Adjunctive Creatine Treatment for Adolescent Females with Major Depressive Disorder who are Non-Responders to Fluoxetine or Escitalopram


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 the SSRIs 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, twenty 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 > 20mg 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.

Oral creatine
Study Type: 
Study Design: 

This is an open-label trial with oral creatine 4 grams per day for eight weeks.  

Primary Outcome Measures: 

The primary hypothesis of the study is that oral creatine supplementation will have a beneficial effect as adjunctive therapy in female adolescents with major depressive disorder who are non-responders to an adequate trial of the SSRIs Fluoxetine or Escitalopram.  

Secondary Outcome Measures: 

Secondary hypotheses include the following: female adolescents with major depression will demonstrate differences from healthy controls in anterior cingulate cortex bioenergetic parameters, as measured by 1H-MRS and 31P-MRS; and that depressed participants who respond to oral creatine supplementation will show bioenergetic changes in the anterior cingulate cortex in the direction of the healthy controls.

Currently enrolling
Assigned Interventions: 

Oral creatine 4 grams per day for eight weeks.

Ages of Eligibility: 
Ages 13 - 18
Inclusion Criteria: 

a.     Participants must meet DSM-IV-TR criteria for Major Depressive Disorder, with current mood state depressed for > 2 weeks.

b.     Participants must be females.

c.     Participants must be between the age of 13 and 18 years.

d.     Participants must have had an adequate trial of Fluoxetine, defined as a trial of  > 8 weeks of treatment, with a dose of  > 40 mg daily for > 4 weeks.  If the participant had a trial of 40mg daily and was unable to tolerate it, a dose of 20 mg for > 8 weeks is acceptable; OR

e.     Participants must have had an adequate trial of escitalopram, defined as a trial of  > 8 weeks of treatment, with a dose of  > 20 mg daily for > 4 weeks.  If the participant had a trial of 20 mg daily and was unable to tolerate it, a dose of 10 mg for > 8 weeks is acceptable.

f.      Participants must have a CDRS-R score of > 40 and a CGI-S score of > 4.

g.     Participants must be able to give informed consent or assent, and parent (s)/guardian (s) must be able to give informed permission for study participation.


Exclusion Criteria: 

a.     Adolescents with an unstable co-morbid medical, neurological, or psychiatric disorder.

b.     Participants with known pre-existing renal disease.

c.     Participants with proteinuria or microalbuminuria.

d.     Pregnant females, nursing mothers, or females of childbearing potential who are unable or unwilling to practice birth control during the study.  Participants who are of child-bearing potential must have a negative urine pregnancy test before each MRS scan.

e.     Participants at high risk for suicidal behaviors, homicidal behaviors, or self-harm.

f.      Participants who in the opinion of the principal investigator are unlikely to be able to comply with the study protocol.

g.     Participants for whom MRS scanning is contraindicated, such as adolescents with ferromagnetic implants or claustrophobia.

h.     Documented or suspected history of mental retardation (IQ < 70).

i.       History of hypersensitivity to creatine.



Tracy Hellem, RN, BSN

Research Manager at the Brain Institute of the University of Utah




The University of Utah

Sponsors & Collaborators: 

 AlzChem LLC


 Dr. Douglas Kondo

Study ID Numbers: 
University of Utah IRB # 00033465