeda Pharma, and Teva. He receives royalties from the Brief Assessment of Cognition in Schizophrenia and the MATRICS Consensus Battery. He has a research grant from Takeda and from the Stanley Medical Research Foundation. Dr. Pinkham has served as a consultant to Roche Pharma Dr. Jorskog has received research grant funding from NIH, Auspex/Teva, Boehringer-Ingelheim and Otsuka. The other authors have no potential Biomedical Conflicts of Interest, (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD)., Method: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as 'Much Improved' or 'Very Much Improved' on the Clinical Global Impression of Change., Results: A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was -4.9 (0.4) at Week 54 (n = 146), - 6.3 (0.7) at Week 80 (n = 66) and -5.1 (2.0) at Week 106 (n = 8)., Conclusions: Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD., Trial Registration Number: NCT02198794., Competing Interests: Competing interests: HHF has received honoraria from Prime Education, Inc, International Parkinson and Movement Disorders Society, Carling Communications, Medscape (speaker in CME events), AbbVie, Biogen, GE Health Care, Inventiv, Kyowa Hakko Kirin, Lundbeck, Merz Pharmaceuticals, Voyager, Sunovion, Pfizer Pharmaceuticals (as a consultant). He has received grant and research support from: AbbVie, Acadia, Teva, Biotie/Acorda Therapeutics, Civitas, Kyowa/Prostrakan, Michael J. Fox Foundation, Movement Disorders Society, NIH/NINDS, Parkinson Study Group, Rhythm, Synosia; he has no owner interest in any pharmaceutical company. He has received royalties from: Demos Publishing (serving as a book author/editor). The Cleveland Clinic has a contract with Teva for his role as a Co-Principal Investigator in SD-809 tardive dyskinesia global studies. He also serves as a member of the publication committee for Acorda Pharmaceuticals but does not receive any personal compensation for this. He receives a stipend from the International Parkinson and Movement Disorders Society for serving as Medical Editor of the MDS Web Site. DS is a former employee of Teva Pharmaceuticals; he has received salary and benefits from Auspex Pharmaceuticals, and has patents pending: US20160346270, US20160287574. MDD is an employee of Teva Pharmaceuticals. SAF has received honoraria from Neurocrine, Lundbeck, Teva, Avanir, UCB, US WorldMeds, Sunovion, Adamas; he has received research support from Ipsen, Medtronic, Auspex, US WorldMeds, Pharm-Olam, Cynapsus Therapeutics/Sunovion, Vaccinex, Solstice, CHDI Foundation, Michael J. Fox Foundation, NIH; he has received royalties from Demos, Blackwell Futura for textbooks, and UpToDate. RAH has served as a consultant for Teva Pharmaceuticals, AbbVie, Inc, Acorda Therapeutics, Adamas Pharmaceuticals, AstraZeneca, Biotie Therapies, Cynapsus Therapeutics, Impax Laboratories, Inc, Lundbeck LLC, Michael J Fox Foundation, Neurocrine Biosciences, Neuropore Therapies, Pfizer Inc, Prexton Therapeutics, US WorldMeds, Guidepoint Global, Gerson Lehrman Group (GLG), LCN Consulting, Putnam Associates, National Parkinson Foundation, eResearch Technology, Inc, Sarepta Therapeutics, Back Bay Life Science, National Institutes of Health, Projects in Knowledge, Vista Research, LifeMax, Peerview Press, ClinicalMind Medical and Therapeutic Communications, Sunovion Pharmaceuticals, Academy for Continued Healthcare Learning, Outcomes Insights, Expert Connect, HealthLogix, Cowen and Company, Pharma Two B, Ltd, RMEI Medical Education for Better Outcomes, ClearView Healthcare Partners, Health Advances, Kyowa Kirin Pharmaceutical Development, Ltd, Quintiles, and Eli Lilly and Company. JJ-S has received research support from Acadia Pharmaceuticals, St. Jude Medical, Biotie, Michael J. Fox Foundation; she has served as a consultant for Teva, St. Jude Medical, Medtronic; she has also received honoraria from Vindico Medical Education. WGO has received research support from Lundbeck, Tremor Research Group, Dystonia Coalition, Restless Leg Syndrome Foundation, Acorda. Speakers’ Bureau: Teva, Lundbeck, UCB, US WorldMeds; he has served as a consultant for Teva, Lundbeck, Acadia. LFJ has received grant support Auspex/Teva, Boehringer Ingelheim, Otsuka, NIH; he has served as a consultant for Roche. SWW has received research support from Teva, Pfizer; he has served as a consultant for Boehringer Ingelheim, Nutria Health. DB has received research support from National Parkinson Foundation; he has served on the speaker’s bureau for Teva Pharmaceuticals and Acadia Pharmaceuticals, Inc; he has served as a consultant for Teva, Cynapsus, Acadia. MSL has served on the speakers’ bureau for Lundbeck, Acadia, and Teva; he has served as a consultant for Teva Neuroscience, US WorldMeds, the Mayo Clinic, Starnes-Davis-Florie, Elite Medical Experts, Spears, Moore, Rebman receives research support from the National Institutes of Health (R01 NS082296, R21 GM118962, U54 TR001456, 5U01 NS090259), Department of Defense (W81XWH-17-1-0062), Michael J. Fox Foundation, Dorothy/Daniel Gerwin Parkinson’s Research Fund, Auspex, Teva, Acorda, US WorldMeds, Axovant and CHDI; and receives royalty payments from Elsevier for editing ‘Animal Models of Movement Disorders’ and ‘Movement Disorders: Genetics and Models.’ DRS has served as a consultant for Eli Lilly, Teva, Lundbeck, and Weston Brain Institute; he has received speaker’s fees from Acadia, Baylor College of Medicine, the Arizona Psychiatric Society, Lundbeck, Teva US World Meds and the Tourette Association of America; he has received research support from Arizona Alzheimer’s Consortium, Axovant, Biotie, Intec, Kyowa, Teva, US WorldMeds, Neurocrine, Michael J. Fox Foundation, and the NIH. KEA has served as a scientific adviser and was the North American study Co-Principal Investigator for LEGATO-HD, Global Principal Investigator for AIM-TD, and Global Co-Principal Investigator for ARM-TD; she was the site Principal Investigator for Pride-HD, First-HD, ARC-HD for Teva; she was the scientific advisor and site Principal Investigator for ENROLL-HD for CHDI Foundation; she was a scientific advisor for Prana and site Principal Investigator for Vaccinex; she served as a consultant for the NeuroNext 105 study for Azevan; she has received salary support from the Griffin Foundation. She has also received honoraria from Vindico Medical Education., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Dr. Buchanan in the past 3 years has served on advisory boards for Avanir, Astellas Pharma, ITI, Inc., and Roche and has served as a consultant for Takeda, and Upsher-Smith Laboratories, Inc. Dr. Csernansky in the last 3 years has served as a consultant for Indivior Pharmaceuticals and Aptinyx, Inc. Dr. Goff has received research support from Avanir Pharmaceuticals. Dr. Green has been a consultant to AiCure, Lundbeck, and Takeda, and he is on the scientific board ofCadent. He has received research funds from FORUM. In the past 3 years, Dr. Jarskog has received research grant funding from Auspex/Teva, Boehringer-Ingelheim and Otsuka. In the past 3 years, Dr. Kimhy has served as a consultant for Neurocog Trials. Dr. Lieberman neither accepts nor receives any personal financial remuneration for consulting, speaking or research activities from any pharmaceutical, biotechnology or medical device companies. He receives support administered through Columbia University and the Research Foundation for Mental Hygiene in the form of funding and medication supplies for investigator initiated research from Denovo, Taisho, Pfizer, Sunovion, and Genentech, and for company sponsored phase II, III and IV studies from Alkermes, Allergan and Boehringer Ingelheim, and is a consultant to or member of the advisory board of Intracellular Therapies, Lilly, Pierre Fabre, Pear Therapeutics and Psychogenics for which he receives no remuneration. He is a paid consultant for Clintara, a clinical research services organization, and holds a patent from Repligen that yields no royalties. Dr. McEvoy has received research grant funding from Alkermes, BoehringerIngelheim, Neurocrine, Takeda, and TEVA and has given disease state talks for Neurocrine. Dr. Marder has served as a consultant for Abbvie, Roche, Otsuka, Teva, Neurocrine, Newron, and Lundbeck. Dr. Marder has received research support from Neurocrine, Takeda, and Boeringer-Ingelheim. Dr. Richard Keefe currently or in the past 3 years has received honoraria, served as a consultant, speaker, or advisory board member for Abbvie, Acadia, Aeglea, Akebia, Akili, Alkermes, Allergan, ArmaGen, Astellas, Avanir, AviNeuro/ChemRar, Axovant, Biogen, Boehringer-Ingelheim, Cerecor, CoMentis, Critical Path Institute, FORUM, Gammon Howard & Zeszotarski, Global Medical Education (GME), GW Pharmaceuticals, Intracellular Therapeutics, Janssen, Kempharm, Lundbeck, Lysogene, MedScape, Mentis Cura, Merck, Merrakris Therapetics, Minerva Neurosciences Inc., Mitsubishi, Montana State University, Monteris, Moscow Research Institute of Psychiatry, Neuralstem, Neuronix, Novartis, NY State Office of Mental Health, Orygen, Otsuka, Paradigm Testing, Percept Solutions, Pfizer, Pharm-Olam, Regenix Bio, Reviva, Roche, Sangamo, Sanofi, SOBI, Six Degrees Medical, Sunovion, Takeda, Targacept, Teague Rotenstreich Stanaland Fox & Holt, Thrombosis Research Institute, University of Moscow, University of Southern California, University of Texas Southwest Medical Center, WebMD, and Wilson Therapeutics. Dr. Keefe has currently or in the past 3 years received research funding from the National Institute of Mental Health and Boehringer-Ingelheim. Dr. Keefe receives royalties from versions of the BAC testing battery, the MATRICS Battery (BACS Symbol Coding), and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). He is also a shareholder in NeuroCog Trials, Inc. and Sengenix. Mr. Kraus, Dr. Gold, Dr. Barch, Ms. Walker, Dr. Chun, Dr. Javitt, Dr. Mesholam-Gately, Dr. Seidman, Ms. Ball, Dr. Kern, Dr. McMahon and Dr. Robinson report no competing interests., (© 2019 Published by Elsevier Inc.)

