Can semaglutide (glucagon-like peptide-1 receptor agonist) cause depressed mood and anhedonia?

Semaglutide and Psychiatric Side Effects: Depression and Anhedonia

Based on emerging case reports and pharmacovigilance data, semaglutide can cause depressed mood and potentially anhedonia, though these psychiatric adverse events are uncommon (occurring in approximately 1.2% of reported cases), with depression being the most frequently reported psychiatric side effect. 1

Evidence for Depression and Mood Disturbances

Case Report Evidence

• Two documented cases demonstrate semaglutide-associated depression developing approximately 1 month after treatment initiation, with symptoms improving or resolving after drug discontinuation. 2
• One case involved a middle-aged man with no prior psychiatric history who developed new-onset depressive symptoms, while another involved a woman with recurrent depressive disorder experiencing symptom recurrence. 2
• A patient in his late 70s with no psychiatric history attempted suicide approximately 1 month after semaglutide initiation, with psychiatric symptoms improving after discontinuation. 3

Pharmacovigilance Data

• Analysis of 31,444 adverse event reports from the EudraVigilance database (2021-2023) identified 372 psychiatric adverse event reports (1.18% of total). 1
• Depression was the most commonly reported psychiatric adverse event (50.3% of psychiatric reports), followed by anxiety (38.7%) and suicidal ideation (19.6%). 1
• Nine deaths and 11 life-threatening outcomes were reported, primarily from completed suicide attempts and depression, occurring predominantly in men. 1

Clinical Context and Nuances

Timing and Presentation

• Psychiatric symptoms typically emerge approximately 1 month after semaglutide initiation or dose escalation, based on available case reports. 2, 3
• The temporal relationship between drug initiation and symptom onset, combined with improvement after discontinuation, suggests a potential causal relationship. 2, 3

Mechanism Considerations

• GLP-1 receptors are present in the central nervous system, including areas involved in mood regulation, which may explain psychiatric effects. 4
• The drug's effects on the autonomic nervous system and vagal nervous activity could contribute to mood disturbances. 4

Mixed Evidence on Mental Health Impact

• Social media analysis revealed contradictory reports: some users experienced marked mood improvement with weight loss, while others reported mood deterioration, increased anxiety, or insomnia. 5
• A randomized controlled trial in patients with major depressive disorder found semaglutide did not worsen depressive symptom severity or increase suicidal ideation frequency, though this was in a monitored clinical trial setting. 6

Clinical Recommendations

Screening and Monitoring

• Screen all patients for personal or family history of depression, anxiety, or suicidal ideation before initiating semaglutide. 1, 3
• Monitor patients regularly for new-onset or worsening depressive symptoms, anxiety, restlessness, and suicidal ideation, particularly during the first 1-2 months of treatment and after dose escalations. 3
• Women may be at higher risk, as they accounted for 65% of psychiatric adverse event reports. 1

Management of Psychiatric Symptoms

• If depressive symptoms, anhedonia, or suicidal ideation develop after semaglutide initiation, strongly consider discontinuing the medication, as symptoms have been documented to improve after discontinuation. 2, 3
• Do not dismiss new psychiatric symptoms as unrelated to the medication, even in patients without prior psychiatric history. 2, 3
• Refer patients with severe psychiatric symptoms or suicidal ideation for immediate psychiatric evaluation. 3

Important Caveats

Establishing Causality

• The reciprocal relationship between metabolic disease, obesity, and depression makes establishing clear cause-and-effect difficult, as weight loss itself can affect mood bidirectionally. 5
• Psychiatric adverse events represent only 1.2% of total adverse event reports, indicating this is an uncommon but potentially serious complication. 1

Contrast with Other Known Side Effects

• While gastrointestinal side effects remain the most common adverse events (nausea, vomiting, diarrhea), the severity and fatal outcomes of psychiatric events warrant heightened vigilance. 7, 1
• Unlike the well-established gastrointestinal effects that typically improve with continued use, psychiatric symptoms may require drug discontinuation. 7, 2