Creatine as a Neuroenergetic and Molecular Target in Depression: A Narrative Review of Mechanistic and Clinical Evidence

Major depressive disorder (MDD) is a leading cause of disability worldwide, and one-third to two-thirds of patients do not reach remission after successive monoaminergic treatments. Impaired brain bioenergetics, including mitochondrial dysfunction and altered brain high-energy phosphate levels, has been proposed to contribute to the anergic, cognitive, and fatigue-related symptoms of MDD. Through the creatine kinase-phosphocreatine (CK-PCr) system, creatine buffers ATP in time and space and supports the fluctuating energy demands of synaptic transmission and plasticity. In this narrative review, we summarize creatine metabolism and critically appraise the preclinical evidence implicating monoaminergic, purinergic, NMDA receptor and nitric oxide, PI3K/Akt/mTORC1, GSK-3β/Nrf2, and BDNF signaling, redox and neuroinflammatory control, and hippocampal neurogenesis in the antidepressant-like effects of creatine. We then review the human evidence, including phosphorus-31 magnetic resonance spectroscopy (31P-MRS) studies of brain high-energy phosphates and randomized trials of adjunctive creatine, and we discuss why the clinical findings remain inconsistent. Human evidence suggests that oral creatine could reach the brain and increase total creatine, yet clinical efficacy has not been established, and existing trials were not designed to test the bioenergetic mechanism. We therefore propose trials that select the dose by 31P-MRS target engagement and stratify patients by bioenergetic markers.