Sys Rev Pharm 2020;11(7):232-239 A multifaceted review journal in the field of pharmacy 232 Systematic Reviews in Pharmacy Vol 11, Issue 7, July-Aug 2020 Metformin as an Antidepressant in Type 2 Diabetes Mellitus Patients Andri Rezano 1,2,3 , Afifa Khairinnisa 4, Savira Ekawardhani 2,3,5* 1 Department of Biomedical Sciences, Division of Cell Biology, Faculty of Medicine Universitas Padjadjaran 2 Biomedical Sciences Master Program, Faculty of Medicine Universitas Padjadjaran 3 Oncology and Stem Cell Working Group, Faculty of Medicine, Universitas Padjadjaran 4 Graduate Program of Anti-aging dan Aesthetic Medicine, Faculty of Medicine, Universitas Padjadjaran 5 Department of Biomedical Sciences, Division of Parasitology, Faculty of Medicine, Universitas Padjadjaran *Correspondence author E-mail: savira@unpad.ac.id ABSTRACT Depression and diabetes are diseases that share similar mechanisms with the aging process, specifically inflammation and oxidative stress. Metformin is an approved drug to treat diabetes but appears to several aging-related mechanisms. It currently targets multiple pathways of aging that involves the AMPK pathway, mTOR pathway, and IGF-1 signaling pathway. Thus, for its aging-related mechanism, glucose metabolism may not be the most important one. This study reviews 12 types of research related to the use of metformin to treat depression. This study used online research engines such as PubMed and Google Scholar to review the current finding of metformin and depression- related issues. We found that metformin targets age-related diseases, such as neurocognitive functions other than to regulate blood glucose levels through multiple biological pathways. And the final result of how metformin can be deployed against the aging process might help other researchers and clinicians to determine how to best use this drug. Keywords: Aging-related mechanisms, AMPK, Depression, Diabetes, IGF-1 signaling Correspondence: Savira Ekawardhani 5 Department of Biomedical Sciences, Division of Parasitology, Faculty of Medicine, Universitas Padjadjaran *Correspondence author E-mail: savira@unpad.ac.id INTRODUCTION Depression is classified as a psychiatric disorder, with 17% of sufferers experiencing a lifetime onset; but this disease can also cause physical changes and it may indirectly influence metabolic syndrome and also be a cause of diabetes. [1,2,3,4] The symptoms of depression are a depressed mood, loss of interest in normal activities, and intrusive or suicidal thoughts. [5,6] Several brain regions and circuits regulate emotion, reward, and executive function; but people with depression may exhibit dysfunctional changes in these regions and circuits which manifest as cognitive dysfunction. [7] A frequently replicated finding in depression is the alteration of brain metabolism in the prefrontal cortex, especially in the dorsolateral and dorsoventral brain regions. [7,8] Depression and dementia are related to the condition of mild cognitive impairment (MCI) which is also associated with neuropsychiatric symptoms. [9] Later on, MCI will influence the development of neurodegenerative disorders such as Alzheimer’s disease (AD). [10,11] Current research has identified similarities in the cognitive alteration that occurs in both typical aging processes and MCI. [10,11,12] Depression, AD, and MCI are common conditions within aging populations. [13] Another highly prevalent disease related to aging is Type 2 Diabetes mellitus (T2DM), which affects around 9% of the worldwide population. [14,15] Due to a high occurrence of both neuropsychiatric diseases and T2DM in elderly populations, the discovery of effective solutions and preventive treatments—such as the use of repurposing drugs—is critical. [14,16] Inflammatory pathway and oxidative stress modulation are the basic mechanisms underlying the relation between diabetes and neuropsychiatric disease. Additional factors include increased cerebral amyloid-β peptides, hyperinsulinemia (in the tissues, including those of the brain which can cause brain insulin resistance), vascular risk factors, and the formation of advanced glycation end-products. [17] The most influential factor of diabetes progression is increased blood glucose levels, that exist as a direct result of diabetes; this condition negatively affects the alternation of episodic memory in vivo studies and even within people who have not been diagnosed with diabetes. [18,19] Metformin is a biguanide compound and a common generic drug that counters the hyperglycemic effect produced by T2DM. It functions as an insulin sensitizer that reduces blood glucose by modifying the AMP- activated protein kinase (AMPK) pathway and down- regulating the IGF-1 signaling pathway. [20] Metformin treatment during pregnancy was uncommon due to its safety and, its ability to cross the placenta whereas there are no side effects of taking metformin for lactating mothers. [21,22] Metformin’s mechanism of action is to elevate the uptake of glucose into muscle cells while also decreasing glucose production, or gluconeogenesis, in the liver by activating the AMPK pathway. [23] Metformin’s effect on inflammation works independently from a patient’s diabetes status. [24] Because of this independent mode of action, previous researchers hypothesized that metformin could be adopted as an anti-inflammatory drug, particularly for uses targeting neurodegenerative diseases, especially in the involvement of neurodegenerative diseases. Metformin works by activating the AMPK pathway, similarly to processes that result from a caloric restriction diet. [25,26] In vivo study of caloric restriction and metformin showed that both treatments can slow the aging process. [27,28] Improved memory is one positive result of caloric restriction within a geriatric population; [29] this indicates that metformin can also work, to prevent or delay the development of