BACKGROUND AND HYPOTHESIS:Our initial smaller study and other recent research suggest that adding a physical exercise program to cognitive training has promise for enhancing the impact on attention and overall cognition. We hypothesized that this would be the case even compared to adding a healthy living training program. STUDY DESIGN:In a randomized clinical trial of individuals with a recent first episode of schizophrenia, we provided cognitive training, 4 h/week for 6 months for all participants. Half were randomized to a physical exercise program and half to a healthy living group. The MATRICS Consensus Cognitive Battery was administered at baseline, 3, and 6 months, with a focus on Attention/Vigilance. Exercise was measured by the International Physical Activity Questionnaire and the number of exercise sessions completed. STUDY RESULTS:Attention/Vigilance was differentially enhanced by cognitive training and physical exercise compared to cognitive training and healthy living group (T score gain of 4.6 vs. -0.2 over 6 months, P < .01). Improvement in Attention/Vigilance by 3 months was significantly associated with number of exercise sessions attended (P = .02) and exercise intensity (P < .03) during that period. Attention/Vigilance gain by 6 months was significantly predicted by total metabolic energy expended during the first 3 months (P = .04) and proportion of group exercise sessions attended (P < .01) over 6 months. In the first 3 months, brain-derived neurotropic factor tended to increase in the exercise condition but decrease in the comparison condition. CONCLUSION:Adding an exercise program to cognitive training enhances the impact on the core deficit in attention in schizophrenia. The gains in attention are significantly related to the amount and intensity of exercise, consistent with the view that physical exercise is driving the attention improvements beyond the effect of cognitive training.

Background:Differences in age of psychosis onset (AOO) in schizophrenia (SCZ) are associated with different illness trajectories. Determining whether AOO differences can be explained by genome-wide or pathway-partitioned polygenic risk for SCZ (SCZ-PRS) may elucidate mechanisms underlying clinical variability. This study examined relationships between AOO, genome-wide SCZ-PRS, and pathway-partitioned SCZ-PRS in a harmonized, multi-ancestry North American dataset (SCZ-NA) and in UK Biobank (SCZ-UKBB). Methods:For each cohort, we computed one genome-wide SCZ-PRS and 18 mutually-exclusive pathway-based PRS derived from previous published and validated neurodevelopmental gene-sets. We evaluated 13 SNP-to-gene mapping strategies, including comparing non-coding SNP-to-gene mappings informed by functional annotations versus distance-based windows. SCZ case-control prediction and AOO associations were tested using logistic and linear mixed models, respectively, controlling for sex, ancestry principal components, and genetic relatedness. Results:Genome-wide SCZ-PRS robustly predicted SCZ case-control status in both cohorts but not AOO. In contrast, pathway-based analyses identified AOO associations for a fetal angiogenesis and a postnatal synaptic signaling and plasticity gene-set across both cohorts ( p < .05), alongside nominal cohort-specific associations in other gene-sets. Associations depended on SNP-to-gene mapping definitions; experimentally informed strategies, particularly those incorporating brain expression Quantitative Trait Locus (eQTL) annotations performed best. Conclusion:Findings suggest that neurovascular and postnatal synaptic signaling and refinement mechanisms contribute to AOO variation in SCZ, and that pathway-informed PRS, especially with brain-specific non-coding SNP-to-gene mappings, can help identify mechanisms contributing to variability in AOO. Replication in larger, prospectively phenotyped cohorts with harmonized AOO definitions will further clarify genetic mechanisms underlying clinical variability in SCZ.

