A systematic review of structural and functional magnetic resonance imaging studies on the neurobiology of depressive symptoms in schizophrenia spectrum disorders.

Depressive symptoms in Schizophrenia Spectrum Disorders (SSDs) negatively impact suicidality, prognosis, and quality of life. Despite this, efficacious treatments are limited, largely because the neural mechanisms underlying depressive symptoms in SSDs remain poorly understood. We conducted a systematic review to provide an overview of studies that investigated the neural correlates of depressive symptoms in SSDs using neuroimaging techniques. We searched MEDLINE, PsycINFO, EMBASE, Web of Science, and Cochrane Library databases from inception through June 19, 2023. Specifically, we focused on structural and functional magnetic resonance imaging (MRI), encompassing: (1) T1-weighted imaging measuring brain morphology; (2) diffusion-weighted imaging assessing white matter integrity; or (3) T2*-weighted imaging measures of brain function. Our search yielded 33 articles; 14 structural MRI studies, 18 functional (f)MRI studies, and 1 multimodal fMRI/MRI study. Reviewed studies indicate potential commonalities in the neurobiology of depressive symptoms between SSDs and major depressive disorders, particularly in subcortical and frontal brain regions, though confidence in this interpretation is limited. The review underscores a notable knowledge gap in our understanding of the neurobiology of depression in SSDs, marked by inconsistent approaches and few studies examining imaging metrics of depressive symptoms. Inconsistencies across studies' findings emphasize the necessity for more direct and comprehensive research focusing on the neurobiology of depression in SSDs. Future studies should go beyond "total score" depression metrics and adopt more nuanced assessment approaches considering distinct subdomains. This could reveal unique neurobiological profiles and inform investigations of targeted treatments for depression in SSDs.

Transdiagnostic Neurobiology of Social Cognition and Individual Variability as Measured by Fractional Amplitude of Low-Frequency Fluctuation in Schizophrenia and Autism Spectrum Disorders.

Fractional amplitude of low-frequency fluctuation (fALFF) is a validated measure of resting-state spontaneous brain activity. Previous fALFF findings in autism and schizophrenia spectrum disorders (ASDs and SSDs) have been highly heterogeneous. We aimed to use fALFF in a large sample of typically developing control (TDC), ASD and SSD participants to explore group differences and relationships with inter-individual variability of fALFF maps and social cognition. fALFF from 495 participants (185 TDC, 68 ASD, and 242 SSD) was computed using functional magnetic resonance imaging as signal power within two frequency bands (i.e., slow-4 and slow-5), normalized by the power in the remaining frequency spectrum. Permutation analysis of linear models was employed to investigate the relationship of fALFF with diagnostic groups, higher-level social cognition, and lower-level social cognition. Each participant's average distance of fALFF map to all others was defined as a variability score, with higher scores indicating less typical maps. Lower fALFF in the visual and higher fALFF in the frontal regions were found in both SSD and ASD participants compared with TDCs. Limited differences were observed between ASD and SSD participants in the cuneus regions only. Associations between slow-4 fALFF and higher-level social cognitive scores across the whole sample were observed in the lateral occipitotemporal and temporoparietal junction. Individual variability within the ASD and SSD groups was also significantly higher compared with TDC. Similar patterns of fALFF and individual variability in ASD and SSD suggest some common neurobiological deficits across these related heterogeneous conditions.

Neurocognitive performance and cognitive biases in young adults with schizotypal traits.

Recent research suggests that neurocognitive deficits in patients with schizophrenia may increase the risk of developing cognitive biases. As such, we set out to determine this predictive relationship as it pertains to the development of a first-episode psychosis. We hypothesized that poorer performance in processing speed would be associated with jumping to conclusions and an externalizing bias. Poorer performance in working memory would be associated with belief inflexibility and jumping to conclusions, and poorer performance in attention would be associated with attention to threat. We hypothesized that all cognitive biases would be associated with subsyndromal positive symptoms, and schizotypal traits would moderate these relationships. Undergraduate students (N = 130) completed the Schizotypal Personality Questionnaire, DAVOS Assessment of Cognitive Biases, Community Assessment of Psychic Experiences, and a computerized neuropsychological assessment battery. Processing speed had a small effect on externalizing bias, which in turn affected subsyndromal positive symptoms. There was no moderating effect of schizotypal traits on externalizing bias, but it was significantly associated with subsyndromal positive symptoms. Only the externalizing bias was associated with subsyndromal positive symptomatology, which might be explained by a restricted range and reduced variance in performance as a result of using a university student sample. This is one of few studies that sought to explain the mechanism responsible for the development of subsyndromal positive symptoms in a healthy sample using self-report measures.

