Abstract / Summary
Pharmacological weight management has expanded rapidly with the introduction of GLP-1 receptor agonists and dual GIP/GLP-1 agonists, yet their comparative effects on mental health remain unclear. We systematically searched PubMed, Embase, Cochrane CENTRAL, PsycINFO, and ClinicalTrials.gov from database inception, without publication-date restrictions; the primary searches were conducted up to May 15, 2026. We included randomized controlled trials of six FDA- or EMA-approved anti-obesity medications reporting eligible mental health outcomes in adults with overweight or obesity. Depression symptom severity, SF-36 Mental Component Summary (MCS), and IWQOL-Lite total score were analyzed using Bayesian random-effects network meta-analysis. Eleven unique trials contributed to at least one efficacy NMA. For depression symptoms, neither naltrexone/bupropion (SMD 0.03; 95% CrI − 0.93 to 0.90) nor orlistat (SMD − 0.46; −2.01 to 1.16) showed a clearly distinguishable effect compared with placebo. SF-36 MCS estimates were uncertain for semaglutide (SMD 0.20; −0.22 to 0.64), liraglutide (SMD 0.18; −0.38 to 0.74), and tirzepatide (SMD 0.17; −0.14 to 0.48). Tirzepatide showed the largest estimated improvement in IWQOL-Lite total score (SMD 0.63; 0.44 to 0.87), followed by liraglutide (SMD 0.30; 0.03 to 0.53) and naltrexone/bupropion (SMD 0.26; 0.03 to 0.48). Psychiatric adverse-event evidence was sparse, with one suicide or self-harm event among 4,216 participants. Certainty of evidence ranged from MODERATE to VERY LOW. Current randomized evidence is insufficient to establish either benefit or harm of approved anti-obesity medications on depressive symptoms, and SF-36 MCS estimates remain uncertain. Tirzepatide, liraglutide, and naltrexone/bupropion probably improve weight-related quality of life, although treatment rankings do not establish clinical superiority. Psychiatric safety evidence remains too sparse for firm conclusions. Future obesity trials should prospectively incorporate standardized depression, anxiety, suicidality, and quality-of-life outcomes. https://www.crd.york.ac.uk/PROSPERO/view/CRD420261400491 , identifier CRD420261400491. Not applicable.