GLP-1 agonists in psychiatry — a new therapeutic direction for depression, addictions, and eating disorders

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for the treatment of type 2 diabetes mellitus and obesity, are increasingly being investigated for their potential relevance to psychiatric disorders. Accumulating preclinical and clinical evidence indicates that GLP-1 signaling extends beyond metabolic regulation and may influence central mechanisms implicated in mood regulation, motivational processing, compulsive reward-seeking, and interoceptive control. This review synthesizes current mechanistic, preclinical, clinical, and registry-based evidence concerning the possible role of GLP-1 RAs in psychiatry, with particular emphasis on major depressive disorder, substance use disorders, and eating disorders. The biological rationale for their psychiatric relevance is supported by evidence of GLP-1-mediated signaling through circumventricular organs, vagal–brainstem pathways, and selected central nervous system regions, including hypothalamic, hippocampal, and mesolimbic reward-related circuits. Proposed mechanisms include modulation of reward salience, attenuation of neuroinflammatory signaling, improvement of metabolic-inflammatory burden, and enhancement of neuroplastic processes. The clinical evidence remains heterogeneous and indication-specific. In depression, the most consistent findings relate to cognitive and motivational domains, particularly in patients with major depressive disorder and coexisting overweight or obesity, whereas broader evidence from metabolic trials suggests modest reductions in depressive symptoms without establishing disorder-specific antidepressant efficacy. In substance use disorders, alcohol use disorder currently represents the most advanced area of investigation, with semaglutide demonstrating favorable outcomes in a phase 2 trial, while exenatide showed no overall reduction in heavy drinking but reduced alcohol cue reactivity and suggested potential benefit in obese participants. Evidence for nicotine use disorder is mixed, and data concerning opioid and stimulant use disorders remain preliminary. In eating disorders, binge-eating phenotypes appear to be the most plausible therapeutic target, whereas evidence for bulimia nervosa is limited and anorexia-spectrum disorders raise important safety concerns due to appetite suppression and weight loss. Overall, the safety profile of GLP-1 RAs in psychiatric populations appears broadly consistent with their established metabolic use, with gastrointestinal adverse effects predominating; however, psychiatric monitoring remains advisable because observational safety data are not fully concordant. Current evidence supports further diagnosis-specific randomized controlled trials but does not yet justify routine psychiatric prescribing outside carefully selected clinical contexts or research settings.