Social cognitive difficulties among those with schizophrenia and first episode psychosis (FEP) are well-documented, but less research has investigated the social cognitive construct of empathy. Empathy has been linked in schizophrenia samples to symptoms and functioning, but minimal work has examined empathy among those with FEP. This study examined associations between empathy, symptoms, and functioning in FEP participants, as well as whether empathy accounts for unique variance in these constructs over and above other social cognitive measures. Participants were 100 people with FEP who were taking part in a larger randomized controlled trial. Two empathy measures, the Interpersonal Reactivity Index (IRI) and Questionnaire of Cognitive and Affective Empathy (QCAE), were administered at baseline, along with measures of symptoms, functioning, and other social cognitive constructs. Results revealed that greater empathy, measured by the IRI, was linked to less severe negative symptoms across multiple domains, while fewer associations were evident for positive symptoms and functioning. Across tested domains, empathy significantly predicted clinical outcomes over and above other social cognitive constructs. However, both empathy measures displayed low internal consistency. Taken together, results suggest that empathy may be important to consider in FEP populations, particularly as it relates to negative symptoms, and empathy predicts unique variance in multiple clinical characteristics. Future work should focus on improving empathy measurement approaches and examining empathy in tandem with broader social cognitive batteries among FEP samples.

OBJECTIVE:Schizophrenia is a neurodevelopmental disorder involving clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for schizophrenia spectrum disorders (SSDs). However, it is unclear how known risk CNVs and broader genome-wide CNVs influence clinical variability. Furthermore, whether biological annotation of CNV scores can improve power for patient stratification is unknown. This study therefore investigated the relationships between severe SSD-related phenotypes and varied CNV metrics, including CNV burden affecting genes involved in different aspects of neurodevelopment. METHODS:This study of 617 individuals with SSDs examined associations of two severe phenotypes-childhood-onset psychosis and borderline intellectual functioning (IQ)-with 1) known risk CNVs, 2) genome-wide deletion burden scores, and 3) novel scores capturing deletion burden in 18 previously validated and mutually exclusive gene sets, representing distinct aspects of neurodevelopment. Associations with borderline IQ were assessed for replicability in 233 relatives of SSD patients, 581 control subjects, and 9,930 youths from the Adolescent Brain Cognitive Development (ABCD) Study. RESULTS:Known SSD-risk CNVs (odds ratio=7.07, 95% CI=1.60, 31.32) and neurodevelopmental disorder (NDD)-risk CNVs (odds ratio=4.56, 95% CI=1.48, 14.10) were associated with borderline IQ in SSDs. Furthermore, beyond effects of known NDD-risk CNVs, deletion of genes involved in regulating gene expression during fetal brain development was associated with borderline IQ across SSD cases and noncases (odds ratio=2.57, 95% CI=1.44, 4.60) and in the ABCD cohort (odds ratio=1.33, 95% CI=1.00, 1.76). Exploratory structural MRI-based analyses showed associations between fetal gene regulatory gene deletions and altered gray matter volume (b=0.09, 95% CI=0.004, 0.17) and cortical thickness (b=0.14, 95% CI=0.05, 0.24) across SSD cases and noncases. CONCLUSIONS:The study results confirm contributions of known risk CNVs to severe phenotypes in SSDs, implicate disrupted fetal brain development in poor cognition, and demonstrate the utility of a neurodevelopmental framework for identifying mechanisms underlying severe SSD-relevant phenotypes.

Objective:Schizophrenia is a neurodevelopmental disorder involving clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for schizophrenia spectrum disorders (SSD). However, how known risk CNVs and broader genome-wide CNVs influence clinical variability is unclear. Furthermore, whether biological annotation of CNV scores can improve power for patient stratification is unknown. Methods:This study examined associations between severe phenotypes in 617 SSD individuals, namely, child-onset psychosis or borderline intellectual functioning (IQ), and: 1) known risk CNVs; 2) genome-wide deletion burden scores; and 3) novel scores capturing deletion burden in 18 previously validated and mutually exclusive gene-sets, representing distinct aspects of neurodevelopment. Associations with borderline IQ were assessed for replicability in 233 SSD-relatives and 581 controls, and 9,930 youth from the Adolescent Brain Cognitive Development (ABCD) Study. Results:Known SSD- (odds ratios (OR)=7.07, 95%CI[1.60,31.32]) and neurodevelopmental disorder (NDD)-risk CNVs (OR=4.56, 95%CI[1.48,14.10]) were associated with borderline IQ in SSD. Furthermore, beyond effects of known NDD-risk CNVs, deletion of genes involved in regulating gene expression during fetal brain development was associated with borderline IQ across SSD cases and non-cases (OR=2.57, 95%CI[1.44,4.60]), and in the ABCD cohort (OR=1.33, 95%CI[1.00,1.76]). Exploratory structural MRI-based analyses showed associations between fetal gene regulatory gene deletions and altered gray matter volume ( b =0.09, 95%CI[0.004,0.17]) and cortical thickness ( b =0.14, 95%CI[0.05,0.24]) across SSD cases and non-cases. Conclusions:Results confirm contributions of known risk CNVs to severe phenotypes in SSD, implicate disrupted fetal brain development in poor cognition, and demonstrate the utility of a neurodevelopmental framework for identifying mechanisms underlying severe SSD-relevant phenotypes.