Background: Schizophrenia is considered a neurodevelopmental disorder with a pathophysiology that likely begins long before the onset of clinical symptoms. White matter abnormalities have been observed in schizophrenia and we hypothesized that the first 2 years of life is a period in which white matter abnormalities associated with schizophrenia risk may emerge., Methods: 38 infants at high risk for schizophrenia and 202 healthy controls underwent diffusion tensor MRIs after birth and at 1 and 2 years of age. Quantitative tractography was used to determine diffusion properties (fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD)) of 18 white matter tracts and a general linear model was used to analyze group differences at each age., Results: Adjusting gestational age at birth, postnatal age at MRI, gender, MRI scanner type, and maternal education, neonates at high risk had significantly lower FA (p = 0.02) and AD (p = 0.03) in the superior segment of the left cingulate, and higher RD in the hippocampal segment of the left cingulate (p = 0.04). High risk one year olds had significantly lower FA (p < 0.01) and AD (p = 0.02) in the hippocampal segment of the left cingulate. High risk two year olds had significantly lower FA in the left prefrontal cortico-thalamic tract (p = 0.04) and higher RD in the right uncinate fasciculus (p = 0.04). None of the tract differences remained significant after correction for multiple comparisons., Conclusions: There is evidence of abnormal white matter development in young children at risk for schizophrenia, especially in the hippocampal segment of left cingulum. These results support the neurodevelopmental theory of schizophrenia and indicate that impaired white matter may be present in early childhood., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Autistic traits are a feature of schizophrenia and has been found to impair social functioning and social cognition. Other influences on social outcomes in schizophrenia include depression and social avoidance. However, challenges in self-assessment of abilities and functioning (i.e., introspective accuracy) and self-assessment bias also contribute to disability. Depression has been studied for its association with introspective accuracy and bias, but autistic traits have not. Participants were 177 patients with schizophrenia who self-reported their everyday functioning and social cognitive ability as well as their depression. All were rated with the PANSS and a separate rater generated all-sources ratings of everyday functioning and social cognitive ability. Correlations between self-reported everyday functioning and social cognitive ability, ratings of everyday functioning and social cognitive ability, and the discrepancies between those ratings were examined for correlations with depression, autistic features and social avoidance. Accuracy was defined by the absolute value of the difference between self-reports and all-sources ratings and bias was defined by the direction of discrepancy (positive vs. negative). There was a statistically significant difference between sources on every measure. Bias was not directional on average, but patients with the lowest levels of depression overestimated their abilities on every measure and those with the highest depression underestimated. Autistic traits were associated with impairments in everyday functioning and underestimation of those impairments, while social avoidance was associated with impaired social functioning and accurate self-assessment. Features of schizophrenia have differential implications for impaired functioning and self-assessment, with autistic features and low levels of depression associated with consistent self-assessment biases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Impairments in self-assessment in schizophrenia have been shown to have functional and clinical implications. Prior studies have suggested that overconfidence can be associated with poorer cognitive performance in people with schizophrenia, and that reduced awareness of performance may be associated with disability. However, overconfidence is common in healthy individuals as well. This study examines the correlations between performance on a social cognitive test, confidence in performance, effort allocated to the task, and correlates of confidence in patients with schizophrenia and healthy controls (HC). Measures included self-reports of depression, social cognitive ability, and social functioning. A performance-based emotion recognition test assessed social cognitive performance and provided the basis for confidence judgments. Although schizophrenia patients had reduced levels of overall confidence, there was a substantial subset of schizophrenic patients who manifested extreme overconfidence and these people had the poorest performance and reported the least depression. Further, a substantial number of HC over-estimated their performance as well. Patients with schizophrenia, in contrast to HC, did not adjust their effort to match task difficulty. Confidence was minimally related to task performance in patients but was associated with more rapid decisions in HC, across both correct and incorrect responses. Performance on social cognitive measures was minimally related to self-reports of social functioning in both samples. These data suggest global self-assessments are based on multiple factors, with confidence affecting self-assessments in the absence of feedback about performance., (© 2019 The Authors.)

