Efficacy and safety profile of oral creatine monohydrate in add-on to cognitive-behavioural therapy in depression: An 8-week pilot, double-blind, randomised, placebo-controlled feasibility and exploratory trial in an under-resourced area.

Pre-clinical and clinical evidence proposes that creatine monohydrate, an affordable nutraceutical, could be a useful adjunct to conventional antidepressant treatments. In this pilot feasibility and exploratory study, we investigate the 8-week effects of creatine in addition to cognitive-behavioural therapy (CBT) versus placebo plus CBT in depression. For the primary efficacy outcome of change in Patient Health Questionnaire-9 depression score at study endpoint, we used mixed-model repeated measures analysis of covariance. Logistic regressions were employed to assess acceptability (any-cause dropouts), tolerability (dropouts for adverse events), and safety (patients experiencing one or more adverse events). We calculated effect sizes adjusted for age, sex, and baseline depression score. One-hundred participants (50 females, mean age= 30.4 ± 7.4 years) with depression (mean PHQ-9 = 17.6 ± 6.3) were randomised to either creatine+CBT (N = 50) or placebo+CBT (N = 50). At 8 weeks, PHQ-9 scores were lower in both study arms, but significantly more so in participants taking creatine (mean difference= -5.12). Treatment discontinuations due to any cause and to adverse events, and proportion of participants with at least one adverse event were comparable between study arms. This hypothesis-generating trial suggests that creatine could be a useful and safe supplement to CBT for depression. Longer and larger clinical trials are warranted.