A mixed-methods study to evaluate the feasibility and preliminary efficacy of delivering the optimal health program (OHP) for youth at clinical high risk (CHR) for psychosis: A study protocol.

Individuals with clinical high risk (CHR) for psychosis experience significant distress, impaired general functioning and a high lifetime risk of self-harm and attempted suicide. The CHR period is an important phase in an individual's mental health where appropriate interventions may reduce the risk of progression to several negative outcomes, including the development of schizophrenia. Given that up to 80% of individuals with CHR have another diagnosable mental illness and almost half experience poor psychosocial functioning, developing interventions that address psychosocial functioning in young people with CHR is of great importance. This mixed-methods study aims to employ qualitative and quantitative methods to adapt an evidence-based comprehensive psychosocial and mental health self-efficacy program, the Optimal Health Program (OHP), and evaluate the feasibility, acceptability and preliminary clinical efficacy in young people with CHR. We aim to recruit 30 CHR participants (age 16-29 years) in a single-arm 12-week exploratory clinical trial. Feasibility metrics will include recruitment, retention, and data completion rates. Acceptability will be informed by the Client Satisfaction Questionnaire. Clinical assessments (psychosis spectrum symptoms, depression, and anxiety), functional measures, and cognitive outcomes will be completed at study entry and repeated post-intervention at 12-weeks. We will run pre-post test data analysis to examine changes following engagement in the OHP intervention. Qualitative interviews will be conducted post-intervention to further evaluate the acceptability of the intervention and the trial design, and will be analyzed using thematic analysis. OHP may enhance the long-term mental health, well-being and functioning of CHR youth. However, the intervention must first be adapted to a CHR population; then, the feasibility and preliminary efficacy of delivering an intervention tailored around the varied needs of the CHR group must be established before a larger-scale appropriately powered study is pursued. Trial registration: The trial is registered with ClinicalTrials.gov NCT05757128.

A systematic review and meta-analysis of neuroimaging studies examining synaptic density in individuals with psychotic spectrum disorders.

BACKGROUND: Psychotic disorders have long been considered neurodevelopmental disorders where excessive synaptic pruning and cortical volume loss are central to disease pathology. We conducted a systematic review of the literature to identify neuroimaging studies specifically examining synaptic density across the psychosis spectrum. METHODS: PRISMA guidelines on reporting were followed. We systematically searched MEDLINE, Embase, APA PsycINFO, Web of Science and The Cochrane Library from inception to December 8, 2023, and included all original peer-reviewed articles or completed clinical neuroimaging studies of any modality measuring synaptic density in participants with a diagnosis of psychosis spectrum disorder as well as individuals with psychosis-risk states. The NIH quality assessment tool for observational cohort and cross-sectional studies was used for the risk of bias assessment. RESULTS: Five studies (k = 5) met inclusion criteria, comprising n = 128 adults (psychotic disorder; n = 61 and healthy volunteers; n = 67 and specifically measuring synaptic density via positron emission tomography (PET) imaging of the synaptic vesicle glycoprotein 2 A (SV2A). Three studies were included in our primary meta-analysis sharing the same outcome measure of SV2A binding, volume of distribution (VT). Regional SV2A VT was reduced in psychotic disorder participants in comparison to healthy volunteers, including the occipital lobe (Mean Difference (MD)= -2.17; 95% CI: -3.36 to -0.98; P < 0.001 ), temporal lobe (MD: -2.03; 95% CI: -3.19 to -0.88; P < 0.001 ), parietal lobe (MD:-1.61; 95% CI: -2.85 to -0.37; P = 0.01), anterior cingulate cortex (MD= -1.47; 95% CI: -2.45 to -0.49; P = 0.003), frontal cortex (MD: -1.16; 95% CI: -2.18 to -0.15; P = 0.02), amygdala (MD: -1.36; 95% CI: -2.20 to -0.52, p = 0.002), thalamus (MD:-1.46; 95% CI:-2.46 to -0.46, p = 0.004) and hippocampus (MD= -0.96; 95% CI: -1.59 to -0.33; P = 0.003). CONCLUSIONS: Preliminary studies provide in vivo evidence for reduced synaptic density in psychotic disorders. However, replication of findings in larger samples is required prior to definitive conclusions being drawn. PROSPERO: CRD42022359018.

