Wegovy Does Not Directly Treat Depression, But Weight Loss May Improve Depressive Symptoms
Wegovy (semaglutide 2.4mg) is not indicated for depression treatment, but pooled analysis from the STEP trials demonstrated a small but statistically significant reduction in depressive symptoms compared to placebo, with participants less likely to shift to more severe depression categories. 1
Evidence on Depression and Mental Health Outcomes
Primary Findings from Clinical Trials
In the STEP 1,2, and 3 trials involving 3,377 participants, mean PHQ-9 depression scores at week 68 were 2.0 with semaglutide versus 2.4 with placebo, showing an estimated treatment difference of -0.56 (95% CI -0.81 to -0.32, P<0.001), though this was not considered clinically meaningful. 1
Participants treated with semaglutide were 37% less likely to shift from baseline to week 68 into a more severe category of depression (odds ratio 0.63,95% CI 0.50-0.79, P<0.001). 1
Suicidal ideation or behavior occurred in 1% or fewer participants during treatment, with no differences between semaglutide and placebo groups based on Columbia-Suicide Severity Rating Scale assessments. 1
Efficacy in Patients Already Taking Antidepressants
Among 539 participants on antidepressants at baseline across STEP trials, semaglutide produced clinically meaningful weight loss regardless of antidepressant use, with mean body weight change of -15.7% versus -0.2% with placebo in STEP 1. 2
The adverse event profile was generally similar between semaglutide and placebo in participants on antidepressants at baseline, indicating no concerning drug interactions. 2
Participants with severe major depressive disorder within 2 years prior to screening or PHQ-9 scores ≥15 at screening were excluded from STEP trials, limiting generalizability to patients with active severe depression. 2
Quality of Life Improvements Beyond Depression
Psychosocial Benefits
All IWQOL-Lite-CT scores (Physical Function, Physical, Psychosocial, and Total Score) improved significantly more with semaglutide 2.4mg than placebo, suggesting broader mental health benefits related to weight loss. 3
SF-36v2 health-related quality of life scores generally favored semaglutide versus placebo across trials, indicating improvements in overall wellbeing. 3
Control of eating improved significantly across all domains (craving control, craving for savory, craving for sweet, and positive mood) up to week 52, with improvements in craving control and craving for savory remaining significant at week 104. 3
Critical Safety Consideration: Case Report of Psychiatric Adverse Events
A case report documented a man in his late 70s with type 2 diabetes and no psychiatric history who developed restlessness, depressive mood, and attempted suicide approximately one month after starting semaglutide, with symptoms improving after discontinuation. 4
This isolated case highlights the importance of monitoring for new-onset psychiatric symptoms, though large-scale trial data do not support increased risk. 1, 4
Clinical Algorithm for Use in Patients with Depression History
Pre-Treatment Assessment
Screen for personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (absolute contraindication). 5
Document baseline PHQ-9 score to establish depression severity before initiating treatment. 1
Confirm patients with severe major depressive disorder (PHQ-9 ≥15) receive psychiatric stabilization before considering semaglutide for weight management. 2
Review current antidepressant regimen, as semaglutide can be safely used with SSRIs and SNRIs based on trial data. 6, 2
Monitoring During Treatment
Reassess PHQ-9 scores at weeks 4,12, and quarterly thereafter to detect any worsening of depressive symptoms. 1
Monitor for new-onset restlessness, depressive mood changes, or suicidal ideation, particularly in the first 1-2 months after initiation or dose escalation. 4
Ensure patients have established mental health support and know to report psychiatric symptoms immediately. 1
Treatment Decisions
Continue semaglutide if depression scores remain stable or improve, as weight loss itself may provide psychosocial benefits. 1, 3
Discontinue semaglutide immediately if new-onset severe depression, suicidal ideation, or unexplained psychiatric symptoms emerge, and refer for urgent psychiatric evaluation. 4
Important Caveats
The observed reduction in depressive symptoms is likely secondary to weight loss and improved quality of life rather than direct antidepressant effects. 1, 3
Semaglutide should never replace appropriate psychiatric treatment for depression, and patients require ongoing mental health monitoring regardless of weight loss medication use. 1
The bidirectional relationship between obesity and mental health means that addressing obesity may improve depression, but depression can also drive weight gain through altered eating behaviors. 6