Introduction

Type 2 diabetes (T2D) is associated with serious complications, including cardiovascular disease, renal disease, ophthalmic disease, neuropathies, infections, and additional conditions.¹ Depression is also common among individuals with T2D, with research indicating a bidirectional relationship, meaning diabetes increases the risk of depression and depression increases the risk of diabetes.²

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Over the years, various classes of medications have been used for the management of T2D, with the latest being the glucagon-like peptide-1 receptor agonists (GLP-1 RAs). These drugs have affected the treatment approach for T2D and also revolutionized obesity treatment by offering significant improvements in weight management.

Beyond their metabolic effects, research suggests that GLP-1 RAs may have other benefits, particularly in the realm of mental health. GLP-1 can originate in and cross the blood-brain barrier into the central nervous system, where GLP-1 receptors are present. As such, GLP-1 and its analogs can directly influence the physiological functions of the brain.³ Given the prevalence of depression and the ongoing search for novel therapeutic options, exploring the neuropsychiatric potential of GLP-1 RAs is of growing interest.

Overview of Studies

To gather information regarding the potential benefits of using GLP-1 RAs in patients with depression, we conducted a search of PubMed. To obtain the highest level of evidence, our search was limited to systematic reviews and meta-analyses published within the past 10 years. Our search included the Medical Subject Headings term for “GLP-1 RAs” and “depression.” Our search yielded 2 relevant records.

Chen et al. conducted a systematic review and meta-analysis to examine the antidepressant effects of GLP-1 RAs.³ The meta-analysis pooled data for 2071 patients from 5 randomized controlled trials and 1 prospective cohort study. In 5 of the studies, GLP-1 RAs were used for the management of T2D, while in 1, a GLP-1 RA was investigated as a potential treatment for Parkinson disease. The meta-analysis indicated that the change from baseline in depression rating scale scores decreased significantly when patients received treatment with GLP-1 RAs compared to control treatments, which included placebo or other drugs for T2D (Standard Mean Difference [SMD] = -0.12, 95% CI [-0.21, -0.03], p_SMD <0.01). Furthermore, a subgroup analysis showed that the effects of GLP-1 RAs on depressive symptoms were consistent in patients with only T2D. The reviewers concluded that GLP-1 RAs may be a potential treatment for alleviating depressive symptoms in humans.³

Similarly, Pozzi et al. conducted a systematic review and meta-analysis of the literature to describe the effect of GLP-1 functional agonists (DPP-4 inhibitors and GLP-1 RAs) on depression rating scales.⁴ The analysis included data from a total of 8 interventional and observational studies. The number of patients included in the analysis was not stated by the reviewers. The reviewers reported that both control treatments (other drugs for T2D or placebo) and GLP-1 functional agonists resulted in a significant reduction of depression rating scores (-0.67, 95% CI -0.99 – -0.36, p < 0.0001 and -1.28, 95% CI -2.34 – -0.21, p = 0.02, respectively). Notably, the test for the difference between the GLP-1 functional agonists and the controls was not statistically significant. In contrast, when the 1 study conducted on non-diabetic patients or the studies that excluded depressed patients were removed from the analysis, the effect of GLP-1 functional agonists was significantly superior to that of control treatments (χ² = 221.5, d.f. = 1, p < 0.00001). The reviewers commented that the results of this analysis must be considered with caution because the number of studies available was low and the heterogeneity was high. Nonetheless, the authors note that if additional trials confirm these findings, GLP-1 functional agonists may be considered as antidepressants, either as adjuncts or as monotherapy.⁴

Clinical Implications

The literature described above suggests that GLP-1 RAs may play a role in the management of depression in patients with T2DM. The effects of other glucose-lowering drugs on depressive symptoms have been previously assessed.³ One meta-analysis found that metformin had no benefit against depressive symptoms compared to control treatments, whereas another meta-analysis reported that pioglitazone exhibited positive effects in improving depressive symptoms compared to control treatments.^5,6 Notably, though, the adverse effects of thiazolidinediones, such as weight gain, pedal edema, fluid retention, and congestive heart failure, may limit the usage of these medications.⁷

Therefore, with a more favorable side effect profile, GLP-1 RAs might be a more attractive approach for managing depression in patients with T2D. However, more robust studies that investigate this are needed before firm conclusions can be drawn. Likewise, data on the comparative efficacy of various GLP-1 RAs with respect to their potential benefits in depression could facilitate the optimal use of these agents. Nonetheless, awareness of the current data pertaining to GLP-1 RAs and depression is useful, and pharmacists should be mindful of these potential benefits during comprehensive drug therapy reviews.

REFERENCES

1. Li Y, Liu Y, Liu S, et al. Diabetic vascular diseases: molecular mechanisms and therapeutic strategies. Signal Transduct Target Ther. 2023;8(1):152. doi:10.1038/s41392-023-01400-z

2. Alzoubi A, Abunaser R, Khassawneh A, Alfaqih M, Khasawneh A, Abdo N. The bidirectional relationship between diabetes and depression: a literature review. Korean J Fam Med. 2018;39(3):137-146. doi:10.4082/kjfm.2018.39.3.137

3. Chen X, Zhao P, Wang W, Guo L, Pan Q. The antidepressant effects of GLP-1 receptor agonists: a systematic review and meta-analysis. Am J Geriatr Psychiatry. 2024;32(1):117-127. doi:10.1016/j.jagp.2023.08.010

4. Pozzi M, Mazhar F, Peeters GGAM, et al. A systematic review of the antidepressant effects of glucagon-like peptide 1 (GLP-1) functional agonists: further link between metabolism and psychopathology: special section on “translational and neuroscience studies in affective disorders.” J Affect Disord. 2019;257:S0165-0327(19)30593-2

5. Kang M, Liu H, Hui J, et al. Metformin use on the risks of depression and anxiety in people with type 2 diabetes. Commun Med (Lond). 2025;5:302. doi:10.1038/s43856-025-01006-2

6. Moulton CD, Hopkins CWP, Ismail K, Stahl D. Repositioning of diabetes treatments for depressive symptoms: a systematic review and meta-analysis of clinical trials. Psychoneuroendocrinology. 2018;91-103. doi:10.1016/j.psyneuen.2018.05.010

7. Eggleton JS, Jialal I. Thiazolidinediones. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.