Creatine Augmentation in Veterans With SSRI-Resistant Major Depression

This is an open-label clinical trial of the investigational drug creatine for augmentation
treatment of female and male Veterans, ages 18-55, with Major Depressive Disorder (MDD) who
have failed to respond to antidepressant treatment with a selective serotonin reuptake
inhibitor (SSRI) drug.

Despite the existence of currently available antidepressant treatments, major depressive
disorder (MDD) remains a leading cause of disability and suffering in this country (Kessler
et al 2003). Furthermore, patients with MDD are at significant risk for suicide attempts and
completed suicide (Claassen et al 2007). MDD is also common among the veteran population.
During fiscal year 2007, the Salt Lake VA saw 1,936 unique patients with a documented
diagnosis of MDD.

Although various antidepressant treatments are currently available, a significant proportion
of individuals with MDD either do not respond to, respond inadequately to, or cannot
tolerate adequate doses of available antidepressant medications. Thus, the need remains to
develop novel antidepressant treatments which may be more effective and/or better tolerated
in treatment-resistant depression. While progress has been made in recent years in
understanding aspects of the neurobiology of this condition, a more comprehensive
understanding of the neurobiology of depression is still lacking and is a major obstacle to
the development of more effective therapies for this disorder.

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.

Based on previous preclinical and clinical studies, we propose that the nutritional
supplement creatine may be a helpful adjunctive treatment for treatment-resistant
depression.

For the proposed study, twenty Veterans between the ages of 18-55 years with MDD will be
recruited for participation in an open-label trial of creatine augmentation. Participants
with depression will have unremitted MDD, despite treatment with an adequate trial of an
approved SSRI antidepressant. MDD Veteran participants will be treated with oral creatine 5
gm daily for eight weeks and will continue to take their current SSRI antidepressant. In
addition, twenty healthy control participants, also Veterans of both genders between the
ages of 18-55, with no history of psychiatric or substance abuse disorder will be recruited.
No treatment will be administered to control participants.

The primary outcome measure for antidepressant efficacy will be the change in
Montgomery-Asberg Depression Rating Scale. For MRS, primary parameters of interest to be
measured include concentrations of b-NTP (primarily reflecting ATP), phosphocreatine, pH,
creatine, and NAA. MDD participants will undergo brain scans at baseline and again after
eight weeks, with 31-Phosphorus Magnetic Resonance Spectroscopy (31P-MRS). Healthy controls
will undergo a single brain scan. The brain scans will be used to measure high-energy
phosphate metabolites globally and in the Anterior Cingulate Cortex (ACC), a 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 is that oral creatine supplementation will have a beneficial effect
as adjunctive therapy in Veterans with SSRI-resistant MDD. Secondary hypotheses include the
following: MDD participants will demonstrate differences from healthy controls in
bioenergetic metabolites in anterior cingulate cortex and globally in the brain, 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 and globally
in the direction of the healthy controls.

Inclusion Criteria for Major Depressive Disorder Participants:

- Must meet DSM-IV TR criteria for MDD, with current depressive episode lasting 4 weeks
or greater.

- Age 18-55 years

- Male

- Montgomery-Asberg Depression Rating Scale (MADRS) of 18 or greater

- Adequate trial of current SSRI antidepressant treatment, with no change in dose for 4
weeks for greater prior to baseline MRI/MRS scan

- Minimal or no response to current antidepressant medication

Exclusion Criteria for Major Depressive Disorder Participants:

- Unstable co-morbid medical, neurologic, or psychiatric illness

- Clinically significant substance use disorder

- Significant risk of suicide, as defined by score of 4 or greater on item 10 of the
MADRS or in the clinical judgment of the study physician

- Inability to give informed consent

- Contraindication to MRI (e.g., pacemaker, ferromagnetic implants in the body,
claustrophobia)

- Individuals with known pre-existing renal disease or who are found to have
proteinuria or microalbuminuria at baseline screening

- History of hypersensitivity to creatine

Inclusion Criteria for Control Participants:

- Physically and mentally healthy

- Age 18-55 years

- Male

Exclusion Criteria for Control Subjects:

- Any history of psychiatric illness or clinically significant substance use disorder

- Any significant medical or neurological condition which is likely to impact the
central nervous system and/or affect the results of MRS imaging

- Inability to give informed consent

- Any medications which are likely to affect the results of MRS imaging as determined
by the PI

- Contraindication to MRI (e.g., pacemaker, ferromagnetic implants in the body,
claustrophobia)