Excessive left anterior hippocampal and caudate activation in schizophrenia underlie cognitive underperformance in a virtual navigation task.

We used a virtual navigation paradigm in a city environment to assess neuroanatomical correlates of cognitive deficits in schizophrenia spectrum disorders (SSD). We studied a total of N = 36 subjects: 18 with SSD and 18 matched unaffected controls. Participants completed 10 rapid, single-trial navigation tasks within the virtual city while undergoing functional magnetic resonance imaging (fMRI). All trials tested ability to find different targets seen earlier, during the passive viewing of a path around different city blocks. SSD patients had difficulty finding previously-encountered targets, were less likely to find novel shortcuts to targets, and more likely to attempt retracing of the path observed during passive viewing. Based on a priori region-of-interest analyses, SSD participants had hyperactivation of the left hippocampus when passively viewing turns, hyperactivation of the left caudate when finding targets, and hypoactivation of a focal area of the dorsolateral prefrontal cortex when targets were initially shown during passive viewing. We propose that these brain-behaviour relations may bias or reinforce stimulus-response navigation approaches in SSD and underlie impaired performance when allocentric spatial memory is required, such as when forming efficient shortcuts. This pattern may extend to more general cognitive impairments in SSD that could be used to design remediation strategies.

Heterogeneity in functional connectivity: Dimensional predictors of individual variability during rest and task fMRI in psychosis.

BACKGROUND: Individuals with schizophrenia spectrum disorders (SSD) often demonstrate cognitive impairments, associated with poor functional outcomes. While neurobiological heterogeneity has posed challenges when examining social cognition in SSD, it provides a unique opportunity to explore brain-behavior relationships. The aim of this study was to investigate the relationship between individual variability in functional connectivity during resting state and the performance of a social task and social and non-social cognition in a large sample of controls and individuals diagnosed with SSD. METHODS: Neuroimaging and behavioral data were analyzed for 193 individuals with SSD and 155 controls (total n = 348). Individual variability was quantified through mean correlational distance (MCD) of functional connectivity between participants; MCD was defined as a global 'variability score'. Pairwise correlational distance was calculated as 1 - the correlation coefficient between a given pair of participants, and averaging distance from one participant to all other participants provided the mean correlational distance metric. Hierarchical regressions were performed on variability scores derived from resting state and Empathic Accuracy (EA) task functional connectivity data to determine potential predictors (e.g., age, sex, neurocognitive and social cognitive scores) of individual variability. RESULTS: Group comparison between SSD and controls showed greater SSD MCD during rest (p = 0.00038), while no diagnostic differences were observed during task (p = 0.063). Hierarchical regression analyses demonstrated the persistence of a significant diagnostic effect during rest (p = 0.008), contrasting with its non-significance during the task (p = 0.50), after social cognition was added to the model. Notably, social cognition exhibited significance in both resting state and task conditions (both p = 0.01). CONCLUSIONS: Diagnostic differences were more prevalent during unconstrained resting scans, whereas the task pushed participants into a more common pattern which better emphasized transdiagnostic differences in cognitive abilities. Focusing on variability may provide new opportunities for interventions targeting specific cognitive impairments to improve functional outcomes.

An SMS text messaging intervention to improve clinical engagement in early psychosis: A pilot randomized-controlled trial.

