Key takeaways
- The FDA's review, completed in January 2024, and the European Medicines Agency's review, completed in April 2024, both found no evidence that GLP-1 receptor agonists cause suicidal thoughts or actions.
- Pooled analyses of the STEP trials found no increase in depressive symptoms or suicidal ideation with semaglutide versus placebo, and a large US cohort study found lower rates of suicidal ideation with semaglutide than with other anti-obesity or diabetes drugs.
- A pharmacovigilance disproportionality analysis found a reporting signal for semaglutide, which is a reason for continued monitoring, not evidence of causation.
- Wegovy's and Zepbound's labels advise monitoring for depression or suicidal thoughts and stopping the drug if they emerge, reflecting the older anti-obesity drug experience and a precautionary stance.
- Patients do report mood effects in both directions, including flattened enjoyment and anxiety during rapid weight loss; any new or worsening mood symptoms should be raised with a clinician promptly.
Why the question arose
In 2023 the Icelandic medicines regulator reported cases of suicidal thoughts and self-harm in patients taking semaglutide and liraglutide, and the European Medicines Agency opened a review. Adverse-event reports in the FDA's system rose with the drugs' explosive growth. Older anti-obesity drugs had real psychiatric problems: rimonabant was withdrawn in 2008 for depression and suicidality, and the labels of most anti-obesity medications approved since then carry monitoring language for that reason. The question of whether GLP-1 agonists shared the problem was legitimate, and the answer that emerged over the following eighteen months was reassuring.
The regulatory reviews
The FDA published its preliminary evaluation in January 2024. It had reviewed the adverse-event reports, the clinical trial data submitted for approval, and the results of a large observational study, and stated that its evaluation "did not find evidence that use of these medicines causes suicidal thoughts or actions." It noted that the reports were often confounded and could not be clearly attributed, and that because of the small number of events it could not definitively rule out a small risk, so it would continue to monitor and would review post-marketing data and meta-analyses. The EMA's Pharmacovigilance Risk Assessment Committee concluded its review in April 2024, finding that the available evidence did not support a causal association between GLP-1 receptor agonists and suicidal or self-injurious thoughts and actions, and did not require a label change.
The trial data
Wadden and colleagues published a post hoc analysis of the STEP 1, 2, 3 and 5 trials in JAMA Internal Medicine in 2024, covering about 3,700 participants without known major psychopathology at baseline. Semaglutide did not increase depressive symptoms on the Patient Health Questionnaire-9 compared with placebo (scores fell slightly in both groups, marginally more with semaglutide), and suicidal ideation on the Columbia scale was rare and similar between groups (about 1% in each). Shifts to more severe depression categories were uncommon and not more frequent with semaglutide. The tirzepatide trials used similar instruments and reported similarly low, balanced rates. The caveat, which the authors stated, is that the trials excluded people with recent major psychiatric illness or suicidal behaviour, so they say little about that group.
The cohort studies
Wang and colleagues, in Nature Medicine in January 2024, used electronic health records of about 240,000 patients and found that semaglutide was associated with a lower risk of first-time suicidal ideation than other anti-obesity medications (hazard ratio about 0.27) and, in patients with diabetes, lower than other glucose-lowering drugs (about 0.36), with lower recurrence in people with prior ideation. A Scandinavian registry study by Ueda and colleagues in JAMA Internal Medicine in 2024 compared GLP-1 agonists with SGLT2 inhibitors in about 300,000 people and found no increase in suicide death, self-harm or incident depression or anxiety. Observational studies cannot prove absence of harm, but they are the right design for detecting a rare effect that trials are too small to see, and they did not detect one.
The signal that keeps monitoring open
Schoretsanitis and colleagues analysed the World Health Organization's global adverse-event database in JAMA Network Open in 2024 and found a disproportionate number of suicidal-ideation reports for semaglutide compared with other drugs, particularly among patients also taking antidepressants. Disproportionality analyses measure reporting, not incidence; they are influenced by publicity, by the population using the drug, and by the drugs it is co-prescribed with. The signal is a reason to keep looking and to be attentive in patients with psychiatric comorbidity. It is not evidence that the drug causes the outcome, and the authors said as much.
