Narrative Review of Five RCTs Finds Inconsistent Benefits for Creatine as MDD Adjunct

Researchers from Ottawa and Toronto screened RCTs testing 2–10 g daily creatine monohydrate for 4–8 weeks. Two linked trials in women receiving 5 g creatine plus escitalopram showed larger Hamilton score drops and higher remission rates versus placebo. Three remaining trials—one in treatment-resistant adults, one in adolescent girls, and one in bipolar disorder—detected no meaningful symptom differences on standard scales. Heterogeneity in dose, duration, and population prevented meta-analysis. The review correctly notes plausible links between impaired cerebral energy metabolism and depressive symptoms yet omits that most included participants were women around age 36, limiting extrapolation. Prior exercise physiology literature shows creatine reliably raises muscle phosphocreatine within weeks, but equivalent brain kinetics remain sparsely mapped in depressed cohorts. Safety data were reassuring except for two mania switches in the bipolar trial. Larger, biomarker-stratified trials are required to test whether baseline mitochondrial function or sex moderates response. No regulatory submission for psychiatric use is underway.