The effects of intranasal oxytocin, a neuropeptide involved in prosocial behavior and modulation of neural networks underlying social cognition and emotion regulation, have been studied in schizophrenia. We tested the hypothesis that twice-daily intranasal oxytocin administered for 12-weeks would improve tertiary and exploratory outcomes of self-reported social symptoms, empathy and introspective accuracy from the Jarskog et al. (2017) randomized controlled trial. Sixty-eight stable outpatients with schizophrenia or schizoaffective disorder were randomized to receive oxytocin (24 IU twice daily) or placebo. Introspective accuracy was assessed with the Specific Level of Functioning Scale and the Interpersonal Perception Task. Empathy was assessed with the Interpersonal Reactivity Index (IRI), and social symptoms were assessed with the Liebowitz Social Anxiety Scale and the Green et al. Paranoid Thoughts Scales. Outcomes were assessed at baseline, six, and twelve weeks. Results demonstrated limited effect of oxytocin with some improvement on the IRI Perspective-Taking Subscale. No additional between-group differences emerged on self-reported symptoms, empathy, or introspective accuracy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Transcranial alternating current stimulation (tACS) modulates endogenous neural oscillations in healthy human participants by the application of a low-amplitude electrical current with a periodic stimulation waveform. Yet, it is unclear if tACS can modulate and restore neural oscillations that are reduced in patients with psychiatric illnesses such as schizophrenia. Here, we asked if tACS modulates network oscillations in schizophrenia. We performed a randomized, double-blind, sham-controlled clinical trial to contrast tACS with transcranial direct current stimulation (tDCS) and sham stimulation in 22 schizophrenia patients with auditory hallucinations. We used high-density electroencephalography to investigate if a five-day, twice-daily 10Hz-tACS protocol enhances alpha oscillations and modulates network dynamics that are reduced in schizophrenia. We found that 10Hz-tACS enhanced alpha oscillations and modulated functional connectivity in the alpha frequency band. In addition, 10Hz-tACS enhanced the 40Hz auditory steady-state response (ASSR), which is reduced in patients with schizophrenia. Importantly, clinical improvement of auditory hallucinations correlated with enhancement of alpha oscillations and the 40Hz-ASSR. Together, our findings suggest that tACS has potential as a network-level approach to modulate reduced neural oscillations related to clinical symptoms in patients with schizophrenia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Individuals with schizophrenia (SZ) display cognitive deficits that have been identified as major determinants of poor functioning and disability, representing a serious public health concern and an important target for interventions. At present, available treatments offer only minimal to moderate benefits to ameliorate cognitive deficits. Thus, there remains an urgent need to identify novel interventions to improve cognition in people with SZ. Emerging evidence from animal and basic human research suggests aerobic exercise training (AE) has beneficial effects on cognition. Preliminary findings suggest that AE is efficacious in improving cognitive functioning in SZ, however the extant studies have been limited by small samples, a dearth of information on biologically-relevant covariates, and limited information on impact on daily functioning. Additionally, while AE-related cognitive benefits have been linked to Brain-Derived Neurotrophic Factor (BDNF) upregulation, this putative mechanism needs confirmation. The present report describes a study protocol designed to address these limitations-we review and summarize the current literature on treatment of cognitive deficits in SZ, state the rationale for employing AE to target these deficits, and describe the current protocol-a multi-site, single-blind, randomized clinical trial aiming to recruit 200 community-dwelling individuals with SZ. Participants are randomized to one of two 12-week interventions: AE using active-play video games ( i.e. , Xbox Kinect) and traditional cardiovascular exercise equipment or a stretching-and-toning (ST) control intervention. Participants undergo assessments of aerobic fitness, cognition, and daily functioning, as well as BDNF and other biomarkers of cognitive change, at baseline and after 6-and 12-weeks., Competing Interests: CONFLICTS OF INTEREST The authors declares that they have no conflicts of interest associated with this project.

