Can Wegovy (semaglutide) increase depressive symptoms in patients, particularly those with a pre-existing history of depression or anxiety disorders?

Can Wegovy Increase Depressive Symptoms?

The current evidence suggests Wegovy (semaglutide) may potentially increase depressive symptoms in some patients, though the overall risk appears low and conflicting data exists—close monitoring for psychiatric symptoms is essential, particularly during the first 1-2 months of treatment, especially in patients with pre-existing depression or anxiety disorders.

Evidence for Psychiatric Adverse Events

The pharmacovigilance data reveals concerning signals that warrant clinical attention:

• Depression was the most commonly reported psychiatric adverse event (50.3%) among GLP-1 receptor agonist users in the EudraVigilance database, followed by anxiety (38.7%) and suicidal ideation (19.6%) 1
• Psychiatric adverse events comprised only 1.2% of total reports for semaglutide, liraglutide, and tirzepatide, but the severity included 9 deaths (primarily from completed suicide) and 11 life-threatening outcomes 1
• Two case reports documented new-onset or recurrent depression occurring approximately 1 month after starting semaglutide, with symptoms improving after discontinuation 2
• One case report described a patient in his late 70s with no psychiatric history who developed restlessness, depressive mood, and attempted suicide one month after semaglutide initiation, with symptoms improving after discontinuation 3

Contradictory Evidence Suggesting Protective Effects

Importantly, large-scale population data presents an opposing perspective:

• A nationwide cohort study of 10,690 GLP-1 RA users showed a 20% reduction in combined anxiety/depression risk (adjusted HR 0.8,95% CI: 0.67-0.95) compared to non-users 4
• The protective effect was more pronounced for anxiety (2.13 per 1,000 person-years reduction) than depression (0.41 per 1,000 person-years reduction) 4
• Patients taking GLP-1 RA for longer than 180 days had anxiety incidence reduced to 2.93 per 1,000 person-years (adjusted HR 0.41,95% CI: 0.27-0.61) 4
• Preclinical research demonstrated that liraglutide (another GLP-1 agonist) attenuated depressive and anxiety-like behaviors in a corticosterone-induced depression mouse model, protected synaptic plasticity, and increased hippocampal neurogenesis 5

Clinical Monitoring Algorithm

Given the conflicting evidence, implement this structured monitoring approach:

Initial Assessment (Before Starting Wegovy):

• Screen for current depression using standardized tools (PHQ-9 score)
• Document history of depression, anxiety disorders, or suicidal ideation
• Assess current psychiatric medications and stability of mental health conditions

Early Treatment Phase (Weeks 1-8):

• Monitor closely for treatment-emergent psychiatric symptoms at weeks 2,4, and 8, particularly watching for new-onset depressive mood, anxiety, restlessness, or suicidal ideation 3, 1
• This mirrors the monitoring recommendations for SSRIs, which also carry risks of treatment-emergent psychiatric symptoms 6

High-Risk Populations Requiring Enhanced Monitoring:

• Patients with pre-existing depression or recurrent depressive disorder 2
• Older adults (case reports suggest vulnerability in patients over 70) 3
• Patients with no apparent psychiatric history (as new-onset cases have been documented) 2, 3

Management of Emerging Symptoms

If depressive symptoms emerge during treatment:

• Consider discontinuation of semaglutide, as case reports demonstrate symptom improvement after stopping the medication 2, 3
• Evaluate whether symptoms began approximately 1 month after initiation, as this timing pattern has been observed in multiple cases 2, 3
• Do not assume symptoms are unrelated to medication simply because psychiatric adverse events represent only 1.2% of total reports—the severity of outcomes (including completed suicides) justifies caution 1

Critical Caveats

The evidence presents a paradox: large population studies suggest protective effects while case reports and pharmacovigilance data document serious psychiatric adverse events. This discrepancy may reflect:

• Individual susceptibility factors not captured in population-level analyses
• Reporting bias in pharmacovigilance databases (serious events more likely to be reported)
• Potential confounding by indication (patients with metabolic disorders may have baseline elevated psychiatric risk)

The fatal outcomes reported (8 of 9 deaths occurring in men from completed suicide) underscore that even if rare, the consequences can be catastrophic 1. Therefore, err on the side of caution with proactive monitoring rather than dismissing concerns based solely on low overall incidence rates.