Psychiatry

Roadmap to precision psychiatry: from consensus vision to biomarker-informed trials

This consensus JAMA Psychiatry article argues that psychiatric drug development has stalled because trials ignore underlying biology and heterogeneity. The authors propose shifting toward precision psychiatry anchored in validated biomarkers that stratify patients by mechanisms rather than DSM categories alone. They recommend redesigning trials to use biomarker enrichment, adaptive designs, and biologically defined subgroups, similar to oncology. Regulators are urged to accept biomarker-informed endpoints, while payers and funders align investment with the high societal burden of mental disorders. Cross-sector collaboration among academia, biotech, industry, regulators, and health systems is positioned as essential for high-risk, high-reward innovations. 1

Genomic factors shared across 14 psychiatric disorders may reshape nosology and target discovery

This Nature GWAS analyzed over one million cases across 14 psychiatric disorders to map shared and disorder-specific genetic architecture. Five latent genomic factors explained most genetic variance, with about two-thirds of each disorder’s common-variant signal captured on average. A schizophrenia–bipolar factor and an internalizing factor spanning depression, PTSD, and anxiety showed extensive polygenic overlap and few disorder-specific loci. Shared signal across all disorders implicated broad transcriptional regulation pathways, while factor-specific pathways mapped to excitatory neurons and oligodendrocyte biology. These findings support transdiagnostic, biology-informed classifications and highlight pleiotropic loci as potential drug targets for common comorbid presentations. 2

In vivo evidence that increased frontal serotonin release links to negative symptoms in schizophrenia

This JAMA Psychiatry PET study assessed frontal serotonin release in 26 adults with schizophrenia versus 28 matched healthy controls using [11C]Cimbi-36 and d-amphetamine. Contrary to the a priori hypothesis, frontal cortex serotonin release was significantly greater in schizophrenia than controls, with a moderate effect size. Higher frontal serotonin release correlated with more severe negative symptoms and poorer social functioning within the schizophrenia group. Exploratory analyses showed particularly elevated serotonin release in deficit schizophrenia compared with both controls and nondeficit schizophrenia. These data implicate heightened frontal serotonergic signaling in negative symptoms and suggest 5-HT–targeted mechanisms as candidates for novel treatments. 3

Suicide-related network deviations predict and change with TMS response in depressed patients

This study examined suicide-related neural circuits in 473 patients with major depressive disorder, including 369 suicidal and 104 non-suicidal individuals. Using a normative model from 943 healthy controls, suicidal patients showed greater deviations in functional connectivity strength within a suicide-related damaged network. After TMS, these deviations decreased significantly overall, with larger reductions in clinical responders, suggesting modulation of suicide-related circuitry. Baseline deviations predicted TMS treatment response with about 75% accuracy and an AUC of 0.72. The authors propose network deviation as a candidate biomarker for suicide risk stratification and TMS targeting in MDD. 4