Current social skill assessments for individuals with schizophrenia require extensive administration times, training, and coding procedures, thus limiting their clinical utility. The purpose of this study was to investigate the psychometric properties of the Brief Impression Questionnaire (BIQ), a novel measure designed to utilize immediate impression formation in the assessment of social skill in schizophrenia. An exploratory factor analysis of the BIQ was conducted, and relationships between the extracted factors and measures of social cognition and functioning were assessed. Additionally, we assessed differences on the BIQ between individuals with schizophrenia and control participants. Twenty-two research assistants at three sites rated participants using the BIQ (154 control participants and 218 individuals with schizophrenia). The results revealed identical one-factor structures for both participant groups. For both groups, the BIQ total score was positively associated with performance on social cognitive and everyday functioning assessments. Further, control participants were rated more positively on all BIQ items and received higher BIQ total scores. In the schizophrenia sample, BIQ scores predicted performance on social functioning assessments while controlling for symptom severity. These results indicate that impression formation may be a viable and efficient tool to measure aspects of social cognition and functioning in people with schizophrenia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Previous research on attributions in schizophrenia has focused on whether individuals make hostile, intentional attributions for ambiguous negative events. It is unclear, however, whether individuals with schizophrenia differ from controls in their general judgments of intentionality judgments in nonconflict and emotionally neutral situations. Research in social psychology suggests that nonclinical individuals present with an automatic bias to see intentionality and that this bias is regulated by the operation of controlled processes. The present study examined whether this general intentionality bias distinguishes individuals with schizophrenia (n = 213) from nonpatient controls (n = 151). Indeed, individuals with schizophrenia were more likely to attribute intentional motives to others' actions relative to controls. This intentionality bias was related to hostility, role functioning, and independent living skills. These findings may provide one domain to examine in future approaches to social cognition in schizophrenia. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Background: Approximately 30% of patients with schizophrenia experience auditory hallucinations that are refractory to antipsychotic medications. Here, we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) that we hypothesized would improve auditory hallucination symptoms by enhancing synchronization between the frontal and temporo-parietal areas of the left hemisphere., Method: 22 participants were randomized to one of three arms and received twice daily, 20 min sessions of sham, 10 Hz 2 mA peak-to-peak tACS, or 2 mA tDCS over the course of 5 consecutive days. Symptom improvement was assessed using the Auditory Hallucination Rating Scale (AHRS) as the primary outcome measure. The Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia (BACS) were secondary outcomes., Results: Primary and secondary behavioral outcomes were not significantly different between the three arms. However, effect size analyses show that tACS had the greatest effect based on the auditory hallucinations scale for the week of stimulation (1.31 for tACS; 1.06 and 0.17, for sham and tDCS, respectively). Effect size analysis for the secondary outcomes revealed heterogeneous results across measures and stimulation conditions., Conclusions: To our knowledge, this is the first clinical trial of tACS for the treatment of symptoms of a psychiatric condition. Further studies with larger sample sizes are needed to better understand the effect of tACS on auditory hallucinations., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objective: This study examined the effect of adjunctive telmisartan on psychopathology and cognition in olanzapine- or clozapine-treated patients with schizophrenia., Method: In a 12-week randomized, double-blind, placebo-controlled study, patients diagnosed with schizophrenia or schizoaffective disorder received either telmisartan (80 mg once per day) or placebo. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessment of Negative Symptoms (SANS), and a neuropsychological battery was used to assess cognitive performance. Assessments for psychopathology and cognition were conducted at baseline and week 12., Results: Fifty-four subjects were randomized, and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). After 12-weeks of treatment, the telmisartan group had a significant decrease in PANSS total score compared withthe placebo group (mean ± SD: - 4.1 ± 8.1 vs. 0.4 ± 7.5, P = 0.038, SCohen's d = 0.57). There were no significant differences between the two groups in change from baseline to week 12 in PANSS subscale scores, SANS total score, or any cognitive measures (P > 0.100)., Conclusion: The present study suggests that adjunctive treatment with telmisartan may improve schizophrenia symptoms. Future trials with larger sample sizes and longer treatment durations are warranted., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Tardive dyskinesia results from exposure to dopamine receptor antagonists, such as typical and atypical antipsychotics. If clinically appropriate, clinicians often manage this disorder by lowering the dose of, or discontinuing, the causative drug. There is a significant unmet need for a treatment option that does not disrupt treatment regimens for underlying psychiatric