The primary hypothesis is that compared to placebo, 10g of daily creatine monohydrate for eight weeks will be associated with significant increases in frontal lobe phosphocreatine and beta-nucleoside triphosphate (β-NTP) concentrations. A secondary hypothesis is that decreased depressive symptoms measured with the Children's Depression Rating Scale-Revised (CDRS-R) and Montgomery-Asberg Depression Rating Scale (MADRS) will be reciprocally correlated with increased β-NTP concentrations.

The current protocol seeks to expand upon the investigators previous work by opening recruitment on a pilot study of creatine 10g daily vs. placebo as a treatment for female adolescents with SSRI-resistant MDD. The purpose of the pilot study is twofold: A) to evaluate several aspects of the feasibility of creatine supplementation as a treatment for this population; and B) to estimate the effect size of adjunctive creatine, to inform the design and implementation of a potential future efficacy trial.

MAJOR DEPRESSIVE DISORDER SUBJECTS

Inclusion Criteria:

1. Participants must be female.
2. Participants must be able to grant informed consent (age >18), or parent/guardian permission plus participant assent (age <18).
3. Participants must meet DSM criteria for Major Depressive Disorder (MDD), with current mood state depressed for > 2 weeks.
4. Participants must be between the ages of 12 and 21.
5. Current CDRS-R raw score of > 40 or MADRS score > 25; and CGI-S score > 3.
6. Participants may be enrolled in individual and/or group psychotherapy, if it has been ongoing for at least 8 weeks.
7. Participants must have been in treatment with an SSRI for at least 8 weeks, the last 4 of which were at a dosage of > 20 mg per day of fluoxetine or its equivalent, e.g. 20 mg per day of paroxetine, 20 mg citalopram, 10 mg escitalopram, or 100 mg sertraline. If the participant attempted, but could not tolerate, a dose comparable to 20 mg fluoxetine, they will be considered eligible. (This definition of "Adolescent SSRI Resistant Depression" is modified from the NIH-sponsored, $17 million TORDIA Randomized Controlled Trial [http://clinicaltrials.gov/ct2/show/NCT00018902\].

Exclusion Criteria:

1. Unstable co-morbid medical, neurological, or psychiatric disorder.
2. Current DSM criteria for substance abuse or dependence (excepting nicotine/cigarettes).
3. Clinically significant suicidal or homicidal risk.
4. Pre-existing renal disease.
5. Proteinuria on baseline urinalysis testing.
6. Pregnancy or breastfeeding.
7. Sexually active and unwilling to practice contraception during the study.
8. Contraindication to magnetic resonance imaging (e.g. ferromagnetic implant or claustrophobic anxiety).
9. History of hypersensitivity to creatine.
10. History of a previous failed therapeutic trial of creatine.
11. Participants may be outpatients or inpatients, but incarcerated persons will be excluded because this study is not approved for "Research Involving Prisoners."

Study Withdrawal Criteria:

1. Withdrawal of parental permission, participant informed consent or participant assent.
2. Onset of a psychotic disorder or bipolar disorder.
3. Intolerable, or clinically-significant side effects to creatine.
4. Worsening depression, as demonstrated by an increase in CDRS-R or MADRS score > 25% from baseline.
5. Positive pregnancy test.
6. A significant change to the participant's medication or psychotherapy treatment from the regimen reported at their baseline/screening visit (e.g. if the SSRI is discontinued).
7. Incarceration, as the study is not approved to conduct "Research Involving Prisoners."
8. If a clinically-significant intracranial lesion is found by the Radiologist on a participant's baseline brain scan, they will be withdrawn from the study and referred for appropriate medical care.
9. The principal investigator retains the right to withdraw participants from the study without their permission, in the event they are unwilling or unable to maintain adherence with the research protocol.

HEALTHY COMPARISON SUBJECTS

Inclusion Criteria:

1. Participants must be able to grant informed consent (age > 18), or parent/guardian permission plus participant assent (age < 18).
2. Participants must be female.
3. Participants must be between the ages of 12 and 21 years.
4. Participants must not meet DSM criteria for a current psychiatric illness or substance use disorder.
5. Participants must have a CDRS-R score < 30.

Exclusion Criteria:

1. Unstable medical or neurological illness.
2. Clinically-significant psychiatric or substance use disorder.
3. Pregnant subjects, due to the unknown effects of MRI/MRS scans on a fetus. In addition, women of childbearing potential who are unable or unwilling to practice contraception during the study will be excluded. Female participants who are of childbearing potential must have a negative urine pregnancy test before the MRI/MRS scan.
4. Participants with a contraindication to MRI/MRS scanning, such as a metallic implant.

Study Withdrawal Criteria:

1. Withdrawal of parental permission or participant assent.
2. Onset of a psychotic disorder or depression.
3. Positive pregnancy test.
4. A significant change to the participant's medication or psychotherapy treatment from the regimen reported at their baseline/screening visit, unless directed by the principal investigator.

Participants are assessed using Montgomery-Åsberg Depression Rating Scale (MADRS) and Children's Depression Rating Scale-Revised (CDRS-R).

Adverse events were collected from participants at every visit, starting after the treatment intervention was dispensed at baseline. Adverse events were assessed up to 8 weeks.

Healthy comparison participants were only seen for a baseline scan. Healthy comparison participants were not exposed to any treatment intervention, therefore, adverse events were not collected.