Antipsychotic-Induced Remodeling of the Gut Microbiota: Drug-Specific Patterns and Molecular Links to Metabolic Adverse Effects

Antipsychotic drugs are essential for the treatment of schizophrenia-spectrum disorders and other severe psychiatric conditions, but several agents produce clinically important metabolic and gastrointestinal adverse effects. Increasing evidence suggests that these outcomes may involve bidirectional interactions between antipsychotics and the gut microbiota. This structured narrative review integrates human, animal, gnotobiotic, in vitro, pharmacokinetic, and multi-omic evidence to examine drug-specific microbiome effects and microbiota-dependent modulation of host responses. Olanzapine has the strongest mechanistic evidence, with germ-free, antibiotic-depletion, colonization, and vagotomy studies supporting a contributory role of the microbiota in weight gain, adiposity, inflammation, altered microbial metabolites, and lipid dysregulation. Risperidone also shows microbiota-dependent metabolic and neurobiological effects, whereas findings for clozapine, quetiapine, aripiprazole, lurasidone, and amisulpride remain more heterogeneous or limited. Across agents, no universal taxonomic pattern has emerged. Functional pathways involving short-chain fatty acids, bile acids, epithelial barrier integrity, immune and neuroendocrine signaling, vagal pathways, and microbial drug metabolism appear more informative than individual taxa or the Firmicutes/Bacteroidota ratio. Current evidence remains limited by methodological heterogeneity, small cohorts, confounding, and predominantly preclinical mechanistic data. Prospective, treatment-naive, drug-specific longitudinal multi-omic studies are required.