Creatine Supplementation in Depression: A Review of Mechanisms, Efficacy, Clinical Outcomes, and Future Directions.

Depression, affecting millions of people worldwide, is a leading cause of disability globally. It affects not only daily functioning but also interpersonal relationships and overall health by increasing the risks of chronic physical and mental illnesses. Creatine, traditionally recognized for boosting physical performance through its role in producing adenosine triphosphate, has recently shown potential as an adjunctive therapy for treating depression. Creatine's ability to enhance brain energy metabolisms and provide neuroprotection suggests that it can alleviate mood disorders by improving mitochondrial function, increasing cellular resilience, and modulating neurotransmitter systems that regulate mood. This narrative review aims to critically evaluate the research on creatine supplementation for depression, focusing on its efficacy, mechanism of action, risks, and benefits as a treatment for mood disorders. It analyzes preclinical and clinical studies to understand creatine's potential as an adjunctive or alternative therapy for major depressive disorder and bipolar depression and underscores any gaps in current research. Both animal models and human trials indicate creatine's efficacy for the treatment of depression. Creatine supplementation reduces depressive symptoms, particularly when combined with selective serotonin reuptake inhibitors, and may improve brain energy metabolism and neuroplasticity. It is generally well tolerated, though caution is warranted due to potential side effects such as manic episodes in bipolar disorder and renal function impairment in patients with kidney dysfunction. Overall, creatine presents a promising addition to current depression treatments, though further research is needed to establish optimal dosing, long-term efficacy, and safety across diverse patient populations.