We examined the effects of combining cognitive training plus aerobic exercise versus cognitive training alone on positive symptoms in recent-onset schizophrenia patients. Sixty-eight participants were randomly assigned to Cognitive Training plus Exercise (CT&E, N = 37) or Cognitive Training alone (CT, N = 31). All participants were also randomly assigned to either oral risperidone or paliperidone palmitate (PP1M) in a concurrent antipsychotic medication study. All participants were provided four weekly sessions of internet-based cognitive training conducted in a group format for 6 months, during which half were randomized to receive a 150 min/week aerobic exercise program. Then participants received 6 additional months of treatment at half of the psychosocial intervention frequency. Reality Distortion, the mean of BPRS ratings of Unusual Thought Content and Hallucinations, was averaged over all available BPRSs during the 3-month pre-baseline period and over four 3-month time periods during the 12 months of intervention. The proportion of BPRS administrations wherein either Unusual Thought Content or Hallucinations was rated >4 was used as a measure of breakthrough psychotic symptoms. Reality Distortion significantly decreased over time for the CT&E group compared to the non-Exercise (CT) group, F(4, 208) = 2.9, p = .02. The proportion of BPRS ratings with breakthrough symptoms decreased over successive 3-month periods for the CT&E group compared to the CT group, F(4, 218) = 6.9, p < .0001. The two medication groups did not significantly differ on either positive symptom outcome, and there were no three-way interactions. Our findings suggest that the enhancing effect of adding aerobic exercise to cognitive training extends beyond cognitive gains and includes positive psychotic symptoms.

Given the difficulties of developing cognitive enhancers for schizophrenia and demonstrating their efficacy, we welcome a review of the measurement procedures and the clinical trial design recommendations developed through the collaboration of academics, industry, National Institute of Mental Health (NIMH), and U.S.A. Food and Drug Administration (FDA) representatives during the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) process. We provide a perspective from investigators who helped to lead the MATRICS initiative. We acknowledge some of the practical challenges in the use of the MATRICS Consensus Cognitive Battery (MCCB) while pointing out that others are overstated. We suggest that a brief MCCB might be used in phase III trials when phase II results had shown no negative impact on any MCCB cognitive domain. The complexities of requiring a functional co-primary measure are discussed. For clinical trial research design to evaluate monotherapies that might have both antipsychotic and cognition-enhancing properties, we agree that the original MATRICS design recommendations may need to be revised, as those recommendations focused on the evaluation of potential adjunctive cognitive enhancers. Horan et al provide a thoughtful summary of the current challenges in obtaining approval for a new drug designed to enhance cognition in schizophrenia.