Disengagement of youth with psychosis from Early Psychosis Intervention (EPI) services continues to be a significant barrier to recovery, with approximately one-third prematurely discontinuing treatment despite the ongoing need. The current pilot trial sought to evaluate the preliminary efficacy and feasibility of a weekly short message service (SMS) intervention to improve engagement in EPI services. This was a longitudinal single-blinded randomized control trial in which participants were assigned to receive either an active or sham SMS intervention over nine months. Sixty-one participants with early psychosis between the ages of 16 and 29 were enrolled, randomized, and received at least part of the intervention. Primary outcomes consisted of participant clinic attendance rates over the course of the intervention and clinician-rated engagement. Secondary measures included patient-rated therapeutic rapport, attitude toward medication, psychopathology, cognition, functioning, and intervention feedback from participants. Compared to the sham group, participants receiving the active intervention did not show improved appointment attendance rates; however, did exhibit some improvements in aspects of engagement, including improved clinician-rated availability, attitude toward medication, positive symptoms, avolition-apathy and social functioning. Thus, contrary to our hypotheses, digitally augmented care did not result in enhanced engagement in EPI services, as measured by clinic attendance, although with some indication that it may contribute to improved attitude toward medication and, potentially, medication adherence. Weekly SMS text messaging appeared to result in a pattern of engagement whereby individuals who were improving clinically attended appointments less often, possibly due to inadvertent use of the intervention to check in with clinicians. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04379349).

Depression in caregivers of patients with schizophrenia: a scoping review.

PURPOSE: Caregivers play a vitally important role in the lives of people with schizophrenia. However, their mental health can often be overlooked. In recent years, with increasing attention to mental health and wellness, common mental illness such as depression in caregivers of people with schizophrenia has received renewed attention. The purpose of this review was to consolidate and synthesize recent literature on (1) the prevalence of depression in caregivers of people with schizophrenia, (2) factors associated with depression in caregivers of people with schizophrenia, and (3) interventions that target depression in caregivers of people with schizophrenia. METHODS: A systematic search focusing on literature published between 2010 and 2022 was done to retrieve relevant articles from the following databases: Ovid MEDLINE, Ovid EMBASE, and Ovid Psych INFO. RESULTS: Twenty-four studies met inclusion criteria and were included in the review. Nine evaluated the prevalence of depression, 18 evaluated factors associated with depression in caregivers, and 6 examined interventions targeting depression. The prevalence of depression and depressive symptoms in samples of caregivers ranged between 12 and 40% across the studies. Females, especially mothers of people with schizophrenia, were more likely to experience depression, followed by younger caregivers. Several factors, including gender, interpersonal relationships, social support, stigma, literacy, and financial constraints, were identified as factors associated with depression in caregivers. Several interventions like yoga, emotional training, and psychoeducation were evaluated, and they showed a significant reduction in the level of depression and depressive symptoms experienced by the caregiver population. CONCLUSIONS: Depression in caregivers in this clinical population may be widespread and warrants further study. There are promising interventions that can target depression in caregivers. Well-designed longitudinal studies may help identify caregivers at risk of developing depression and further inform targets for intervention.

The Toronto Adolescent and Youth Cohort Study: Study Design and Early Data Related to Psychosis Spectrum Symptoms, Functioning, and Suicidality.

BACKGROUND: Psychosis spectrum symptoms (PSSs) occur in a sizable percentage of youth and are associated with poorer cognitive performance, poorer functioning, and suicidality (i.e., suicidal thoughts and behaviors). PSSs may occur more frequently in youths already experiencing another mental illness, but the antecedents are not well known. The Toronto Adolescent and Youth (TAY) Cohort Study aims to characterize developmental trajectories in youths with mental illness and understand associations with PSSs, functioning, and suicidality. METHODS: The TAY Cohort Study is a longitudinal cohort study that aims to assess 1500 youths (age 11-24 years) presenting to tertiary care. In this article, we describe the extensive diagnostic and clinical characterization of psychopathology, substance use, functioning, suicidality, and health service utilization in these youths, with follow-up every 6 months over 5 years, including early baseline data. RESULTS: A total of 417 participants were enrolled between May 4, 2021, and February 2, 2023. Participants met diagnostic criteria for an average of 3.5 psychiatric diagnoses, most frequently anxiety and depressive disorders. Forty-nine percent of participants met a pre-established threshold for PSSs and exhibited higher rates of functional impairment, internalizing and externalizing symptoms, and suicidality than participants without PSSs. CONCLUSIONS: Initial findings from the TAY Cohort Study demonstrate the feasibility of extensive clinical phenotyping in youths who are seeking help for mental health problems. PSS prevalence is much higher than in community-based studies. Our early data support the critical need to better understand longitudinal trajectories of clinical youth cohorts in relation to psychosis risk, functioning, and suicidality.

