Can Glucagon-like peptide-1 (GLP-1) analogs, such as liraglutide (Victoza) or semaglutide (Ozempic), be used as a first-line treatment for depression?

GLP-1 Receptor Agonists for Depression Treatment

GLP-1 receptor agonists should not be used as first-line treatment for depression, as there is insufficient evidence supporting their efficacy for this indication compared to established antidepressant therapies. 1

Current Evidence on GLP-1 RAs and Depression

The relationship between GLP-1 receptor agonists (GLP-1 RAs) and depression has been explored in recent research, but findings remain preliminary and mixed:

• A 2023 systematic review found inconsistent results regarding GLP-1 RAs' ability to prevent depression in patients with diabetes, with only two of four studies showing significant risk reduction 2

• A 2024 meta-analysis showed modest improvements in depression rating scales in patients taking GLP-1 RAs compared to controls (SMD = -0.12,95% CI [-0.21, -0.03]), primarily in patients with type 2 diabetes 3

• Recent research suggests GLP-1 RAs may have beneficial effects on mental health in patients with and without mental disorders, but studies specifically targeting depression as a primary outcome are limited 4

First-Line Treatment for Depression

According to established guidelines, first-line pharmacological treatment for depression should be:

1. For mild depression: Antidepressants are not recommended as initial treatment 1

2. For moderate to severe depression: Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine or tricyclic antidepressants (TCAs) are recommended 1

3. Evidence-based psychotherapies such as cognitive behavioral therapy (CBT), interpersonal therapy, and problem-solving treatment should be considered, particularly for mild to moderate depression 1

Potential Considerations for GLP-1 RAs in Special Populations

While not first-line for depression, GLP-1 RAs might warrant consideration in specific clinical scenarios:

• Patients with comorbid obesity and depression: GLP-1 RAs have established efficacy for weight management 5, 6, which could theoretically benefit some depressed patients, though this is not an approved indication

• Patients with comorbid type 2 diabetes and depression: The modest antidepressant effects observed in diabetic populations might be relevant, but should not replace standard depression care 3

Important Caveats and Limitations

• Antidepressant use may diminish the weight loss effects of GLP-1 RAs, with one study showing patients on citalopram/escitalopram or bupropion experiencing less weight loss when taking GLP-1 RAs compared to those not on antidepressants 7

• GLP-1 RAs have significant gastrointestinal side effects that may affect adherence, with real-world discontinuation rates of 20-50% within the first year 6

• The American College of Physicians guidelines emphasize that for depression treatment, the choice between cognitive behavioral therapy and antidepressants should be made after discussing advantages and disadvantages with patients, including potential adverse effects and patient preferences 1

• The cost-effectiveness of GLP-1 RAs is a concern, with these medications considered low value as first-line therapy for their approved indications (diabetes), and would likely be even less cost-effective for depression 1

Conclusion

While emerging research suggests potential benefits of GLP-1 RAs on mood and depressive symptoms, particularly in patients with diabetes or obesity, the current evidence is insufficient to recommend them as first-line treatment for depression. Established treatments including SSRIs, TCAs, and evidence-based psychotherapies remain the standard of care for depression management.