Creatine Treatment for Female Adolescents With Depression Who Are Non-Responders to Fluoxetine or Escitalopram
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to see if creatine, which is a naturally occurring chemical in
      the body, is effective for treating Major Depressive Disorder (MDD) in female teenagers.
      Creatine may have effects of interest in the brain. The reason for the MRI component of this
      study is to learn about new ways to see inside the brain. The investigators will use magnetic
      fields and radio waves to look at the brain and chemicals in the brain. The investigators
      hope that this technique will have medial use in the future.

      The primary hypothesis of the study is that oral creatine supplementation will have a
      beneficial effect as adjunctive therapy in female adolescents with MDD who are non-responders
      to an adequate trial of the SSRIs Fluoxetine or Escitalopram.
    

Detailed description: 
      This is an open-label clinical trial of the investigational drug creatine, for augmentation
      treatment of female adolescents with Major Depressive Disorder (MDD) who have failed to
      respond to first-line treatment with Fluoxetine or Escitalopram. Widely used by high school
      and college athletes in the U.S., creatine is an over-the-counter nutritional supplement with
      annual sales of more than $200 million. Studies in animals show that creatine improves the
      performance of female rats in the Porsolt Forced Swim test, which is used to predict the
      efficacy antidepressant compounds. Human neuroimaging studies indicate that patients with MDD
      have abnormal levels of high-energy phosphate metabolites in brain, primarily adenosine
      triphosphate (ATP) and phosphocreatine. Research has also shown that creatine supplementation
      induces changes in these high-energy phosphate metabolites that are associated with a
      positive response to antidepressants. For the proposed study, ten female adolescents between
      the ages of 13-18 with MDD will be recruited for participation in an open-label trial of
      creatine. Participants with depression will have unremitted MDD despite treatment with
      Fluoxetine at a dose > 40mg daily for > 4 weeks or Escitalopram at a dose of > 10 mg daily
      for > 4 weeks. Depressed participants will be treated with oral creatine 4gm daily for eight
      weeks, and will continue to take Fluoxetine or Escitalopram as prescribed. In addition, ten
      healthy control participants with no history of psychiatric or substance abuse disorder will
      be recruited. No treatment will be administered to the control participants. The primary
      outcome measure will be the Children's Depression Rating Scale (CDRS-R), which was used in
      the Treatment for Adolescents with Depression Study (TADS) clinical trial (March et al., JAMA
      2004; 292(7):807-20) and the Treatment of Resistant Depression in Adolescents (TORDIA) study
      (Brent et al., JAMA 2008;299(8):901-13). All study participants will undergo brain scans at
      baseline and again after six weeks, with 31-Phosphorus Magnetic Resonance Spectroscopy
      (31P-MRS). The brain scans will be used to measure high-energy phosphate metabolites in the
      Anterior Cingulate Cortex (ACC), an anatomical region of the brain that has been implicated
      in MDD. 31P-MRS is a non-invasive neuroimaging technique that does not expose participants to
      radiation. At the magnetic field strength utilized (3T), magnetic resonance imaging is
      FDA-approved and has no known adverse effects. The research team will use data from 31P-MRS
      scans to compare levels of high-energy phosphate metabolites in MDD participants vs. healthy
      controls. In addition, comparison of pre- and post-treatment metabolite levels will be
      conducted in the MDD participants. The primary hypothesis of the study is that oral creatine
      will show efficacy as an augmentation treatment for female adolescents with MDD whose
      depression has not responded to Fluoxetine or Escitalopram. Secondary hypotheses include the
      following: adolescents with treatment-resistant MDD will show differences at baseline from
      healthy controls in high-energy phosphate metabolites in the ACC; and that brain scans in
      depressed adolescents who respond to creatine will show normalization of high-energy
      phosphate metabolites in the ACC.
    

Intervention name(s): Creatine Monohydrate
Intervention type(s): Drug
Intervention description(s): Creapure brand of creatine monohydrate
Other intervention name(s): Creapure
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Depression; Females; Adolescents