Neuroimaging and Biosample Collection in the Toronto Adolescent and Youth Cohort Study: Rationale, Methods, and Early Data.

BACKGROUND: The Toronto Adolescent and Youth (TAY) Cohort Study will characterize the neurobiological trajectories of psychosis spectrum symptoms, functioning, and suicidality (i.e., suicidal thoughts and behaviors) in youth seeking mental health care. Here, we present the neuroimaging and biosample component of the protocol. We also present feasibility and quality control metrics for the baseline sample collected thus far. METHODS: The current study includes youths (ages 11-24 years) who were referred to child and youth mental health services within a large tertiary care center in Toronto, Ontario, Canada, with target recruitment of 1500 participants. Participants were offered the opportunity to provide any or all of the following: 1) 1-hour magnetic resonance imaging (MRI) scan (electroencephalography if ineligible for or declined MRI), 2) blood sample for genomic and proteomic data (or saliva if blood collection was declined or not feasible) and urine sample, and 3) heart rate recording to assess respiratory sinus arrhythmia. RESULTS: Of the first 417 participants who consented to participate between May 4, 2021, and February 2, 2023, 412 agreed to participate in the imaging and biosample protocol. Of these, 334 completed imaging, 341 provided a biosample, 338 completed respiratory sinus arrhythmia, and 316 completed all 3. Following quality control, data usability was high (MRI: T1-weighted 99%, diffusion-weighted imaging 99%, arterial spin labeling 90%, resting-state functional MRI 95%, task functional MRI 90%; electroencephalography: 83%; respiratory sinus arrhythmia: 99%). CONCLUSIONS: The high consent rates, good completion rates, and high data usability reported here demonstrate the feasibility of collecting and using brain imaging and biosamples in a large clinical cohort of youths seeking mental health care.

Cognition and Educational Achievement in the Toronto Adolescent and Youth Cohort Study: Rationale, Methods, and Early Data.

BACKGROUND: Both cognition and educational achievement in youths are linked to psychosis risk. One major aim of the Toronto Adolescent and Youth (TAY) Cohort Study is to characterize how cognitive and educational achievement trajectories inform the course of psychosis spectrum symptoms (PSSs), functioning, and suicidality. Here, we describe the protocol for the cognitive and educational data and early baseline data. METHODS: The cognitive assessment design is consistent with youth population cohort studies, including the NIH Toolbox, Rey Auditory Verbal Learning Test, Wechsler Matrix Reasoning Task, and Little Man Task. Participants complete an educational achievement questionnaire, and report cards are requested. Completion rates, descriptive data, and differences across PSS status are reported for the first participants (N = 417) ages 11 to 24 years, who were recruited between May 4, 2021, and February 2, 2023. RESULTS: Nearly 84% of the sample completed cognitive testing, and 88.2% completed the educational questionnaire, whereas report cards were collected for only 40.3%. Modifications to workflows were implemented to improve data collection. Participants who met criteria for PSSs demonstrated lower performance than those who did not on numerous key cognitive indices (p < .05) and also had more academic/educational problems. CONCLUSIONS: Following youths longitudinally enabled trajectory mapping and prediction based on cognitive and educational performance in relation to PSSs in treatment-seeking youths. Youths with PSSs had lower cognitive performance and worse educational outcomes than youths without PSSs. Results show the feasibility of collecting data on cognitive and educational outcomes in a cohort of youths seeking treatment related to mental illness and substance use.

Care Pathways and Initial Engagement in Early Psychosis Intervention Services Among Youths and Young Adults.

