Major Depressive Disorder
Conditions
Keywords
Major Depressive Disorder, Creatine, Brain Chemistry, Magnetic Resonance Spectroscopy, Treatment Resistance, Selective Serotonin Reuptake Inhibitor (SSRI) Resistance
Brief summary
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.
Detailed description
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.
Interventions
DRUGCreatine
Creatine is a nutritional supplement.
DRUGPlacebo
The placebo is an inactive ingredient similar in appearance, weight and density to the active treatment.
Sponsors
Perry Renshaw
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
12 Years to 21 Years
Healthy volunteers
Yes
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Phosphocreatine (PCr) Concentrations | Baseline and 8 weeks | PCr will be measured through phosphorus magnetic resonance spectroscopy (31P-MRS). This will be performed in a 3 Tesla magnetic resonance imaging (MRI) scanner. Creatine concentration before and after treatment. By convention, 31P MRS data are typically reported as metabolite ratios. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | 8 weeks | The Children's Depression Rating Scale-Revised (CDRS-R) and Montgomery-Asberg Depression Rating Scale (MADRS) will be administered to understand the severity of depressive symptoms, and how these symptoms change throughout the course of the study. The CDRS-R has a range of minimum score 17 and maximum score 113, with higher scores indicating more severe depression. The MADRS has a range of 0 to 60 with higher scores indicating more severe depressive symptoms. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Creatine 28 Subjects randomized to this study arm will receive 10 grams of creatine daily for 8 weeks.
Creatine: Creatine is a nutritional supplement. | 28 |
| Placebo 23 Subjects randomized to this study arm will receive 10 grams of placebo daily for 8 weeks.
Placebo: The placebo is an inactive ingredient similar in appearance, weight and density to the active treatment. | 23 |
| Healthy Comparison 20 Subjects seen for screening and baseline scan. No randomization or treatment intervention for subjects enrolled as a Healthy Comparison. | 20 |
| Total | 71 |
Baseline characteristics
| Characteristic | Creatine | Placebo | Healthy Comparison | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 14 Participants | 9 Participants | 7 Participants | 30 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 14 Participants | 13 Participants | 41 Participants |
| Age, Continuous | 17.6 years STANDARD_DEVIATION 2.2 | 17.8 years STANDARD_DEVIATION 2 | 17.4 years STANDARD_DEVIATION 3.2 | 17.6 years STANDARD_DEVIATION 2.4 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 27 Participants | 19 Participants | 16 Participants | 62 Participants |
| Region of Enrollment United States | 28 participants | 23 participants | 20 participants | 71 participants |
| Sex: Female, Male Female | 28 Participants | 23 Participants | 20 Participants | 71 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 23 |
| other Total, other adverse events | 18 / 28 | 15 / 23 |
| serious Total, serious adverse events | 1 / 28 | 0 / 23 |
Outcome results
Primary
Brain Phosphocreatine (PCr) Concentrations
PCr will be measured through phosphorus magnetic resonance spectroscopy (31P-MRS). This will be performed in a 3 Tesla magnetic resonance imaging (MRI) scanner. Creatine concentration before and after treatment. By convention, 31P MRS data are typically reported as metabolite ratios.
Time frame: Baseline and 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Creatine | Brain Phosphocreatine (PCr) Concentrations | Week 8 | .1876206 Ratio | Standard Deviation 0.0121833 |
| Creatine | Brain Phosphocreatine (PCr) Concentrations | Baseline | .1812802 Ratio | Standard Deviation 0.011512 |
| Placebo | Brain Phosphocreatine (PCr) Concentrations | Week 8 | .181464 Ratio | Standard Deviation 0.008267 |
| Placebo | Brain Phosphocreatine (PCr) Concentrations | Baseline | .1796093 Ratio | Standard Deviation 0.0070168 |
| Healthy Comparison | Brain Phosphocreatine (PCr) Concentrations | Baseline | .1850427 Ratio | Standard Deviation 0.0059435 |
| Healthy Comparison | Brain Phosphocreatine (PCr) Concentrations | Week 8 | NA Ratio | — |
Secondary
Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS)
The Children's Depression Rating Scale-Revised (CDRS-R) and Montgomery-Asberg Depression Rating Scale (MADRS) will be administered to understand the severity of depressive symptoms, and how these symptoms change throughout the course of the study. The CDRS-R has a range of minimum score 17 and maximum score 113, with higher scores indicating more severe depression. The MADRS has a range of 0 to 60 with higher scores indicating more severe depressive symptoms.
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Creatine | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | MADRS Baseline | 28.71428 score on a scale | Standard Deviation 5.394491 |
| Creatine | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | CDRS-R Week 8 | 41.95833 score on a scale | Standard Deviation 12.47773 |
| Creatine | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | MADRS Week 8 | 16.16667 score on a scale | Standard Deviation 11.21981 |
| Creatine | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | CDRS-R Baseline | 58.28571 score on a scale | Standard Deviation 6.980699 |
| Placebo | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | MADRS Baseline | 31.47826 score on a scale | Standard Deviation 4.832368 |
| Placebo | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | CDRS-R Baseline | 60.3913 score on a scale | Standard Deviation 6.719978 |
| Placebo | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | MADRS Week 8 | 18.73684 score on a scale | Standard Deviation 11.29819 |
| Placebo | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | CDRS-R Week 8 | 44.15789 score on a scale | Standard Deviation 10.25921 |
| Healthy Comparison | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | MADRS Week 8 | NA score on a scale | — |
| Healthy Comparison | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | CDRS-R Baseline | 21.9 score on a scale | Standard Deviation 2.425739 |
| Healthy Comparison | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | CDRS-R Week 8 | NA score on a scale | — |
| Healthy Comparison | Children's Depression Rating Scale-Revised (CDRS-R); Montgomery-Asberg Depression Rating Scale (MADRS) | MADRS Baseline | 2.315789 score on a scale | Standard Deviation 2.029029 |