Does semaglutide (Ozempic) increase the risk of suicidal ideation or behavior in patients without a prior psychiatric disorder?

Does Ozempic Increase Suicidal Risk?

Based on the highest-quality evidence available, semaglutide (Ozempic) does not increase suicidal risk and may actually be associated with a modest reduction in depressive symptoms compared to placebo. 1

Evidence from Controlled Clinical Trials

The most robust data comes from a 2024 post hoc analysis of the STEP 1,2,3, and 5 trials involving 3,681 participants without known major psychopathology. 1 This analysis demonstrated:

• Semaglutide was associated with statistically significant reduction in depressive symptoms compared to placebo, with an estimated treatment difference of -0.56 points on the PHQ-9 scale (95% CI: -0.81 to -0.32, P < .001). 1
• Participants treated with semaglutide were 37% less likely to shift to a more severe category of depression from baseline to week 68 (odds ratio 0.63,95% CI: 0.50-0.79, P < .001). 1
• Suicidal ideation or behavior occurred in 1% or fewer of participants across both semaglutide and placebo groups, with no statistical difference between groups. 1
• Psychiatric disorder adverse events were generally balanced between semaglutide and placebo groups. 1

Real-World Evidence Supports Safety

A 2024 retrospective cohort study of 240,618 patients with overweight or obesity from the TriNetX Analytics Network found that semaglutide was associated with lower risk of both incident and recurrent suicidal ideation compared to non-GLP1R agonist medications. 2

• Incident suicidal ideation was 73% less likely with semaglutide (HR = 0.27,95% CI: 0.20-0.36). 2
• Recurrent suicidal ideation was 56% less likely with semaglutide (HR = 0.44,95% CI: 0.32-0.60). 2
• These findings were consistent across sex, age, and ethnicity stratification, and were replicated in 1,589,855 patients with type 2 diabetes. 2

Isolated Case Reports Do Not Establish Causation

While individual case reports have described depressive symptoms or suicidal behavior temporally associated with semaglutide use 3, 4, 5, these isolated reports cannot establish causation and must be weighed against the large-scale controlled trial and real-world data showing no increased risk or even protective effects. 1, 2

• One case report described a patient in his late 70s who developed depressive symptoms and attempted suicide approximately one month after starting semaglutide, with improvement after discontinuation. 3
• Another report described two cases of semaglutide-associated depression that improved after drug discontinuation. 5
• A third case involved a 67-year-old man who self-injected a four-fold overdose of semaglutide in what may have been suicidal behavior. 4

However, these case reports represent anecdotal observations that cannot control for confounding factors such as underlying psychiatric conditions, concurrent life stressors, or the psychological impact of chronic disease. 1, 2

Regulatory Context and Monitoring Requirements

Despite the reassuring trial data, regulatory agencies have investigated concerns about GLP-1 receptor agonists and suicidal ideation. 2 Current FDA labeling for semaglutide lists "suicidal ideation and behavior" as a safety concern requiring monitoring, though causality remains unestablished. 6

• Naltrexone/bupropion ER carries a black-box warning for suicidal behavior/ideation in people younger than 24 years with depression, providing context for how regulatory agencies approach psychiatric risks with weight-loss medications. 6
• Liraglutide and semaglutide list "suicidal ideation and behavior" as safety concerns requiring monitoring, though this appears to be precautionary rather than evidence-based. 6

Clinical Recommendations

For patients without pre-existing major psychiatric disorders, semaglutide can be prescribed without specific concern for increased suicidal risk. 1, 2 However, prudent clinical practice includes:

• Screen all patients with obesity for mental health concerns at baseline and during treatment, as obesity itself is associated with numerous psychosocial complications. 1
• Monitor for depressive symptoms and suicidal ideation during treatment, particularly in the first few months after initiation or dose escalation. 3
• Maintain a lower threshold for psychiatric evaluation if mood changes or behavioral changes emerge during treatment. 3, 5
• Consider discontinuation and psychiatric referral if significant depressive symptoms or suicidal ideation develop, even though causation is uncertain. 3, 5

Common Pitfalls to Avoid

• Do not withhold semaglutide from appropriate candidates based solely on theoretical psychiatric concerns when the evidence shows no increased risk and possible benefit. 1, 2
• Do not dismiss patient-reported mood changes as unrelated to medication, even though large trials show no signal—individual variation exists and warrants clinical attention. 3, 5
• Do not assume that case reports establish causation—temporal association does not prove causality, and the background rate of depression and suicidal ideation in patients with obesity and diabetes is substantial. 1, 2