Importance: Broad efforts to improve access to early psychosis intervention (EPI) services may not address health disparities in pathways to care and initial engagement in treatment. Objective: To understand factors associated with referral from acute hospital-based settings and initial engagement in EPI services. Design, Setting, and Participants: This retrospective cohort study used electronic medical record data from all patients aged 16 to 29 years who were referred to a large EPI program between January 2018 and December 2019. Statistical analysis was performed from March 2022 to February 2023. Exposures: Patients self-reported demographic information in a structured questionnaire. The main outcome for the first research question (referral source) was an exposure for the second research question (initial attendance). Main Outcomes and Measures: Rate of EPI referral from acute pathways compared with other referral sources, and rate of attendance at the consultation appointment. Results: The final study population included 999 unique patient referrals. At referral, patients were a mean (SD) age of 22.5 (3.5) years; 654 (65.5%) identified as male, 323 (32.3%) female, and 22 (2.2%) transgender, 2-spirit, nonbinary, do not know, or prefer not to answer; 199 (19.9%) identified as Asian, 176 (17.6%) Black, 384 (38.4%) White, and 167 (16.7%) other racial or ethnic groups, do not know, or prefer not to answer. Participants more likely to be referred to EPI services from inpatient units included those who were older (relative risk ratio [RRR], 1.10; 95% CI, 1.05-1.15) and those who identified as Black (RRR, 2.11; 95% CI, 1.38-3.22) or belonging to other minoritized racial or ethnic groups (RRR, 1.79; 95% CI, 1.14-2.79) compared with White participants. Older patients (RRR, 1.16; 95% CI, 1.11-1.22) and those who identified as Black (RRR, 1.67; 95% CI, 1.04-2.70) or belonging to other minoritized racial or ethnic groups (RRR, 2.11; 95% CI, 1.33-3.36) were more likely to be referred from the emergency department (ED) compared with White participants, whereas participants who identified as female (RRR, 0.51 95% CI, 0.34-.74) had a lower risk of ED referral compared with male participants. Being older (odds ratio [OR], 0.95; 95% CI, 0.90-1.00) and referred from the ED (OR, 0.40; 95% CI, 0.27-0.58) were associated with decreased odds of attendance at the consultation appointment. Conclusions and relevance: In this cohort study of patients referred to EPI services, disparities existed in referral pathways and initial engagement in services. Improving entry into EPI services may help facilitate a key step on the path to recovery among youths and young adults with psychosis.

Characterization and prediction of individual functional outcome trajectories in schizophrenia spectrum disorders (PREDICTS study): Study protocol.

Schizophrenia spectrum disorders (SSDs) are associated with significant functional impairments, disability, and low rates of personal recovery, along with tremendous economic costs linked primarily to lost productivity and premature mortality. Efforts to delineate the contributors to disability in SSDs have highlighted prominent roles for a diverse range of symptoms, physical health conditions, substance use disorders, neurobiological changes, and social factors. These findings have provided valuable advances in knowledge and helped define broad patterns of illness and outcomes across SSDs. Unsurprisingly, there have also been conflicting findings for many of these determinants that reflect the heterogeneous population of individuals with SSDs and the challenges of conceptualizing and treating SSDs as a unitary categorical construct. Presently it is not possible to identify the functional course on an individual level that would enable a personalized approach to treatment to alter the individual's functional trajectory and mitigate the ensuing disability they would otherwise experience. To address this ongoing challenge, this study aims to conduct a longitudinal multimodal investigation of a large cohort of individuals with SSDs in order to establish discrete trajectories of personal recovery, disability, and community functioning, as well as the antecedents and predictors of these trajectories. This investigation will also provide the foundation for the co-design and testing of personalized interventions that alter these functional trajectories and improve outcomes for people with SSDs.

Modeling Effort-Based Decision Making: Individual Differences in Schizophrenia and Major Depressive Disorder.

