Creatine Treatment for Female Adolescents With Depression 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 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.

Selection of Major Depressive Disorder Participants:

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

- Participants must be females

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

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

- 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.

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

- 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.

Selection of Healthy Control Participants:

- Participants must be females between the ages of 13 and 18 years.

- Participants must not meet DSM-IV-TR diagnostic criteria for a psychiatric or
substance abuse disorder.

- 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 for creatine treatment study of female adolescents with MDD:

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

- Participants with known pre-existing renal disease.

- Participants with proteinuria or microalbuminuria.

- 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.

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

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

- Participants who meet DSM-IV-TR criteria for current substance abuse or substance
dependence, with the exception of nicotine abuse or dependence.

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

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

- History of hypersensitivity to creatine.

Exclusion criteria for healthy controls:

- Clinically significant psychiatric or substance abuse disorder.

- Unstable medical or neurological illness.

- Pregnant adolescents, due to the unknown effects of MRS scanning on a developing
fetus.

- Females of childbearing potential who are unable or unwilling to practice
contraception during the study.

- Positive urine pregnancy test.

- Participants with a contraindication to MRS scanning, such as ferromagnetic implant
or claustrophobia.

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