Walk into your gym’s supplement aisle and you’ll find creatine, sold by the bathtub to people chasing bigger muscles. It is one of the most studied compounds in sports science. What far fewer people know is that the brain runs on much the same chemicals as muscles, and creatine, which helps provide energy, may be important from the neck up as well as from the neck down. A new systematic review published today in Brain Medicine takes that quiet potential seriously and asks tough questions. Can creatine help treat depression?
What researchers focused on
The review team, led by Bassam Jelios Fares of the University of Ottawa, did not conduct any new trials. They gathered what already existed. After reviewing the literature, they settled on six published reports describing five randomized controlled trials. In such studies, neither patients nor doctors know who received the real compound and who received a placebo.
These trials were conducted in five countries: South Korea, the United States, Brazil, Israel, and India, and enrolled 238 participants at baseline, of whom 126 received creatine and 112 received a placebo. The average age was 36 years. Most of the participants were women. Two of the trials included only women.
Four of the trials investigated major depressive disorder. One study studied bipolar disorder patients experiencing depressive episodes. The authors did not combine the numbers into a single statistic because the studies differed widely in design. They instead summarized them as stories and let each trial speak for itself.
split decision
Here the story refuses a clean resolution. Two of the five trials, all drawn from the same study of women with major depressive disorder, found real effects. Adding 5 grams of creatine per day to the antidepressant escitalopram reduced depression symptoms even more than a placebo after eight weeks. This effect was large by normal statistical standards, with a Cohen’s d for the Hamilton Depression Rating Scale of 1.13, and more women reached remission.
Another trial found that combining creatine with cognitive behavioral therapy resulted in sharper reductions in symptoms on a standard questionnaire than when treatment was combined with a placebo.
The image then turns dark. The remaining three trials found nothing. One person found no benefit in giving 5 or 10 grams of creatine a day to people who were already unresponsive to the drug. Another experiment tested several doses in adolescent girls and found no difference from a placebo.
A final study looked at bipolar patients in a depressive episode and again found no treatment effect. To make matters worse, two of the bipolar patients taking creatine developed hypomanic or manic episodes. This is a sobering reminder that the same compound can behave very differently depending on the diagnosis.
Why creatine is important for the brain
The logic behind the experiment isn’t all that far-fetched. The brain is an expensive organ, consuming energy at a rate disproportionate to its size. Creatine helps cells rebuild adenosine triphosphate, the molecule that pays for its work. Studies of people with mood disorders have found changes in creatine metabolism in the brain, and impairments in energy production have been proposed as one of the causes of depression.
Creatine may also fine-tune the pathways that control dopamine and serotonin, the neurotransmitters that most antidepressants target. The author is careful here. They point out that the association between brain creatine and mood remains correlational, with no proven causation, and that there are many moving parts in the biology of depression.
“The signals are interesting, but they’re not a verdict,” said Bassam Gerus Fares, lead author of the review and a student at the University of Ottawa’s medical school.
Two trials showed one direction and three trials showed another direction. It’s not evidence that would change clinical practice. That’s the kind of thing that indicates the question is worth exploring further. ”
Bassam Gerios Fares, Faculty of Medicine, University of Ottawa
Corresponding author Nicholas Fabiano, a psychiatry resident at the University of Ottawa, called the study a starting point, not a conclusion. “Creatine appears to be a safe intervention. The adverse events we found were limited to mild gastrointestinal discomfort. We cannot yet say with certainty whether creatine has an effect on symptoms of depression or whether the results can be generalized to all people.”
what happens next
This review does not pretend to solve problems. The authors point out obvious limitations. The trials were small. Gender was imbalanced, with two studies enrolling only women. Quality was mixed, with two trials judged to be at low risk of bias and three with some concerns, mainly due to how patients were allocated and how missing data was handled. The authors stress that the results of this study are not yet generalizable.
What they are looking for is more rigorous work. Larger trials. The longest one is over 8 weeks. Studies testing creatine alongside exercise and studies looking at higher doses, keeping in mind that more is not always better.
There are even intriguing clues from animal studies that creatine produced different changes in depression-like behavior in male and female rodents, which may help explain why human trials involving more women are more promising. For now, creatine remains a promising lead rather than a proven treatment. The molecules that build muscle are attracting attention from those who study the mind.
