729. From metabolic dysregulation and shared genetic etiology to suicidality: the psychiatric promise and safety debate of GLP-1 receptor agonists

Abstract

Abstract Background Metabolic and psychiatric disorders frequently co-occur, and growing evidence links this overlap to suicide risk. Large population and genomic studies indicate shared alterations in insulin signalling, lipid metabolism, and immune–inflammatory activity, mechanisms also implicated in stress regulation and suicidal behaviour through inflammation, HPA-axis activation, and impaired brain insulin signalling. Individuals with metabolic syndrome show higher rates of suicidal ideation and attempts, supporting the clinical relevance of metabolic health in suicide prevention. In parallel, GLP-1 receptor agonists (GLP-1RAs), widely used for diabetes and obesity, entered regulatory review after concerns about a possible increase in suicidality. Aims & Objectives To connect metabolic psychiatry, psychiatric genomics, and clinical psychopharmacology around a practical question: can GLP-1 pathway modulation improve cardiometabolic outcomes while informing testable hypotheses across psychiatric domains? Objectives are to (i) integrate mechanistic and genomic evidence for shared metabolic–psychiatric liability, (ii) interpret the GLP-1RA suicidality safety debate using the best available trial/observational/regulatory evidence, and (iii) outline a precision cross-therapy framework to support patient stratification and trial endpoints relevant to psychiatry. Method Evidence-based synthesis of published population/genomic studies, mechanistic work on insulin and immune–inflammatory pathways, and the GLP-1RA clinical development and post-marketing literature, prioritising randomised trials, high-quality meta-analyses, large observational datasets, and regulator assessments. The lecture separates signal detection from causal inference in low base-rate outcomes and distinguishes putative direct CNS effects from benefits mediated by cardiometabolic change. Results Population and genomic evidence supports shared metabolic–psychiatric liability involving insulin signalling, lipid metabolism, and immune–inflammatory pathways. Regarding suicidality, comprehensive evaluations report very low event rates and no evidence supporting a causal association, including a 2025 systematic review/meta-analysis of 144 randomised trials and regulator conclusions . Beyond suicidality, psychiatric safety signals relevant to clinical adoption include: (i) post-hoc analyses from the STEP programme showing semaglutide 2.4 mg did not increase depression symptoms or suicidal ideation/behaviour versus placebo; and (ii) randomised data in antipsychotic-treated schizophrenia showing clinically meaningful weight loss without evidence of psychotic symptom worsening in the available trial programmes. Emerging preclinical and early clinical data suggest potential effects on mood, cognition, and stress regulation, motivating hypothesis-driven repurposing prospects across depression, binge-eating, and addiction. Discussion & Conclusions GLP-1RAs define a near-term agenda for metabolic psychiatry with clear clinical implementation pathways and a safety debate that can be addressed with disciplined endpoint ascertainment. The proposed next step is precision cross-therapy: define transdiagnostic immuno-metabolic phenotypes using clinical measures, biomarkers, and polygenic scores; embed psychiatric endpoints in metabolic RCTs (anhedonia, cognition, craving, quality of life, adherence); and apply drug-target genetics to prioritise candidates and justify repurposing pipelines. This framework supports multi-site collaboration around harmonised stratification and endpoints, with direct relevance to both clinical services and development programmes.