illnesses. We aimed to assess the efficacy, safety, and tolerability of fixed doses of deutetrabenazine-a novel vesicular monoamine transporter-2 inhibitor-in patients with tardive dyskinesia., Methods: We did this double-blind, randomised, placebo-controlled, phase 3 trial at 75 centres in the USA and Europe. Patients aged 18-80 years with tardive dyskinesia (≥3 months before screening) were randomly assigned centrally (1:1:1:1), via interactive response technology, to receive one of three fixed doses of deutetrabenazine (12 mg/day, 24 mg/day, or 36 mg/day) or matching placebo. Randomisation was stratified by baseline use of dopamine receptor antagonists. Patients were started on oral deutetrabenazine 12 mg/day, and this dose was increased through week 4 until the randomised dose was achieved, then maintained over 8 weeks. During the treatment period, patients, investigators, their site personnel, and sponsor were masked to group assignment. The primary efficacy endpoint was change in Abnormal Involuntary Movement Scale (AIMS) score from baseline to week 12 in patients with at least one post-baseline rating. The primary efficacy analysis was done in the modified intention-to-treat population (baseline AIMS score ≥6 and at least one post-baseline rating). The safety analysis was done in patients who received any study drug. This trial is registered with ClinicalTrials.gov, number NCT02291861., Findings: Between Oct 29, 2014, and Aug 19, 2016, we randomly assigned 298 patients to receive at least one dose of placebo (n=74), deutetrabenazine 12 mg/day (n=75), 24 mg/day (n=74), or 36 mg/day (n=75); 222 patients comprised the modified intention-to-treat population and 293 patients comprised the safety population. From baseline to week 12, the least-squares mean AIMS score improved by -3·3 points (SE 0·42) in the deutetrabenazine 36 mg/day group, -3·2 points (0·45) in the 24 mg/day group, and -2·1 points (0·42) in the 12 mg/day group, with a treatment difference of -1·9 points (SE 0·58, 95% CI -3·09 to -0·79; p=0·001), -1·8 points (0·60, -3·00 to -0·63; p=0·003), and -0·7 points (0·57, -1·84 to 0·42; p=0·217), respectively, versus -1·4 points (0·41) in the placebo group. The rate of adverse events was similar between patients in the deutetrabenazine 36 mg/day group (n=38/74 [51%]), 24 mg/day group (n=32/73 [44%]), and 12 mg/day group (n=36/74 [49%]), and those in the placebo group (n=34/72 [47%]). Serious adverse events were reported in four (5%) patients given deutetrabenazine 36 mg/day, six (8%) patients given 24 mg/day, and two (3%) patients given 12 mg/day, compared with four (6%) patients given placebo. Two (1%) patients in the safety population died, one each in the deutetrabenazine 24 mg/day and 36 mg/day groups; neither death was deemed related to study drug by the investigator or sponsor., Interpretation: Deutetrabenazine 24 mg/day and 36 mg/day provided a significant reduction in tardive dyskinesia, with favourable safety and tolerability. These findings suggest that dosing regimens could be individualised and tailored for patients on the basis of dyskinesia control and tolerability., Funding: Teva Pharmaceutical Industries., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Social cognition is impaired in people with schizophrenia and these deficits are strongly correlated with social functioning. Oxytocin is a hypothalamic peptide that contributes to maternal infant bonding and has diverse pro-social effects in adults. This study tested the hypothesis that 12weeks of intranasal oxytocin will improve social cognitive function in outpatients with schizophrenia and schizoaffective disorder. Sixty-eight eligible participants were randomized to oxytocin (24IU twice daily) or placebo. Social cognitive function was assessed using the Emotion Recognition-40, Brüne Theory of Mind, Reading the Mind in the Eyes test, Trustworthiness task and Ambiguous Intentions Hostility Questionnaire at baseline, 6weeks and 12weeks. In addition, social function was assessed using the Specific Levels of Functioning Scale and a role-play test, and psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Fifty-five participants completed the 12-week trial. The study found no evidence for a differential advantage of oxytocin over placebo on social cognition. Among secondary outcomes, there was a modest advantage for oxytocin over placebo on a component of social functioning, although there was also evidence that the placebo group outperformed the oxytocin group on the role-play task. No between-group differences emerged on measures of psychopathology in pre-specified comparisons, but oxytocin showed significant within-group reduction in PANSS negative symptoms and significant between-group improvement in negative symptoms in the schizophrenia subgroup. Further testing is needed to clarify whether oxytocin has therapeutic potential for social cognitive deficits and/or negative symptoms in people with schizophrenia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD)., Methods: One hundred seventeen patients with moderate to severe TD received deutetrabenazine or placebo in this randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, and stable psychoactive medication treatment. Primary endpoint was the change in AIMS score from baseline to week 12. Secondary endpoints included treatment success at week 12 on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change., Results: For the primary endpoint, deutetrabenazine significantly reduced AIMS scores from baseline to week 12 vs placebo (least-squares mean [standard error] -3.0 [0.45] vs -1.6 [0.46], p = 0.019). Treatment success on CGIC (48.2% vs 40.4%) favored deutetrabenazine but was not significant. Deutetrabenazine and placebo groups showed low rates of psychiatric adverse events: anxiety (3.4% vs 6.8%), depressed mood/depression (1.7% vs 1.7%), and suicidal ideation (0% vs 1.7%, respectively). In addition, no worsening in parkinsonism, as measured by the Unified Parkinson's Disease Rating Scale motor subscale, was noted from baseline to week 12 in either group., Conclusions: In patients with TD, deutetrabenazine was well tolerated and significantly reduced abnormal movements., Classification of Evidence: This study provides Class I evidence that in patients with TD, deutetrabenazine reduces AIMS scores., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: AQW051, an α7-nicotinic acetylcholine receptor partial agonist, enhanced cognitive function in rodent models of learning and memory. This study evaluated brain activation during performance of a working memory task (WMT) and an episodic memory task (EMT), and the effect of AQW051 on task-related brain activation and performance in subjects with schizophrenia., Methods: This was a double-blind, randomized, placebo-controlled, multicenter, 2-period cross-over trial (NCT00825539) in participants with chronic, stable schizophrenia. Participants, stratified according to smoking status, were randomized (1:1:1:1:1:1) to 1 of 6 sequence groups that determined the study drug dose (AQW051 7.5mg, 50mg or 100mg) and order of administration versus placebo. The primary outcome was brain activation in a priori target regions of interest (ROIs) during performance of the WMT and EMT, measured using functional magnetic resonance imaging. The effect of AQW051 on task-related (EMT and WMT) brain activation and performance was also assessed, as were safety and tolerability., Results: Overall, 60 of 68 enrolled participants completed the study (AQW051 then placebo: 7.5mg n=9; 50mg n=11; 100mg n=10. Placebo then AQW051: 7.5mg n=10; 50mg n=11; 100mg n=9). Significant task-related brain activation (5% significance level) was observed with placebo. During the WMT, a medium effect size was observed in the inferior prefrontal cortex with AQW051 100mg versus placebo (0.431; p=0.105). During the EMT encoding phase, a large effect size was observed in the anterior hippocampus (0.795; p=0.007) and a medium effect size in the posterior hippocampus (0.476; p=0.079) with AQW051 7.5mg. No other medium/large effect sizes were observed with any dose on either task. Effects on brain activation were generally not associated with changes in cognitive performance. AQW051 was well tolerated with an acceptable safety profile., Conclusions: Overall, no consistent effects of AQW051 on brain regions involved in the performance of a WMT or EMT were observed; however, this study presents a model for evaluating potential response to pharmacological interventions for cognitive impairment in schizophrenia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Auditory hallucinations are resistant to pharmacotherapy in about 25% of adults with schizophrenia. Treatment with noninvasive brain stimulation would provide a welcomed additional tool for the clinical management of auditory hallucinations. A recent study found a significant reduction in auditory hallucinations in people with schizophrenia after five days of twice-daily transcranial direct current stimulation (tDCS) that simultaneously targeted left dorsolateral prefrontal cortex and left temporo-parietal cortex., Hypothesis: We hypothesized that once-daily tDCS with stimulation electrodes over left frontal and temporo-parietal areas reduces auditory hallucinations in patients with schizophrenia., Methods: We performed a randomized, double-blind, sham-controlled study that evaluated five days of daily tDCS of the same cortical targets in 26 outpatients with schizophrenia and schizoaffective disorder with auditory hallucinations., Results: We found a significant reduction in auditory hallucinations measured by the Auditory Hallucination Rating Scale (F2,50=12.22, P<0.0001) that was not specific to the treatment group (F2,48=0.43, P=0.65). No significant change of overall schizophrenia symptom severity measured by the Positive and Negative Syndrome Scale was observed., Conclusions: The lack of efficacy of tDCS for treatment of auditory hallucinations and the pronounced response in the sham-treated group in this study contrasts with the previous finding and demonstrates the need for further optimization and evaluation of noninvasive brain stimulation strategies. In particular, higher cumulative doses and higher treatment frequencies of tDCS together with strategies to reduce placebo responses should be investigated. Additionally, consideration of more targeted stimulation to engage specific deficits in temporal organization of brain activity in patients with auditory hallucinations may be warranted., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Purpose of Review: This article reviews the recent evidence for therapeutic strategies for patients with treatment-resistant schizophrenia (TRS) not responding to or only partially responding to clozapine., Recent Findings: A number of pharmacological and nonpharmacological biological approaches for clozapine-resistant TRS have been evaluated in clinical trials. Among these, the evidence supporting clozapine augmentation by pharmacological approaches is weak and the reported benefits were modest at best. However, the results of a recent randomized trial suggest that electroconvulsive therapy (ECT) may be efficacious for the short-term treatment of patients with clozapine-resistant TRS., Summary: There is currently insufficient evidence for efficacy of pharmacological augmentation strategies to clozapine. ECT may be a promising option, but further research is necessary to confirm its long-term effects. Moreover, further controlled studies are warranted to clarify the potential of other biological and psychosocial approaches to serve as adjuvant treatments in patients with clozapine-resistant TRS.

