Creatine As A Potential Treatment for Depression?

Major depression affects about 16% of all Americans at some point during their lifetime and is the leading contributor to disability worldwide⁽¹⁾.
 
The escalation of depression among the public and the modest efficacy of currently available treatments have encouraged efforts to identify modifiable patient factors associated with depression onset, severity and lasting effects.

Recent population-based studies report protective effects of a healthy diet against depression⁽²⁾ proposing that dietary change or nutritional supplementation may provide a viable prevention or intervention strategy for major depression.

While nutritional medicine has gained substantial attention in psychiatry⁽³⁾, specific nutrients’ influences on depression risk have yet to be fully explained.

Several nutrients with known neurobiological activity that may influence mood are being investigated as monotherapeutic and adjunctive therapies for major depression.

Creatine, a nitrogenous organic acid endogenous to all vertebrates, plays a crucial role in brain bioenergetics and is another promising nutraceutical candidate for depression. In humans’ creatine is continuously replenished through synthesis within the body and diet. Approximately 2g for an average adult is excreted daily in the urine as creatinine.

Replenishing this lost creatine through the diet would require an average person to consume approximately 500 g of raw meat per day⁽⁴⁾.

Creatine monohydrate is actively being researched for its antidepressant effects, yet little is known about the link between dietary creatine and depression risk. Early evidence of creatine’s potential efficacy as an antidepressant emerged during a clinical trial for Parkinson disease. When compared with placebo, creatine was associated with a significant reduction in depressive symptoms following 2 years of treatment⁽⁵⁾.

Other randomized clinical depression trials have largely demonstrated that creatine supplementation accelerates antidepressant response^(6-8).

The association between creatine intake and depression risk is relatively currently unknown.

A very recent study investigated a large, population-based, U.S. sample to determine creatine’s relationship with depression within the context of the North American diet⁽⁹⁾.  

This study had 3 specific aims:

1. Measure the prevalence of depression among community-dwelling adults in the U.S. across quartiles of dietary creatine intake.
2. Examine the relationship between average daily dietary creatine intake and self-reported symptoms of depression.
3. Investigate potential modification of the association between average daily dietary creatine intake and depression by sex, age, and antidepressant/anxiolytic medication use.

Major findings of this creatine research

This is the first study to examine the relationship between dietary creatine intake and risk of depression in a nationally representative U.S. sample.

Research indicated that major depressive disorder prevalence among U.S. adults follows a step-wise decrease corresponding to an incremental increase in dietary creatine consumption.

Depression prevalence was 42% higher among adults in the lowest quartile (0-0.6 g) compared to adults in the highest quartile (0.70-3.16 g) of creatine consumption.
 
In comparison, depression prevalence among persons with low creatine intake mirrors what has been estimated among persons with chronic medical conditions such as Type 2 Diabetes Mellitus⁽¹⁰⁾.

The risk of screening positive for depression was 31% lower among adults in the highest, compared to lowest, quartile of creatine consumption.

Mechanism of how creatine aids in depression

Creatine may mitigate pathophysiologic components of depression through its role as a brain energy buffer, anti-oxidant, and neuroprotectant.  Adults with major depression disorder demonstrate alterations in a brain bioenergetics system for which creatine, in the form of creatine phosphate, is a substrate, facilitating rapid regeneration of adenosine triphosphate (ATP) in tissues with variable energy demands, such as muscle and brain⁽⁴⁾.

A very recent study investigated the premise that clinical depression may be associated with low creatine concentrations in the brain and low prefrontal grey matter volume⁽¹¹⁾.

This was the first study to examine the relationship of both prefrontal creatine and grey matter volume with depression/low mood in a group of individuals who self-reported a wide range of depression severities.  

As depicted in the figures below; results indicated that people who experience subclinical depressive symptoms and low mood have lower concentrations of creatine and lower grey matter volume in the prefrontal cortex. 

What does this all mean?

These findings extend those of previous research, by indicating that depression, when considered as a continuum that ranges from subclinical depression to severe depression, is associated with low creatine and grey matter volume in the prefrontal cortex.

The findings could partly explain why increasing creatine levels via administration of creatine supplements has been shown to have potential in alleviating depressive symptoms in depressed patients. 

Figures: The middle figure shows the relationship between DASS depression scores and creatine in the prefrontal voxel depicted in the top figure. The bottom figure shows the correlation between concentrations of creatine in the voxel in the top figure and grey matter volume in all participants. Adapted from⁽¹¹⁾

Summary

Creatine is a naturally-occurring organic acid that serves as an energy buffer and energy shuttle in tissues, such as brain and skeletal muscle, that exhibit dynamic energy requirements. Evidence, deriving from a variety of scientific domains, that brain bioenergetics are altered in depression and related disorders is vastly growing.

Clinical studies in neurological conditions such have indicated that creatine might have an antidepressant effect, and early clinical studies in depressive disorders—especially major depressive disorder—indicate that creatine may have an important antidepressant effect.

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References:
1.    Organization, W.H., Depression And Other Common Mental Disorders: Global Health Estimates. 2017, World Health Organization: Geneva.
2.    Lai, J.S., et al., A systematic review and meta-analysis of dietary patterns and depression in community-dwelling adults. Am J Clin Nutr, 2014. 99(1): p. 181-97.
3.    Sarris, J., et al., Nutritional medicine as mainstream in psychiatry. Lancet Psychiatry, 2015. 2(3): p. 271-4.
4.    Wyss, M. and R. Kaddurah-Daouk, Creatine and creatinine metabolism. Physiol Rev, 2000. 80(3): p. 1107-213.
5.    Bender, A., et al., Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial. Neurology, 2006. 67(7): p. 1262-4.
6.    Hellem, T.L., et al., Creatine as a Novel Treatment for Depression in Females Using Methamphetamine: A Pilot Study. J Dual Diagn, 2015. 11(3-4): p. 189-202.
7.    Kondo, D.G., et al., Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study. J Affect Disord, 2011. 135(1-3): p. 354-61.
8.    Roitman, S., et al., Creatine monohydrate in resistant depression: a preliminary study. Bipolar Disord, 2007. 9(7): p. 754-8.
9.    Bakian, A.V., et al., Dietary creatine intake and depression risk among U.S. adults. Transl Psychiatry, 2020. 10(1): p. 52.
10.    Wang, Y., et al., Depression among people with type 2 diabetes mellitus, US National Health and Nutrition Examination Survey (NHANES), 2005-2012. BMC Psychiatry, 2016. 16: p. 88.
11.    Faulkner, P., et al., Relationship between depression, prefrontal creatine and grey matter volume. J Psychopharmacol, 2021. 35(12): p. 1464-1472.