Can Glucagon-like peptide-1 (GLP-1) receptor agonists be used as a first-line treatment for depression?

GLP-1 Receptor Agonists for Depression: Not Recommended as First-Line Treatment

GLP-1 receptor agonists should not be used as first-line treatment for depression, as there are established evidence-based treatments with stronger efficacy data including SSRIs, SNRIs, and cognitive behavioral therapy that should be prioritized.

Current Evidence for GLP-1 RAs in Depression

The evidence supporting GLP-1 receptor agonists (GLP-1 RAs) for depression treatment is preliminary and insufficient to recommend them as first-line therapy:

• A recent meta-analysis (2024) including 2,071 participants showed only a small effect size for GLP-1 RAs in reducing depressive symptoms (SMD = -0.12,95% CI [-0.21, -0.03]) 1
• Research suggests potential neuroprotective and antidepressant properties of GLP-1 RAs, but studies show mixed results regarding their ability to prevent incident depression in patients with diabetes 2
• Interestingly, acute and chronic administration of GLP-1 RAs may have divergent effects on mood, with acute administration potentially causing anxiety-like behavior while chronic administration might reduce depression-like behavior 3

First-Line Treatment Recommendations for Depression

According to established guidelines, first-line treatments for depression should include:

• Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed first-line agents 4
• Cognitive behavioral therapy (CBT) shows similar response rates to antidepressants and is recommended as a viable first-line option 5, 4
• The American College of Physicians recommends either CBT or antidepressants as viable choices for initial MDD treatment based on comparable efficacy 5

Clinical Considerations for Depression Treatment

When treating depression, clinicians should:

1. Begin with established first-line treatments (SSRIs, CBT)
2. Allow adequate trial duration (6-8 weeks) before determining efficacy
3. Monitor using standardized measures (e.g., PHQ-9) every 2-4 weeks
4. Continue treatment for at least 4-9 months after achieving remission
5. Consider second-step therapies (switching to another antidepressant, augmentation) if first-line treatment fails 5

Potential Future Role of GLP-1 RAs

While not recommended as first-line therapy, GLP-1 RAs may have potential applications:

• Recent large-scale data from the US Department of Veterans Affairs suggests GLP-1 RA use was associated with reduced risk of substance use and psychotic disorders, seizures, and neurocognitive disorders compared to usual care 6
• They may be particularly beneficial in patients with comorbid type 2 diabetes and depression, though more research is needed 1
• The mechanisms through which GLP-1 RAs might affect mood include neuroprotection, modulation of inflammation, stress response, energy metabolism, and gut-brain crosstalk 7

Common Side Effects of GLP-1 RAs

When considering GLP-1 RAs, be aware of potential adverse effects:

• Gastrointestinal symptoms (nausea, vomiting, diarrhea) are common, particularly during initial treatment 5
• May cause weight loss, which could be problematic in older adults experiencing unexplained weight loss 5
• Increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis, and drug-induced pancreatitis compared to usual care 6

Conclusion

While emerging research on GLP-1 RAs and depression is promising, the current evidence base does not support their use as first-line treatment for depression. Established treatments like SSRIs, SNRIs, and CBT have stronger efficacy data and should be prioritized. GLP-1 RAs may have a future role in specific patient populations, particularly those with comorbid metabolic conditions, but more robust clinical trials are needed before they can be recommended as primary depression treatments.