February 5, 2014

Creatine as a Natural Adjunct to Depression Treatment

New study offers clinicians another tool for treating major depression
A randomized, double-blind placebo-controlled trial of women with major depressive disorder showed that creatine enhanced the effect of a selective serotonin reuptake inhibitor.


Lyoo IK, Yoon S, Kim TS, et al. A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry. 2012 Sep 1;169(9):937-945.


Eight-week double-blind, placebo-controlled, randomized clinical trial


Fifty-two women aged 19 to 65 years diagnosed with major depressive disorder were enrolled and randomly assigned to receive escitalopram (Lexapro) in addition to either creatine (5 g/day, n=25) or placebo (n=27).

Study parameters assessed

Efficacy was primarily assessed by changes in the Hamilton Depression Rating Scale (HAM-D) score. Baseline averages were 26.9 and 26.7 for the creatine and placebo group, respectively. With 0 to 7 considered healthy mood, scores above 20 are generally considered diagnostic for depression and valid for a clinical depression study.

Primary outcome measures

HAM-D score

Key findings

In comparison to the placebo augmentation group, by the second week volunteers taking creatine had average HAM-D scores of 14.7, versus 20.3 for the placebo group (95% confidence interval [CI]: 0.98–1.59), with improvements continuing on at weeks 4 and 8. There were no differences between treatment groups in the proportion of patients who discontinued treatment prematurely (creatine: n=8, 32.0%; placebo: n=5, 18.5%) or in the overall frequency of all reported adverse events (creatine: 36 events; placebo: 45 events).

Practice Implications

Any means of improving the efficacy of antidepressant medications is welcome in clinical practice. A 2010 meta-analysis in the New England Journal of Medicine concluded antidepressant medications work no better than placebo in mild to moderate cases of depression.1 When medications do work, they typically take a minimum of 6 weeks to gain noticeable clinical benefit that warrants continuation, and can still take up to 12 weeks to render full benefit.
Creatine is a popular exercise supplement known for its benefit in helping athletic performance. It also may have value for neurological conditions like muscular dystrophy.2 Creatine supplementation reduces oxidative DNA damage and lipid peroxidation.3 As far as its role for depression, it is postulated that brain creatine reserves are able to shift brain creatine kinase activity, thereby increasing Adenosine triphosphate (ATP) production, perhaps improving brain bioenergetics in depression.4 Creatine may also exert neuroprotective effects by buffering ATP levels against neurotoxic assaults and harmful levels of glutamate.5
Creatine in high doses should be used with caution in those with kidney disease, hypertension, diabetes mellitus, or those taking diuretics.
A 2010 depression study in Sprague Dawley rats found that female, but not male, rats benefited from creatine supplementation.6 The authors of this study suggested that gender differences in creatine clearance and varying hormonal environment may play a role. A 2008 trial of 8 unipolar and two bipolar patients with treatment-resistant depression were treated for 4 weeks with 3–5 g/day of creatine monohydrate. One patient improved considerably after 1 week, and 7 patients significantly improved. Unfortunately, the 2 patients with bipolar developed hypomania/mania symptoms.7
The results of creatine supplementation in this current study give some exciting preliminary results. Concordant with naturopathic philosophy, creatine may aid mood by supporting underlying brain chemistry. While this most recent human study did have a relatively high dropout rate of 20% and 32% for placebo and creatine group respectively, the symptoms of agitation, insomnia, and nausea were attributed to the medication use.
While more information is needed, it is theoretically possible that creatine may also support other natural mood enhancers, such as 5-HTP, hypericum (St. John’s wort) and S-adenosyl methionine (SAMe). Research on these combinations has not been performed.
In my practice, most first-time patients with depression are already on at least 1 antidepressant. Many are on more than 1, and in round-robin style have already tried a few different antidepressant medications. From a naturopathic perspective, any natural supplement that we can offer to help medication work faster and better is welcome as a first step. Once patients feel better, they may begin to work on the underlying causes of their mood challenges. Please note it is prudent to avoid creatine supplementation in bipolar patients until more studies are conducted.
Of note, creatine in high doses should be used with caution in those with kidney disease, hypertension, diabetes mellitus, or those taking diuretics.


This study was relatively small and involved only Korean women who had not been on any prior medication therapy. It is unknown if ethnicity plays a role, and treatment-naïve patients are more likely to respond to any treatment, possibly raising the success rate higher than would be expected in patients who have taken medications previously. Also, because men were not included in the study, we do not know if creatine use would elicit a similar response in men.

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  1.  Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303(1):47-53.
  2.  Banerjee B, Sharma U, Balasubramanian K, Kalaivani M, Kalra V, Jagannathan NR. Effect of creatine monohydrate in improving cellular energetics and muscle strength in ambulatory Duchenne muscular dystrophy patients: a randomized, placebo-controlled 31P MRS study. Magn Reson Imaging. 2010;28(5):698-707.
  3.  Rahimi RJ. Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced by a single bout of resistance exercise. Strength Cond Res. 2011;25(12):3448-3455.
  4.  Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
  5.  Roy BD, Bourgeois JM, Mahoney DJ, Tarnopolsky MA. Dietary supplementation with creatine monohydrate prevents corticosteroid-induced attenuation of growth in young rats. Can J Physiol Pharmacol. 2002;80(10):1008-1014.
  6.  Allen PJ, D'Anci KE, Kanarek RB, Renshaw PF. Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology. 2010;35(2):534-546.
  7.  Roitman S, Green T, Osher Y, Karni N, Levine J. Creatine monohydrate in resistant depression: a preliminary study. Bipolar Disord. 2007;9(7):754-758.