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Schizophrenia for many patients is a lifelong mental disorder with significant consequences on most functional domains. One fifth to one third of patients with schizophrenia experience persistent psychotic symptoms despite adequate trials of antipsychotic treatment, and are considered to have treatment-resistant schizophrenia (TRS). Clozapine is the only medication to demonstrate efficacy for psychotic symptoms in such patients. However, clozapine is not effective in 40%-70% of patients with TRS and it has significant limitations in terms of potentially life-threatening side effects and the associated monitoring. Accordingly, a number of pharmacological and non-pharmacological biological approaches for clozapine-resistant TRS have emerged. This article provides a brief updated critical review of recent therapeutic strategies for TRS, particularly for clozapine-resistant TRS, which include pharmacotherapy, electroconvulsive therapy, repetitive transcranial magnetic stimulation, and transcranial direct current stimulation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

Objective: Clozapine, an evidence-based treatment of refractory schizophrenia, is associated with increased weight gain and metabolic dysregulation compared with most antipsychotics in short-term clinical trials. However, there are limited data describing comparative long-term metabolic risks. In this report, we examined whether short-term differences persist with long-term exposure to clozapine., Methods: The data of all patients in a university-based clinic with a psychotic illness or a mood disorder with psychotic features, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis, and treated with an antipsychotic in calendar year 2012 were examined. A total of 307 patients met the criteria; 96 patients were treated with clozapine and the remaining 211 patients were treated with 1 or more non-clozapine antipsychotics. Body mass index, type 2 diabetes, hypertension, dyslipidemia, and obesity were compared., Results: The mean duration of the clozapine treatment was 7.6 years (range, 2 months to 21 y). On all metabolic measures, there were no statistically significant differences between the clozapine and non-clozapine groups (mean body mass index, 31 vs 32; type 2 diabetes, 17% vs 18%; dyslipidemia, 35% vs 38%; hypertension, 32% vs 39%; and obesity, 48% vs 54%). Removing the olanzapine-treated patients (n = 51) from the non-clozapine group did not change the findings., Conclusions: In this university-based clinic sample with a large number of clozapine-treated patients, we found no evidence of increased risk in any individual measure for those receiving clozapine. Although speculative, the relative contribution of the increased short-term metabolic risk associated with clozapine may be diminished over time because multiple other variables likely also impact metabolic risk during the life span. Although speculative, the relative contribution of the increased short-term metabolic risk associated with clozapine may be diminished over time due to the accumulated impact of other variables that also impact metabolic risk across the life span.

Schizophrenia is characterized by an abnormal dopamine system, and dopamine blockade is the primary mechanism of antipsychotic treatment. Consistent with the known role of dopamine in reward processing, prior research has demonstrated that patients with schizophrenia exhibit impairments in reward-based learning. However, it remains unknown how treatment with antipsychotic medication impacts the behavioral and neural signatures of reinforcement learning in schizophrenia. The goal of this study was to examine whether antipsychotic medication modulates behavioral and neural responses to prediction error coding during reinforcement learning. Patients with schizophrenia completed a reinforcement learning task while undergoing functional magnetic resonance imaging. The task consisted of two separate conditions in which participants accumulated monetary gain or avoided monetary loss. Behavioral results indicated that antipsychotic medication dose was associated with altered behavioral approaches to learning, such that patients taking higher doses of medication showed increased sensitivity to negative reinforcement. Higher doses of antipsychotic medication were also associated with higher learning rates (LRs), suggesting that medication enhanced sensitivity to trial-by-trial feedback. Neuroimaging data demonstrated that antipsychotic dose was related to differences in neural signatures of feedback prediction error during the loss condition. Specifically, patients taking higher doses of medication showed attenuated prediction error responses in the striatum and the medial prefrontal cortex. These findings indicate that antipsychotic medication treatment may influence motivational processes in patients with schizophrenia.

Objective: The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder., Method: In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16., Results: Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was -3.0 kg (95% CI=-4.0 to -2.0) for the metformin group and -1.0 kg (95% CI=-2.0 to 0.0) for the placebo group, with a between-group difference of -2.0 kg (95% CI=-3.4 to -0.6). Metformin also demonstrated a significant between-group advantage for BMI (-0.7; 95% CI=-1.1 to -0.2), triglyceride level (-20.2 mg/dL; 95% CI=-39.2 to -1.3), and hemoglobin A1c level (-0.07%; 95% CI=-0.14 to -0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation., Conclusions: Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.