UNIVERSITY OF OTTAWA — A systematic review on creatine as an add-on therapy for depression was published in Brain Medicine on June 30, 2026. The review, co-authored by Bassam Jeryous Fares and Nicholas Fabiano of the University of Ottawa, found mixed results and indicated a need for further research.

Fares, a student in the Faculty of Medicine, is the first author, and Fabiano, a psychiatry resident, is the corresponding author. The review analyzed six published reports detailing five randomized controlled trials and did not pool the trial numbers into a single statistic due to differences in study design. The trials took place in South Korea, the United States, Brazil, Israel, and India.

The trials included 238 participants at baseline, with 126 receiving creatine and 112 receiving a placebo. The average age of participants was 36 years, and most participants were women. Two trials were exclusively composed of women. Four of the trials focused on major depressive disorder, while one trial examined people with bipolar disorder who were experiencing a depressive episode.

Two trials involving women with major depressive disorder showed that adding creatine to standard treatment reduced depressive symptoms more effectively than a placebo. In one of these trials, the addition of five grams of creatine daily to the antidepressant escitalopram resulted in a greater reduction of depressive symptoms after eight weeks compared to escitalopram combined with a placebo. More women in this trial reached remission in the creatine group. Another trial, which paired creatine with cognitive behavioral therapy, also demonstrated a greater reduction in symptoms on a standard questionnaire compared to therapy with a placebo.

Conversely, three of the five trials found no benefit from creatine. One trial observed no effect of creatine, administered at five or ten grams daily, in people who had not responded to prior medication. Another trial involving adolescent girls who received various doses of creatine found no difference in outcomes compared to a placebo. Additionally, the trial focused on people with bipolar disorder reported no treatment benefit. Two participants with bipolar disorder who were taking creatine developed hypomania or mania during that trial.

"The signal is interesting, but it is not a verdict," Fares said. He added, "Two trials pointed one way and three pointed another." Fares stated, "That is not the kind of evidence on which you change clinical practice. It is the kind that tells you the question is worth further exploration."

Fabiano commented on the safety of creatine. "Creatine appears to be a safe intervention," Fabiano said. He noted, "The adverse events we found were limited to mild gastrointestinal discomfort." However, Fabiano cautioned, "We cannot yet reliably say that creatine helps with depressive symptoms or if the findings are generalizable to everyone."