ABSTRACT Serotonin fosters cognitive flexibility, but how, exactly, remains unclear. We show that serotonin reduces belief stickiness: the tendency to get “stuck” in a belief about the state of the world despite incoming contradicting evidence. Participants performed a task assessing belief stickiness in a randomized, double-blind, placebo-controlled study using a single dose of the selective serotonin reuptake inhibitor (SSRI) escitalopram. In the escitalopram group, higher escitalopram plasma levels reduced belief stickiness more, resulting in better inference about the state of the world. Moreover, participants with sufficiently high escitalopram plasma levels had less belief stickiness, and therefore better state inference, than participants on placebo. Exaggerated belief stickiness is exemplified by obsessions: “sticky” thoughts that persist despite contradicting evidence. Indeed, participants with more obsessions had greater belief stickiness, and therefore worse state inference. The opposite relations of escitalopram and obsessions with belief stickiness may explain the therapeutic effect of SSRIs in obsessive-compulsive disorder.

OBJECTIVES:Major depressive disorder (MDD) is associated with significant impairment in occupational functioning. The Lam Employment Absence and Productivity Scale (LEAPS) is a self-report questionnaire validated for the assessment of work productivity and absenteeism in patients with MDD. Our study objective was to establish a minimal clinically important difference (MCID) for the LEAPS. METHODS:Data from the Canadian Biomarker Integration Network in Depression (CAN-BIND)-1 study was used. CAN-BIND-1 involved participants with MDD treated with escitalopram for 8 weeks (n = 138). Assessments included the LEAPS, Sheehan Disability Scale (SDS), and Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR). The MCID for the LEAPS was calculated using both distribution (value equivalent to half the standard deviation for LEAPS baseline scores) and anchor-based (comparing to the SDS work item) methods. RESULTS:The LEAPS total score was significantly correlated (p < 0.01) with other measures including SDS work item (r = 0.598), SDS total score (r = 0.609), and QIDS-SR (r = 0.678). Using the distribution-based method, the MCID value for LEAPS total score was 3.0 and MCID for LEAPS productivity subscale score was 1.5. Using the anchor-based method, the MCID value for the LEAPS total score was shown to lie between 2.7 and 3.5 and for the LEAPS productivity subscale score between 0.9 and 1.4. CONCLUSIONS:Establishing an MCID is important for determining clinically relevant change in the LEAPS, both for treatment studies and for individual patients in clinical care. For clinical use, the proposed MCID is 3 points for the LEAPS total score and 2 points for the LEAPS productivity subscale score.

Abstract Background Our understanding of the interplay between genetic and environmental factors (Gene x Environment Interaction, or GxE) determining mental health disorders has improved through the proliferation of genome-wide interaction association studies (GWIAS) and targeted GxE analyses. Moreover, multivariate modelling approaches, such as structural equation modelling (SEM) and polygenic risk scores (PRS), offer opportunities for the integration of clinical and genome-wide genotype data in building improved biopsychosocial models of mental illness aetiology and their response to treatment. Aims & Objectives We propose to construct a SEM framework to uncover the inter-correlation and directed structure of mental health phenotypes by leveraging the joint predictive capacity of PRS for comorbid traits that share underlying biological and environmental risk pathways. The proposed model will be capable of linking latent constructs to their observed measurements; these will include disease severity, comorbidities and clinical histories, and behaviours and lifestyle factors such as physical and social activity. Method Our gene-by-environment SEM (GESEM) will be initially developed and tested using four well- characterized clinical cohorts for older adults diagnosed with late-life depression and treated with antidepressants (CAN-BIND, IRL-GREY, STOP-PD II and IMPACT; n =1,238). The primary outcome will be antidepressant remission. Multiple PRS will be calculated to capture underlying genetic risk across vulnerable pathways which contribute to comorbidities. This selection will be made based on new, largely unpublished work from our group on the impact of PRS and targeted GxE studies on psychiatric outcomes across the lifespan. Each PRS will be calculated using both clumping and thresholding (PRSice-2) and continuous shrinkage (PRS-CS-auto) methods across selected cohorts using well-powered publicly available GWAS summary statistics. The multilevel GESEM model will include interactions between symptoms and comorbidities (i.e., observed measurements), which are caused by unobserved factors (i.e.,latent constructs), and are subject to modification by background PRS. We will compare our GESEM model against existing SEM-based approaches to GxE, including local SEM (LOSEM). Discussion & Conclusion An open-source R package of the analytical code will be created and shared with the research community. This work has the potential to improve upon existing PRS-based predictive models in a clinical setting.

International collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs) have become increasingly essential in advancing global health, particularly within psychiatric research. These partnerships not only accelerate scientific discovery and enhance public health, but they also bring to light significant challenges in equity and fairness. Specifically, research partnerships often suffer from imbalances, such as "helicopter" research approaches or the exploitation and marginalization of LMIC researchers. Here, we present a consensus report by members of the International Society for Psychiatric Genetics, outlining key considerations and strategies for planning, implementing, and disseminating equitable collaborative research. Throughout the collaboration process, we identified both challenges and opportunities and provided recommendations to maximize the benefits of these partnerships. Among our considerations, we emphasize that Equitable Collaboration must begin with comprehensive stakeholder engagement, fostering a participatory environment that includes local communities, governments, and institutions from both HICs and LMICs. Among the potential challenges we identify are differences in ethical research and data-sharing frameworks across countries, inequalities in research resources and infrastructure, and reduced visibility of research conducted in LMICs. These factors can significantly impact research outcomes and their applicability. In conclusion, while global collaboration in psychiatric genetics presents complex challenges, it also offers substantial opportunities for impactful research and improved global mental health.

Introduction: Cognitive rehabilitation is essential for schizophrenia treatment since it improves function. Moreover, the relationship between cognitive rehabilitation and functioning is significantly affected by negative symptoms and social cognition. Integrated Psychological Therapy (IPT) is a promising approach that integrates interventions in neurocognition, social cognition, and functional level. This study examines IPT's efficacy in chronic middle-aged inpatients. Methods: A randomized controlled study involved 44 individuals with schizophrenia. Twenty-one IPT participants received 50 biweekly sessions and medication, while twenty-three control participants received treatment as usual/supportive therapy and pharmacotherapy. Pre- and post-intervention and six- and twelve-month followups were arranged to assess neurocognition, social perception, psychopathology, and functioning using the Matrics Consensus Cognitive Battery, Social Perception Scale, Positive and Negative Syndrome Scale, and Global Assessment of Functioning. Results: Speed of processing, attention/vigilance, overall composite, and neurocognitive composite scores improved significantly in the IPT group. Social Perception Scale performance improved in all areas after the intervention and persisted for 6 months. Positive, negative, and total psychopathology symptoms decreased significantly post-intervention and at the 12-month follow-up, whereas participants' functioning improved significantly. Conclusions: Middle-aged chronic inpatients with schizophrenia may benefit from IPT in neurocognition, social perception, psychopathology, and functioning. This field of study may provide insight into schizophrenia treatment, hence further research is encouraged.

Background Emerging evidence suggests a role for the gut microbiome in schizophrenia (SCZ) and antipsychotic-induced metabolic perturbations. Using human fecal microbiota transplantation (FMT) in mice, this study investigated the role of gut microbiome in metabolic changes related to SCZ and antipsychotic (olanzapine) treatment. Methods 5-6 weeks old germ-free NIH Swiss mice of both sexes received microbiota from either SCZ patients (SCZ-FMT) or healthy controls (HC-FMT) followed by a diet with or without olanzapine for six-weeks. Food intake and body weight were monitored weekly, and an intraperitoneal glucose tolerance test and open field test were performed. Serum glucose, and insulin were measured. Gut microbiome characterization and short-chain fatty acids (SCFAs) quantification were performed in the cecal samples using 16S rRNA gene sequencing and gas chromatography-mass spectrometry, respectively. Results Olanzapine treatment decreased the locomotor activity in the open field test, irrespective of sex or microbiota. Female SCZ-FMT recipient mice exhibited insulin resistance compared to HC-FMT, irrespective of olanzapine treatment. Female SCZ-FMT mice showed significantly lower alpha-diversity compared to HC-FMT, whereas olanzapine treatment increased alpha-diversity. SCZ-FMT and olanzapine treatment differentially altered the microbial abundances, and metabolic pathways in male and female mice. Interestingly, cecal SCFAs, mainly acetate levels, were significantly decreased in female SCZ-FMT mice compared to HC-FMT, while olanzapine treatment increased acetate levels in male mice. Both male and female SCZ-FMT mice showed elevated levels of isovaleric acid compared to HC-FMT. Conclusion These preliminary findings suggest that gut microbiome could be a predisposing factor contributing to the intrinsic risk of developing type 2 diabetes associated with SCZ in females. ![Figure][1] Graphical abstract ### Competing Interest Statement MKH has received Alkermes consultant fees. Canadian Institutes of Health Research, https://ror.org/01gavpb45 University of Toronto [1]: pending:yes