BACKGROUND: A critical facet of motivation is effort-based decision making, which refers to the mental processes involved in deciding whether a potential reward is worth the effort. To advance understanding of how individuals with schizophrenia and major depressive disorder utilize cost-benefit information to guide choice behavior, this study aimed to characterize individual differences in the computations associated with effort-based decision making. METHODS: One hundred forty-five participants (51 with schizophrenia, 43 with depression, and 51 healthy control participants) completed the Effort Expenditure for Rewards Task, with mixed effects modeling conducted to estimate the predictors of decision making. These model-derived, subject-specific coefficients were then clustered using k-means to test for the presence of discrete transdiagnostic subgroups with different profiles of reward, probability, and cost information utilization during effort-based decision making. RESULTS: An optimal 2-cluster solution was identified, with no significant differences in the distribution of diagnostic groups between clusters. Cluster 1 (n = 76) was characterized by overall lower information utilization during decision making than cluster 2 (n = 61). Participants in this low information utilization cluster were also significantly older and more cognitively impaired, and their utilization of reward, probability, and cost was significantly correlated with clinical amotivation, depressive symptoms, and cognitive functioning. CONCLUSIONS: Our findings revealed meaningful individual differences among participants with schizophrenia, depression, and healthy control participants in their utilization of cost-benefit information in the context of effortful decision making. These findings may provide insight into different processes associated with aberrant choice behavior and may potentially guide the identification of more individualized treatment targets for effort-based motivation deficits across disorders.

Multivariate Associations Among White Matter, Neurocognition, and Social Cognition Across Individuals With Schizophrenia Spectrum Disorders and Healthy Controls.

BACKGROUND AND HYPOTHESIS: Neurocognitive and social cognitive abilities are important contributors to functional outcomes in schizophrenia spectrum disorders (SSDs). An unanswered question of considerable interest is whether neurocognitive and social cognitive deficits arise from overlapping or distinct white matter impairment(s). STUDY DESIGN: We sought to fill this gap, by harnessing a large sample of individuals from the multi-center Social Processes Initiative in the Neurobiology of the Schizophrenia(s) (SPINS) dataset, unique in its collection of advanced diffusion imaging and an extensive battery of cognitive assessments. We applied canonical correlation analysis to estimates of white matter microstructure, and cognitive performance, across people with and without an SSD. STUDY RESULTS: Our results established that white matter circuitry is dimensionally and strongly related to both neurocognition and social cognition, and that microstructure of the uncinate fasciculus and the rostral body of the corpus callosum may assume a "privileged role" subserving both. Further, we found that participant-wise estimates of white matter microstructure, weighted by cognitive performance, were largely consistent with participants' categorical diagnosis, and predictive of (cross-sectional) functional outcomes. CONCLUSIONS: The demonstrated strength of the relationship between white matter circuitry and neurocognition and social cognition underscores the potential for using relationships among these variables to identify biomarkers of functioning, with potential prognostic and therapeutic implications.

Disengagement from early psychosis intervention services: an observational study informed by a survey of patient and family perspectives.

Approximately one-third of patients with early psychosis disengage from services before the end of treatment. We sought to understand patient and family perspectives on early psychosis intervention (EPI) service engagement and use these findings to elucidate factors associated with early disengagement, defined as dropout from EPI in the first 9 months. Patients aged 16-29 referred to a large EPI program between July 2018-February 2020 and their family members were invited to complete a survey exploring facilitators and barriers to service engagement. A prospective chart review was conducted for 225 patients consecutively enrolled in the same EPI program, receiving the NAVIGATE model of coordinated specialty care, between July 2018-May 2019. We conducted a survival analysis, generating Kaplan-Meier curves depicting time to disengagement and Cox proportional hazards models to determine rate of disengagement controlling for demographic, clinical, and program factors. The survey was completed by 167 patients and 79 family members. The top endorsed engagement facilitator was related to the therapeutic relationship in both patients (36.5%) and families (43.0%). The top endorsed barrier to engagement was medication side effects in both patients (28.7%) and families (39.2%). In Cox proportional hazards models, medication nonadherence (HR = 2.37, 95% CI = 1.17-4.80) and use of individual psychotherapy (HR = .460, 95% CI = 0.220-0.962) were associated with early disengagement, but some of the health equity factors expected to affect engagement were not. Findings suggest that delivery of standardized treatment may buffer the effects of health disparities on service disengagement in early psychosis.

Behavioural phenotypes of intrinsic motivation in schizophrenia determined by cluster analysis of objectively quantified real-world performance.

