Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study

J Affect Disord. 2011 Dec;135(1-3):354-61. doi: 10.1016/j.jad.2011.07.010. Epub 2011 Aug 9.


Background: Adolescent major depressive disorder (MDD) is a life-threatening brain disease with limited interventions. Treatment resistance is common, and the illness burden is disproportionately borne by females. 31-Phosphorus magnetic resonance spectroscopy ((31)P MRS) is a translational method for in vivo measurement of brain energy metabolites.

Methods: We recruited 5 female adolescents who had been on fluoxetine (Prozac®) for ≥ 8 weeks, but continued meet diagnostic criteria for MDD with a Children's Depression Rating Scale-Revised (CDRS-R) raw score ≥ 40. Treatment response was measured with the CDRS-R. (31)P MRS brain scans were performed at baseline, and repeated following adjunctive creatine 4 g daily for 8 weeks. For comparison, 10 healthy female adolescents underwent identical brain scans performed 8 weeks apart.

Results: The mean CDRS-R score declined from 69 to 30.6, a decrease of 56%. Participants experienced no Serious Adverse Events, suicide attempts, hospitalizations or intentional self-harm. There were no unresolved treatment-emergent adverse effects or laboratory abnormalities. MDD participants' baseline CDRS-R score was correlated with baseline pH (p=0.04), and was negatively correlated with beta-nucleoside triphosphate (β-NTP) concentration (p=0.03). Compared to healthy controls, creatine-treated adolescents demonstrated a significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up (31)P MRS brain scans.

Limitations: Lack of placebo control; and small sample size.

Conclusions: Further study of creatine as an adjunctive treatment for adolescents with SSRI-resistant MDD is warranted.

Publication types

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

MeSH terms

  • Adolescent
  • Antidepressive Agents / therapeutic use*
  • Creatine / therapeutic use*
  • Depressive Disorder / chemically induced
  • Depressive Disorder / drug therapy
  • Depressive Disorder, Major / diagnosis
  • Depressive Disorder, Major / diagnostic imaging*
  • Depressive Disorder, Major / drug therapy*
  • Female
  • Fluoxetine / adverse effects
  • Fluoxetine / therapeutic use
  • Follow-Up Studies
  • Humans
  • Magnetic Resonance Imaging
  • Magnetic Resonance Spectroscopy*
  • Magnetics
  • Phosphocreatine / metabolism
  • Phosphocreatine / therapeutic use
  • Phosphorus / therapeutic use
  • Radionuclide Imaging
  • Serotonin Uptake Inhibitors / adverse effects
  • Serotonin Uptake Inhibitors / therapeutic use
  • Treatment Outcome


  • Antidepressive Agents
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Phosphocreatine
  • Phosphorus
  • Creatine