Effects of Creatine Monohydrate Augmentation on Brain Metabolic and Network Outcome Measures in Women With Major Depressive Disorder

Biol Psychiatry. 2016 Sep 15;80(6):439-447. doi: 10.1016/j.biopsych.2015.11.027. Epub 2015 Dec 15.


Background: Creatine monohydrate (creatine) augmentation has the potential to accelerate the clinical responses to and enhance the overall efficacy of selective serotonin reuptake inhibitor treatment in women with major depressive disorder (MDD). Although it has been suggested that creatine augmentation may involve the restoration of brain energy metabolism, the mechanisms underlying its antidepressant efficacy are unknown.

Methods: In a randomized, double-blind, placebo-controlled trial, 52 women with MDD were assigned to receive either creatine augmentation or placebo augmentation of escitalopram; 34 subjects participated in multimodal neuroimaging assessments at baseline and week 8. Age-matched healthy women (n = 39) were also assessed twice at the same intervals. Metabolic and network outcomes were measured for changes in prefrontal N-acetylaspartate and changes in rich club hub connections of the structural brain network using proton magnetic resonance spectroscopy and diffusion tensor imaging, respectively.

Results: We found MDD-related metabolic and network dysfunction at baseline. Improvement in depressive symptoms was greater in patients receiving creatine augmentation relative to placebo augmentation. After 8 weeks of treatment, prefrontal N-acetylaspartate levels increased significantly in the creatine augmentation group compared with the placebo augmentation group. Increment in rich club hub connections was also greater in the creatine augmentation group than in the placebo augmentation group.

Conclusions: N-acetylaspartate levels and rich club connections increased after creatine augmentation of selective serotonin reuptake inhibitor treatment. Effects of creatine administration on brain energy metabolism and network organization may partly underlie its efficacy in treating women with MDD.

Trial registration: ClinicalTrials.gov NCT00729755.

Keywords: Antidepressant; Brain bioenergetics; Creatine monohydrate; Major depressive disorder; Network organization; Selective serotonin reuptake inhibitor.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / metabolism
  • Brain / drug effects*
  • Brain / metabolism*
  • Case-Control Studies
  • Citalopram / therapeutic use
  • Creatine / pharmacology*
  • Creatine / therapeutic use*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / metabolism
  • Diffusion Tensor Imaging
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Middle Aged
  • Neural Pathways / physiology
  • Prefrontal Cortex / metabolism*
  • Proton Magnetic Resonance Spectroscopy
  • Young Adult


  • Citalopram
  • Aspartic Acid
  • N-acetylaspartate
  • Creatine

Associated data

  • ClinicalTrials.gov/NCT00729755