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Clinical Trial
. 2024 Nov 1;184(11):1290-1300.
doi: 10.1001/jamainternmed.2024.4346.

Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology: Post Hoc Analysis of the STEP 1, 2, 3, and 5 Trials

Thomas A Wadden  1 , Gregory K Brown  1 , Christina Egebjerg  2 , Ofir Frenkel  2 , Bryan Goldman  3 , Robert F Kushner  4 , Barbara McGowan  5 , Maria Overvad  2 , Anders Fink-Jensen  6
Affiliations
Clinical Trial

Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology: Post Hoc Analysis of the STEP 1, 2, 3, and 5 Trials

Thomas A Wadden et al. JAMA Intern Med. .

Abstract

Importance: Obesity is associated with numerous psychosocial complications, making psychiatric safety a consideration for treating people with obesity. Few studies have investigated the psychiatric safety of newly available antiobesity medications.

Objective: To evaluate the psychiatric safety of subcutaneous semaglutide, 2.4 mg, once weekly in people without known major psychopathology.

Design, setting, and participants: This post hoc analysis of pooled data from the randomized, double-blind, placebo-controlled, multicenter phase 3a STEP 1, 2, and 3 trials (68 weeks; 2018-2020) and phase 3b STEP 5 trial (104 weeks; 2018-2021) included adults with overweight or obesity; STEP 2 participants also had type 2 diabetes. Trial designs have been published previously.

Interventions: Semaglutide, 2.4 mg, vs placebo.

Main outcomes and measures: Depressive symptoms and suicidal ideation/behavior were assessed using the Patient Health Questionnaire (PHQ-9) and Columbia-Suicide Severity Rating Scale, respectively. Psychiatric and nervous system disorder adverse events were investigated.

Results: This analysis included 3377 participants in the STEP 1, 2, and 3 trials (2360 women [69.6%]; mean [SD] age, 49 [13] years) and 304 participants in STEP 5 (236 women [77.6%]; mean [SD] age, 47 [11] years). In the STEP 1, 2, and 3 trials, mean (SD) baseline PHQ-9 scores for the semaglutide, 2.4 mg, and placebo groups were 2.0 (2.3) and 1.8 (2.3), respectively, indicating no/minimal symptoms of depression. PHQ-9 scores at week 68 were 2.0 (2.9) and 2.4 (3.3), respectively; the estimated treatment difference (95% CI) between groups was -0.56 (-0.81 to -0.32) (P < .001). Participants treated with semaglutide vs placebo were less likely to shift (from baseline to week 68) to a more severe category of PHQ-9 depression (odds ratio, 0.63; 95% CI, 0.50-0.79; P < .001). Based on the Columbia-Suicide Severity Rating Scale, 1% or fewer of participants reported suicidal ideation/behavior during treatment, with no differences between semaglutide, 2.4 mg, and placebo. Psychiatric disorder adverse events were generally balanced between groups. Similar results were observed in STEP 5.

Conclusions and relevance: The results of this post hoc analysis suggest that treatment with semaglutide, 2.4 mg, did not increase the risk of developing symptoms of depression or suicidal ideation/behavior vs placebo and was associated with a small but statistically significant reduction in depressive symptoms (not considered clinically meaningful). People with obesity should be monitored for mental health concerns so they can receive appropriate support and care.

Trial registration: ClinicalTrials.gov Identifiers: STEP 1 (NCT03548935), 2 (NCT03552757), 3 (NCT03611582), and 5 (NCT03693430).

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Wadden reported grants from Novo Nordisk during the conduct of the study and personal fees from Novo Nordisk, advisory board service for WeightWatchers and Eli Lilly, and grant support from Eli Lilly outside the submitted work. Dr Egebjerg reports employment with and being a shareholder in Novo Nordisk. Dr Brown reported personal fees from the Research Foundation for Mental Hygiene Inc and Oui Therapeutics Inc outside the submitted work. Dr Frenkel reported personal fees from Novo Nordisk during the conduct of the study and personal fees from and being a shareholder in Novo Nordisk outside the submitted work. Dr Goldman reported employment with and being a shareholder of Novo Nordisk during the conduct of the study. Dr Kushner reported personal fees from Novo Nordisk outside the submitted work. Dr McGowan reported personal fees from Novo Nordisk, Eli Lilly, and Astra Zeneca, grants from Novo Nordisk, and being a shareholder in Reset Health outside the submitted work. Dr Overvad reported employment with Novo Nordisk. Dr Fink-Jensen reported grants from Novo Nordisk A/S outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Patient Health Questionnaire 9 (PHQ-9) Scores Over Time During the STEP 1, 2, 3, and 5 Trials
Data are mean PHQ-9 scores over time from baseline to week 68 for STEP 1, 2, and 3 (A) and to week 104 for STEP 5 (B). Error bars represent the SD of the mean. Data are for the in-trial period for all participants in the safety analysis set.
See this image and copyright information in PMC

Comment on

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