Tirzepatide and Semaglutide linked to lower anxiety and depression hazards vs. naltrexone-bupropion in obesity

The neuropsychiatric effects of newer anti-obesity medications, particularly GLP-1 and GIP receptor agonists like tirzepatide and semaglutide, remain unclear in real-world clinical settings. While these drugs are highly effective for obesity and type 2 diabetes (T2D), understanding their impact on mental health is crucial for comprehensive patient care. Current anti-obesity treatments often have their own neuropsychiatric side effect profiles, necessitating a clearer picture of how these novel agents compare in routine care.

Researchers utilized a United States electronic health record network spanning 2020-2025 to identify adults with obesity who newly initiated tirzepatide or semaglutide. These patients were then matched one-to-one with new users of other anti-obesity medications: naltrexone-bupropion, phentermine, or phentermine-topiramate. The primary endpoint was the time to the first recorded diagnosis of a neuropsychiatric condition over a 24-month follow-up period. Bariatric surgery recipients were also included as a contextual comparator group to provide broader insights into weight loss interventions.

Compared to naltrexone-bupropion, initiation of semaglutide was associated with significantly lower hazards of anxiety disorder in adults with T2D (hazard ratio 0.67, 95% CI 0.51-0.87) and without T2D (hazard ratio 0.73, 95% CI 0.64-0.83). Similarly, semaglutide reduced depression hazards in both strata (with T2D: hazard ratio 0.69, 95% CI 0.50-0.95; without T2D: hazard ratio 0.53, 95% CI 0.45-0.61). Tirzepatide also showed reduced hazard ratios versus naltrexone-bupropion for anxiety disorder (with T2D: hazard ratio 0.55, 95% CI 0.40-0.76; without T2D: hazard ratio 0.78, 95% CI 0.68-0.89) and depression (with T2D: hazard ratio 0.49, 95% CI 0.33-0.72; without T2D: hazard ratio 0.57, 95% CI 0.49-0.66).