Intrinsic motivation deficits are a prominent feature of schizophrenia that substantially impacts functional outcome. This study used cluster analysis of innate real-world behaviours captured during two open-field tasks to dimensionally examine heterogeneity in intrinsic motivation in schizophrenia patients (SZ) and healthy controls (HC). Wireless motion capture quantified participants' behaviours aligning with distinct aspects of intrinsic motivation: exploratory behaviour and effortful activity in the absence of external incentive. Cluster analysis of task-derived measures identified behaviourally differentiable subgroups, which were compared across standard clinical measures of general amotivation, cognition, and community functioning. Among 45 SZ and 47 HC participants, three clusters with characteristically different behavioural phenotypes emerged: low exploration (20 SZ, 19 HC), low activity (15 SZ, 8 HC), and high exploration/activity (10 SZ, 20 HC). Low performance in either dimension corresponded with similar increased amotivation. Within-cluster discrepancies emerged for amotivation (SZ > HC) within the low exploration and high performance clusters, and for functioning (SZ < HC) within all clusters, increasing from high performance to low activity to low exploration. Objective multidimensional characterization thus revealed divergent behavioural expression of intrinsic motivation deficits that may be conflated by summary clinical measures of motivation and overlooked by unidimensional evaluation. Deficits in either aspect may hinder general motivation and functioning particularly in SZ. Multidimensional phenotyping may help guide personalized remediation by discriminating between intrinsic motivation impairments that require amelioration versus unimpaired tendencies that may facilitate remediation.

Metformin for the prevention of clozapine-induced weight gain: A retrospective naturalistic cohort study.

OBJECTIVE: Clozapine is presently the sole antipsychotic with an indication for treatment-resistant Schizophrenia, but is associated with significant weight gain and other metabolic aberrations. This retrospective chart review aimed to evaluate the effectiveness of adjunctive metformin in preventing clozapine-induced weight gain. METHODS: We conducted a retrospective chart review of patients newly initiated on clozapine at the Centre for Addiction and Mental Health in Canada, from November 2014 to April 2021. Our primary outcome was body weight at 6 and 12 months after clozapine initiation. Other metabolic parameters served as secondary outcomes. RESULTS: Among 396 patients (males: 71.5%, mean age: 42.8 years) initiated on clozapine, 69 were on metformin or prescribed it ≤3 months after clozapine initiation. The clozapine+metformin group demonstrated less weight gain compared with the clozapine-only group at 6 months (clozapine+metformin: -0.15 kg [SE = 1.08] vs. clozapine-only: 2.99 kg, SE = 0.54) and 12 months after clozapine initiation (clozapine+metformin: -0.67 kg, SE = 1.22 vs. clozapine-only: 4.72 kg, SE = 0.67). Adaptive changes were also observed for fasting glucose (F = 3.10, p = 0.046) and triglycerides (F = 8.56, p < 0.001) in the clozapine+metformin group compared with clozapine only. CONCLUSION: In this large retrospective naturalistic cohort study, co-prescription of clozapine and metformin was associated with less weight gain and related metabolic dysfunction at 6 and 12 months after initiation versus clozapine alone. These findings provide evidence for the effectiveness of metformin in preventing clozapine-induced weight gain; larger randomized controlled trials are needed to confirm these results.

Distinct profiles of psychological and neuropsychological functions underlying goal-directed pursuit in schizophrenia.

OBJECTIVES: Several components are known to underlie goal-directed pursuit, including executive, motivational and volitional functions. These were explored in schizophrenia spectrum disorders in order to identify subgroups with distinct profiles. METHODS: Multiple executive, motivational and volitional tests were administered to a sample of outpatients with schizophrenia spectrum diagnoses (n = 59) and controls (n = 63). Research questions included whether distinct profiles exist and whether some functions are impacted disproportionately. These questions were addressed via cluster analysis and profile analysis, respectively. RESULTS: Some such functions were significantly altered in schizophrenia while others were unaffected. Two distinct profiles emerged, one characterized by energizing deficits, reduced reward sensitivity and few subjective complaints; while another was characterized by markedly increased punishment sensitivity, intact reward sensitivity and substantial subjective reporting of avolitional symptoms and boredom susceptibility. CONCLUSION: These findings highlight the importance of considering distinct patterns of strengths and deficits in functions governing goal-directed pursuit in schizophrenia that demarcate identifiable subtypes. These distinctions have implications for treatment, assessment and research.