TOPLINE:

Once-weekly subcutaneous tirzepatide administered for 72 weeks was not associated with an increased risk for depression compared with placebo in adults with overweight or obesity, with or without type 2 diabetes (T2D), and without known major psychopathology.

METHODOLOGY:

• Tirzepatide produced clinically meaningful weight loss in trials of adults with obesity or overweight, with and without T2D; however, concerns remained regarding its potential effect on depression and suicidal thoughts or behaviors.
• Researchers conducted a pooled post hoc analysis of data from three clinical trials to assess the psychiatric safety of tirzepatide in adults with overweight or obesity, with or without T2D, and no known major psychopathology.
• Participants received either once-weekly subcutaneous tirzepatide (5, 10, or 15 mg or a maximum tolerated dose of 10 or 15 mg) or placebo for 72 weeks, as an adjunct to diet and physical activity modification.
• Psychiatric safety was assessed using the Patient Health Questionnaire-9 (PHQ-9) for depression and the Columbia-Suicide Severity Rating Scale for suicidal ideation and behavior; PHQ-9 scores ≥ 15 typically triggered referral to a mental health professional.
• Outcomes were assessed at multiple timepoints during the 72-week treatment period, with safety monitoring continued during an additional 4-week off-treatment follow-up.

TAKEAWAY:

• Researchers included 4056 adults (mean age, 47.2 years; 63% female), among whom 2806 received tirzepatide and 1250 received placebo.
• Mean depression scores were 2.7 vs 2.6 for the tirzepatide group vs the placebo group at baseline, decreasing to 1.9 and 2.4, respectively, at week 72, indicating no or minimal symptoms in both groups.
• The tirzepatide group was less likely to shift to a more severe category of depressive symptoms than the placebo group (18.2% vs 24.3%; P < .001); only 1.2% vs 2.3% of participants in the tirzepatide group vs the placebo group reached a PHQ-9 score ≥ 15.
• Rates of suicidal ideation and behavior remained low and similar in both groups (0.6%), with nonfatal suicidal behavior reported in 0.1% of participants receiving the tirzepatide group and none receiving placebo.
• The proportion of participants reporting at least one psychiatric adverse event (6.8% vs 8.2%) or nervous system disorder (15.8% vs 13.0%) was similar between the tirzepatide and placebo groups.

IN PRACTICE:

“Given the high risk of depression and anxiety in people with obesity — particularly with BMI > 40 kg/m² — we support ongoing monitoring of mental health in all such individuals, whether or not engaged in weight management, so that they may receive psychiatric care as needed,” the authors of the study wrote.

SOURCE:

The study was led by Thomas A. Wadden, Perelman School of Medicine, University of Pennsylvania, Philadelphia. It was published online in Obesity.

LIMITATIONS:

The assessment of tirzepatide’s psychiatric safety was limited by screening criteria that excluded participants with a lifetime history of suicide attempts, current PHQ-9 scores > 15, and active or unstable major depressive disorder or other severe psychiatric illnesses within the past 2 years.

DISCLOSURES:

The study was funded by Eli Lilly and Company. Some authors reported serving on advisory boards, receiving institutional research grants, receiving royalties for commercial use related to the Columbia-Suicide Severity Rating Scale, volunteering as scientific advisors, reviewing grants, holding trustee and advisory roles at academic institutions, and/or receiving compensation for consulting or medical advisory service. Four authors declared being employees and shareholders of Eli Lilly and Company.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.