Black and Latino Americans are more likely to be diagnosed with psychotic disorders compared to White Americans. Furthermore, there are well documented ethnoracial disparities in access to second-generation antipsychotics including long-acting injectables (LAIs). LAI medications have the potential to help attenuate disparities by improving adherence and thus reducing relapse. Given this knowledge, a more concerted effort is needed to examine the clinical response and adherence to these medications in the early stages of psychosis. The present study examined positive symptoms and medication adherence in response to oral versus LAI risperidone in a sample of Black (N = 24), Latino (N = 34), and White (N = 17) first-episode psychosis patients. Participants were recruited from local psychiatric hospitals and enrolled in a randomized controlled trial. Participants were randomly assigned to receive oral or LAI risperidone. Findings suggest that Latino patients were less likely to benefit from LAI risperidone and also had higher rates of nonadherence across medication conditions. Both Black and White patients benefited from LAI in terms of positive symptoms and medication adherence. Future studies should examine sociocultural factors that could be influencing the acceptability of LAIs for Latino first-episode patients as well as develop culturally responsive interventions to improve medication adherence and clinical outcomes. In addition, greater advocacy and equitable policies are likely needed to ensure access to LAIs for minoritized populations.

BACKGROUND:Cognitive impairment associated with schizophrenia (CIAS) negatively impacts daily functioning, quality of life, and recovery, yet effective pharmacotherapies and practical assessments for clinical practice are lacking. Despite the pivotal progress made with establishment of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) for clinical research, implementation of the full MCCB is too time-consuming and cost-ineffective for most clinicians in clinical practice. STUDY DESIGN:Here we discuss current assessments in relation to delivery format (interview-based and performance-based), validity, ease of use for clinicians and patients, reliability/reproducibility, cost-effectiveness, and suitability for clinical implementation. Key challenges and future opportunities for improving cognitive assessments are also presented. STUDY RESULTS:Current assessments that require 30 min to complete would have value in clinical settings, but the associated staff training and time required might preclude their application in most clinical settings. Initial profiling of cognitive deficits may require about 30 min to assist in the selection of evidence-based treatments; follow-up monitoring with brief assessments (10-15 min in duration) to detect treatment-related effects on global cognition may complement this approach. Guidance on validated brief cognitive tests for the strategic monitoring of treatment effects on CIAS is necessary. CONCLUSIONS:With increased advancements in technology-based and remote assessments, development of validated formats of remote and in-person assessment, and the necessary training models and infrastructure required for implementation, are likely to be of increasing clinical relevance for future clinical practice.

AIM:Research has demonstrated that participation in aerobic exercise can have significant beneficial effects across both physical and mental health domains for individuals who are in the early phase of schizophrenia. Despite these notable benefits of exercise, deficits in motivation and a lack of methods to increase engagement are significant barriers for exercise participation, limiting these potentially positive effects. Fortunately, digital health tools have the potential to improve adherence to an exercise program. The present study examined the role of motivation for exercise and the effects of an automated digital text messaging program on participation in an aerobic exercise program. METHODS:A total of 46 first-episode psychosis participants from an ongoing 12-month randomized clinical trial (Enhancing Cognitive Training through Exercise Following a First Schizophrenia Episode (CT&E-RCT)) were included in an analysis to examine the efficacy of motivational text messaging. Personalized motivational text message reminders were sent to participants with the aim of increasing engagement in the exercise program. RESULTS:We found that participants with higher levels of intrinsic motivation to participate in a text messaging program and in an exercise intervention completed a higher proportion of individual, at-home exercise sessions. In a between groups analysis, participants who received motivational text messages, compared to those who did not, completed a higher proportion of at-home exercise sessions. CONCLUSION:These results indicate the importance of considering a person's level of motivation for exercise and the potential utility of using individualized and interactive mobile text messaging reminders to increase engagement in aerobic exercise in the early phase of psychosis. We emphasize the need for understanding how individualized patient preferences and needs interplay between intrinsic motivation and digital health interventions for young adults.

