Glucagon-like peptide 1 (GLP-1) receptor agonists as a protective factor for incident depression in patients with diabetes mellitus: A systematic review.

Glucagon-like peptide 1 (GLP-1) receptor agonists are widely used for glycemic control in patients with diabetes mellitus (DM) and are primarily indicated for type 2 diabetes mellitus (T2DM). GLP-1 receptor agonists have also been shown to have neuroprotective and antidepressant properties. Replicated evidence suggests that individuals with DM are significantly more likely to develop depression. Herein, we aim to investigate whether GLP-1 receptor agonists can be used prophylactically on patients with DM to lower the risk of incident depression. We conducted a systematic search for English-language articles published on the PubMed/MEDLINE, Scopus, Embase, APA, PsycInfo, Ovid and Google Scholar databases from inception to June 6, 2022. Four retrospective observational studies were identified that evaluated the neuroprotective effects of GLP-1 receptor agonists on incident depression in patients with DM. We found mixed results with regards to lowering the risk of incident depression, with two studies demonstrating a significant reduction in risk and two studies showing no such effect. A single study found that dulaglutide may lower susceptibility to depression. Our results were limited by high interstudy heterogeneity, paucity of literature, and lack of controlled trials. While we did not find evidence of GLP-1 receptor agonists significantly lowering risk of incident depression in patients with DM, promising neuroprotective data presented in two of the included papers, specifically on dulaglutide where information is scarce, provide the impetus for further investigation. Future research should focus on better elucidating the neuroprotective potential of different classes and doses of GLP-1 receptor agonists using controlled trials.
Competing Interests: Declaration of competing interest R.S.M has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC); speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, Atai Life Sciences. R.S.M is a CEO of Braxia Scientific Corp. T.G.R was supported in part by the National Institute on Aging (NIA) through Yale School of Medicine (#T32AG019134) in the past 3 years. T.G.R has also been funded by the NIA (#R21AG070666), National Institute of Mental Health (#R21MH117438) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut. T.G.R serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. T.G.R has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. TGR is currently a co-editor-in-chief of Mental Health Science and has received honorarium payments from the publisher, John Wiley & Sons, Inc. R.H has received research grant support from NUS iHeathtech Other Operating Expenses (R-722-000-004-731). L.M.W.L has received personal fees from Braxia Scientific Corp and honoraria from Medscape. All other authors have no conflicts of interest to declare. K.M.T has received personal fees from Braxia Scientific Corp.
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