Specter of Suicidality with Antiobesity Med Looms Despite Disparate Study Findings

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Reports of suicidality and thoughts of self-harm with use of the GLP-1 receptor agonist antiobesity medication semaglutide are consistent with an analysis of World Health Organization (WHO) adverse drug reaction (ADR) data,¹ but the association was not evident in either an analysis of data from clinical trials² or a large population cohort study³ published concurrently in JAMA Internal Medicine.

"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..." report Thomas Wadden, PhD, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, and colleagues.

"This cohort study, including mostly patients with type 2 diabetes, does not show an association between use of GLP-1 receptor agonists and an increased risk of suicide death, self-harm, or incident depression and anxiety-related disorders," conclude Peter Ueda, MD, PhD, Division of Clinical Epidemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden, and colleagues.

Concern with the spontaneous reports to both the US Food and Drug Administration⁴ and the European Medicines Agency⁵ may not be allayed by these 2 studies; however, as an accompanying editorialpoints out that neither evaluated the risk for patients with history of mental illness.⁶

"Neither study clearly answers the question of whether GLP-1 receptor agonists worsen symptoms among patients with preexisting mental health problems such as moderate or severe depression, as these patients were excluded from the trials examined by Wadden et al, (and these) symptoms were not captured by Ueda et al," observe Timothy Anderson, MD, MAS, Division of General Internal Medicine, Department of Medicine, University of Pittsburgh, and Deborah Grady, MD, MPH, Professor Emeritus of Medicine and of Epidemiology and Biostatistics, University of California San Francisco Department of Medicine.

Although the post hoc analysis of clinical trials (pooled data of the STEP 1, 2, 3 and data from the STEP 5 placebo-controlled semaglutide dose finding clinical trials) by Wadden et al had the benefit of granular data from multiple mental health questionnaires, candidates for the trials were excluded if they had a history of major depression during the previous 2 years or other severe psychiatric disorders, including schizophrenia or bipolar disorder.

The active-comparator new-user cohort study conducted by Ueda et al excluded patients for self-harm within 3 months prior to baseline. The exclusion, they indicate, was to avoid outcome misclassifications. "Potential follow-up health care visits after a self-harm event may be registered with self-harm as the diagnosis and could be erroneously regarded as a new event in the analysis," they explained.

A secondary outcome assessed by Ueda et al was a composite of incident depression and anxiety-related disorder—from recorded diagnoses during hospitalizations or clinic visits, or filled prescriptions for antidepressants—but this was also subject to the patient history. "For this analysis, we further excluded patients with previous psychiatric disorders...at any time prior to cohort entry."

The association did emerge in the analysis of WHO ADR reports, for semaglutide but not liraglutide, and with a stronger signal in those with coreported use of antidepressants and benzodiazepines.

"In our sensitivity analyses, the disproportionality remained significant when focusing on coreported antidepressants or benzodiazepaines, suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide," indicate Georgios Schoretsanitis, MD, PhD, The Zucker Hillside Hospital, Behavioral Health Pavilion, and colleagues.

Despite not finding an associated risk, both Wadden et al and Ueda et al consider the possibility that a GLP-1RA pharmacologic action could manifest as suicidality. Wadden et al point out that this class of drugs enters brain regions that regulate energy intake, and "may interact with mood influencing pathways." Ueda et al characterize the suggestion of an underlying mechanism as "plausible."

Schoretsanitis et al offer an alternative hypothesis that very rapid weight loss related to adjustment in eating patterns could have "ultimately exacerbated mental distress in highly vulnerable patients." An editorial accompanying the analysis of WHO data adds that evaluating the role of appetite suppressants is particularly challenging because of the bidirectional relation between obesity and depression.⁷

Each of these investigators advise continued vigilance, particularly in patients with history of mental health problems. "While reassuring, the study could not rule out smaller absolute risk differences for suicide death, and future studies with more outcome evens should be performed as data accumulate," Ueda et al recommend.

"Controlled investigations and continued postmarketing surveillance are needed to assess the safety and effectiveness of semaglutide, 2.4 mg and similar medications in people with obesity and major psychopathology," Wadden et al conclude.

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. Schoretsanitis G, Weiler S, Barbui C, et al. Disproportionality analysis from world health organization data on semaglutide, liraglutide and suicidality. JAMA Netw Open. 2024;7(8):e2423385.

2. Wadden TA, Brown GK, Egebjerg C, et al. 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. JAMA Int Med. 2024:e244346

3. Ueda P, Söderling J, Wintzell V, et al. GLP-1 receptor agonist use and risk of suicide death. JAMA Int Med. 2024:e244369.

4. Update on FDA's ongoing evaluation of reports of suicidal thoughts or actions in patients taking a certain type of medicines approved for type 2 diabetes and obesity. US Food and Drug Administration. March 8, 2024. Accessed September 23, 2024. https://www.fda.gov/drugs/fda-drug-safety-podcasts/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type

5. EMA statement on ongoing review of GLP-1 receptor agonists. European Medicines Agency. July 11, 2023. Accessed September 23, 2024. https://www.ema.europa.eu/en/news/ema-statement-ongoing-review-glp-1-receptor-agonists

6. Anderson TS, Grady D. Glucagon-like peptide-1 receptor agonists and suicidality—two important pieces of data but an incomplete puzzle. JAMA Int Med. 2024. Online ahead of print.

7. Salvo F, Faillie J-L. GLP-1 receptor agonists and suicidality—caution is needed. JAMA Netw Open. 2024;7(8):e2423335.