Psychiatric Adverse Events Associated with Semaglutide: A Systematic Review of Evidence and Implications for Clinical Practice

Abstract

Background: The clinical use of semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist authorized for the treatment of type 2 diabetes and obesity, is quickly growing.. However, concerns have emerged regarding its potential psychiatric adverse effects, including depression, suicidal ideation, and self-harm, prompting an ongoing safety review by the European Medicines Agency (EMA). Despite these concerns, systematic evidence on psychiatric outcomes associated with semaglutide remains limited.
Objectives: In order to guide clinical practice and regulatory decision-making, this systematic review sought to compile the existing data on mental adverse events linked to semaglutide, assess their timing, severity, and resolution, identify relevant risk factors, and investigate underlying processes.
Methods: A comprehensive literature search was analyzed in PubMed using the search string ((Psychiatric) OR (Adverse Events)) AND (Semaglutide), restricted to the last five years. Studies were included if they reported psychiatric adverse events associated with semaglutide in the form of randomized controlled trials, observational studies, or case reports. The Newcastle-Ottawa Scale and the Cochrane Risk of Bias instrument (RoB 2) were used to evaluate the quality of the study. Because of the variation among investigations, a narrative synthesis was carried out.
Results: 12 studies were included, comprising 11 randomized controlled trials and one post-hoc analysis, with sample sizes ranging from 48 to 17,604 participants and follow-up durations from 9 weeks to 4 years. The overall findings did not support an association between semaglutide and increased psychiatric adverse events. A post-hoc analysis of the STEP 1–5 trials demonstrated a small but significant reduction in depressive symptoms compared to placebo (PHQ-9 difference −0.56, P<0.001). The SELECT cardiovascular outcomes trial found serious psychiatric adverse events and suicidal ideation rates to be virtually identical between semaglutide and placebo groups (0.7% vs 0.6% and 0.11% vs 0.11%, respectively). The STEP 4 trial showed lower psychiatric event rates with continued semaglutide versus placebo following discontinuation. Semaglutide was also associated with fewer psychiatric events than liraglutide in the STEP 8 trial, and no worsening of psychotic symptoms was observed in patients with schizophrenia spectrum disorder.
Conclusion: Current evidence does not support a causal link between semaglutide and increased psychiatric adverse events at the population level, with several studies suggesting modest mental health benefits. However, the systematic exclusion of patients with active psychiatric disorders from clinical trials, combined with published case reports of semaglutide-associated depression and ongoing regulatory scrutiny, highlights a critical evidence gap. Clinicians should maintain individualized psychiatric monitoring, particularly in patients with a prior psychiatric history, and future research should prioritize psychiatric populations with standardized assessment tools.