Why the labels still say what they say
Wegovy's and Zepbound's labels include, under warnings and precautions, that suicidal behaviour and ideation have been reported with other weight-management products, that patients should be monitored for depression or suicidal thoughts or behaviour, and that the drug should be discontinued if they emerge. That language reflects the class history and regulatory caution rather than a finding specific to these drugs; the FDA left it in place after its 2024 review. It is sensible advice regardless of causation, because a large weight-loss journey is itself a period of psychological change.
What patients actually report
The trials measure depression and suicidality with scales. Patients describe something broader. Some report improved mood, energy and self-esteem as weight falls and food preoccupation lifts. Some describe a flattening: less pleasure in food, drink and sometimes other rewards, consistent with the drugs' action on reward circuits, which the alcohol article discusses. Some report anxiety, irritability or low mood during the escalation weeks, when nausea, poor sleep, low intake and rapid change coincide. Some find that food had been managing an emotional load that is now unmanaged. None of these is captured well by a trial's depression scale, all are worth taking seriously, and the appropriate response is a conversation with a clinician, a dose hold, and psychological support where it is needed, not silence.
Who should be more careful
People with a current or recent major depressive episode, bipolar disorder, an eating disorder, a history of suicidal behaviour, or active substance use were excluded from or under-represented in the trials, and the evidence in those groups is thinner. That is not a contraindication; many people with treated psychiatric conditions take these drugs without difficulty and some benefit. It is a reason for the prescriber to know the history, for the psychiatric clinician to know about the prescription, and for both to agree on how mood will be monitored, particularly in the first months. Telehealth intakes that do not ask about psychiatric history are doing a worse job than those that do; a patient with a relevant history should volunteer it.
Practical guidance
Tell the prescriber about any psychiatric history and medications at intake. Expect mood to move during rapid weight loss and treat changes as information. Keep sleep, protein and calories adequate, because the escalation weeks are hard on all three and each affects mood. If low mood, hopelessness, anxiety that does not settle, or any thought of self-harm appears, contact a clinician the same day and do not wait for the next scheduled visit; the labels say to stop the drug if such symptoms emerge, and that decision should be made with a clinician. In the United States, the 988 Suicide and Crisis Lifeline is available by call or text at any hour for anyone in distress, whether or not medication is involved.
This article addresses a sensitive subject in an informational context. If any of it touches on something you are experiencing yourself, the right first step is a conversation with a clinician or a trusted person, and resources exist to help find one.
Frequently asked questions
Do GLP-1 drugs cause suicidal thoughts?
The FDA (January 2024) and the European Medicines Agency (April 2024) each reviewed the reports and trial data and found no evidence of a causal link. Pooled trial data and a large cohort study found no increase, and in the cohort study a lower rate, with semaglutide. Monitoring continues because a reporting signal exists in pharmacovigilance data.
Can tirzepatide or semaglutide cause depression?
Trial data do not show increased depressive symptoms versus placebo. Some patients report low mood, flattened enjoyment or anxiety, particularly during rapid weight loss, and both labels advise monitoring. Any new or worsening mood symptoms should be reported to a clinician.
Should I take a GLP-1 if I have a history of depression?
The trials excluded people with recent major psychiatric illness, so evidence in that group is thinner. Many patients with treated depression take these drugs without difficulty. Discuss it with the prescriber, ensure the psychiatric clinician knows, and agree on how mood will be monitored.
Sources
- FDA. 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. January 11, 2024.
- European Medicines Agency, PRAC. Meeting highlights, April 2024: GLP-1 receptor agonists and suicidal thoughts.
- Wang W, Volkow ND, Berger NA, et al. Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nat Med 2024;30:168-176.
- 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 Intern Med 2024;184:1290-1300.
- 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:e2423385.
- Wegovy (semaglutide) prescribing information, Novo Nordisk, 2025; Zepbound (tirzepatide) prescribing information, Eli Lilly, 2025 (warnings and precautions).
- Ueda P et al. GLP-1 receptor agonist use and risk of suicide death. JAMA Intern Med 2024;184:1301-1312.
Citations are to primary sources (peer-reviewed trials, FDA labeling and announcements, and provider pricing pages). See our sources policy and corrections log.