Systematic Review of Five RCTs Shows Mixed Creatine Augmentation Effects in Depression

Researchers at the University of Ottawa screened published literature and identified five double-blind placebo-controlled trials conducted across South Korea, the United States, Brazil, Israel, and India. Doses ranged from 5 to 10 g daily for 6–8 weeks; 126 participants received creatine and 112 received placebo. Because of heterogeneity in populations, dosing, and outcome measures, no meta-analysis was performed and each trial was evaluated separately. Two trials enrolling women with major depressive disorder reported clinically meaningful gains: one pairing 5 g creatine with escitalopram yielded a Cohen’s d of 1.13 on the Hamilton Depression Rating Scale and higher remission rates; another adding creatine to cognitive behavioral therapy showed similar augmentation. The remaining three trials, including one in treatment-resistant depression, one in adolescent girls, and one in bipolar depression, found no separation from placebo. Creatine supports brain phosphocreatine stores that buffer ATP during high neuronal demand. Prior spectroscopy studies have documented reduced creatine levels in prefrontal cortex of depressed patients, providing a mechanistic rationale. However, the review underscores that current evidence is limited by small samples, short durations, and inconsistent diagnostic groups. Two cases of hypomania in bipolar participants further signal the need for diagnosis-specific safety data. Future work should prioritize adequately powered, multi-site trials that stratify by sex, baseline brain creatine levels measured by MRS, and concurrent pharmacotherapy. Such designs could clarify whether creatine represents a low-cost adjunct for a subset of patients or remains an intriguing but unproven hypothesis.