BACKGROUND:Research using latent variable models demonstrates that pre-attentive measures of early auditory processing (EAP) and cognition may initiate a cascading effect on daily functioning in schizophrenia. However, such models fail to account for relationships among individual measures of cognition and EAP, thereby limiting their utility. Hence, EAP and cognition may function as complementary and interacting measures of brain function rather than independent stages of information processing. Here, we apply a data-driven approach to identifying directional relationships among neurophysiologic and cognitive variables. METHODS:Using data from the Consortium on the Genetics of Schizophrenia 2, we estimated Gaussian Graphical Models and Bayesian networks to examine undirected and directed connections between measures of EAP, including mismatch negativity and P3a, and cognition in 663 outpatients with schizophrenia and 630 control participants. RESULTS:Chain structures emerged among EAP and attention/vigilance measures in schizophrenia and control groups. Concerning differences between the groups, object memory was an influential variable in schizophrenia upon which other cognitive domains depended, and working memory was an influential variable in controls. CONCLUSIONS:Measures of EAP and attention/vigilance are conditionally independent of other cognitive domains that were used in this study. Findings also revealed additional causal assumptions among measures of cognition that could help guide statistical control and ultimately help identify early-stage targets or surrogate endpoints in schizophrenia.

Coordinated Specialty Care (CSC) and embedded group therapeutic interventions have been effective in improving outcomes for individuals experiencing recent first-episode schizophrenia, including cognitive performance and functioning. Treatment response varies substantially, with some patients experiencing limited or no improvement. Motivation has emerged as a key determinant of treatment engagement and efficacy. However, the impact of intrinsic and extrinsic aspects of motivation has not been directly examined with treatment outcomes in first-episode schizophrenia. This study investigated whether baseline levels of intrinsic and extrinsic motivation predicted cognitive and functional gains over 6 and 12 months in CSC. Forty participants with firstepisode schizophrenia completed a 12-month CSC treatment period. Baseline measures of intrinsic and extrinsic motivation were obtained for group therapeutic interventions and work/school, as well as measures of cognition and functioning (role and social) at baseline, 6 months, and 12 months. Results revealed that higher baseline scores of intrinsic motivation for group therapeutic interventions were significantly predictive of greater cognitive gains at 12 months, and a similar tendency was observed at 6 months. Additionally, baseline scores of intrinsic motivation for work/school predicted role gains at 6 months, with a similar tendency observed at 12 months. Extrinsic motivation did not consistently impact treatment outcomes, except for work/school-related extrinsic motivation, which was linked to greater social functioning gains at 12 months. These findings provide insight into the factors influencing treatment outcomes for individuals with first-episode schizophrenia and highlight the importance of intrinsic motivation as a modifiable personal variable that can enhance response to CSC.

Background The cognitive model of negative symptoms of schizophrenia suggests that defeatist performance beliefs (DPB), or overgeneralized negative beliefs about one's performance, are an intermediary variable along the pathway from impaired neurocognitive performance to negative symptoms and functioning in daily life. Although reliable associations between these variables have been established in chronic schizophrenia, less is known about the nature of these relationships in recent-onset schizophrenia (ROSz). This current study tested the associations between DPB and variables in the cognitive model (neurocognitive performance, negative symptoms, functioning) as well as mediation by DPB of the association between neurocognitive performance and negative symptoms in ROSz. Methods A total of 52 participants (32 adults with ROSz and 20 non-psychiatric healthy comparators; HC) completed in-lab measures of neurocognitive performance, self-reported defeatist performance beliefs, and clinician administered measures of negative symptoms and functional outcome. Bivariate relationships among these variables were tested with Pearson correlations. Bootstrapped regression analyses were conducted to test the strength of the indirect effect of neurocognitive performance on negative symptoms through DPB. Results Defeatist performance beliefs were significantly elevated in ROSz, and were associated with neurocognitive performance, negative symptoms, and functional outcome as predicted by the cognitive model. There was a significant indirect effect of neurocognition on experiential negative symptoms through DPB, indicating DPB are a partial mediator of the relationship between neurocognitive performance and negative symptoms. Conclusion These findings are consistent with the cognitive model of negative symptoms and extend previous findings in both ROSz and established schizophrenia. Specifically, these data demonstrate that DPB are elevated among ROSz and the associations with neurocognition and clinical outcomes (e.g., negative symptoms and functioning) are of similar magnitude to those reported in chronic schizophrenia. DPB may therefore be a viable treatment target in the early course of illness.