Creatine Augmentation in Veterans With SSRI-Resistant Major Depression

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Doug Kondo, University of Utah
ClinicalTrials.gov Identifier:
NCT01175616
First received: August 3, 2010
Last updated: May 20, 2014
Last verified: May 2014

August 3, 2010
May 20, 2014
September 2012
April 2014   (final data collection date for primary outcome measure)
Change in Montgomery-Asberg Depression Rating Scale (MADRS) Score [ Time Frame: screening; baseline; weeks 1, 2, 4, 5, 8, and 10 ] [ Designated as safety issue: No ]
The primary clinical outcome measure will be the change in MADRS; response will be defined as a 50% or greater decrease in MADRS score from baseline and a Clinical Global Impression Scale (CGI) improvement score of 1 or 2
Change in the Montgomery Asberg Depression Rating Scale (MADRS) score [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
The primary clinical outcome measure will be the change in MADRS; response will be defined as a 50% or more decrease in MADRS score from baseline and a Clinical Global Impression (CGI) improvement score of 1 or 2.
Complete list of historical versions of study NCT01175616 on ClinicalTrials.gov Archive Site
Changes in 3T 31Phosphorus Magnetic Resonance Spectroscopy metabolites [ Time Frame: Baseline and 8 weeks ] [ Designated as safety issue: No ]
The primary neuroimaging outcome measures will be changes in 3T 31P-MRS metabolites (PCr and β-NTP) globally and in the anterior cingulate cortex
Changes in 3T 31P-MRS metabolites [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
The primary neuroimaging outcome measures will be changes in 3T 31P-MRS metabolites (PCr and b-NTP) globally and in the anterior cingulate cortex.
Not Provided
Not Provided
 
Creatine Augmentation in Veterans With SSRI-Resistant Major Depression
Creatine Augmentation in Female & Male Veterans With Selective Serotonin Reuptake Inhibitor-Resistant Major Depressive Disorder

The purpose of this study is to determine whether creatine will be helpful as an adjunctive treatment for treatment-resistant major depressive disorder (MDD) in female and male Veterans. We hypothesize that Veterans receiving creatine will show decreased depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). We will also use 31-Phosphorus Magnetic Resonance Spectroscopy (31-P MRS) brain scans to compare levels of neurochemicals related to energy metabolism in the brain, before-and-after treatment with creatine, and between healthy controls and MDD participants.

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.

Interventional
Phase 2
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Major Depressive Disorder
Drug: Creatine
Creatine will be given at a dose of 5 grams per day to adult male veterans with SSRI-resistant depression for eight weeks. Creatine is dispensed as a powder.
Other Name: Creapure
  • No Intervention: Healthy Control
    20 adult male veterans free from psychiatric disorders or uncontrolled medical illnesses will be recruited as healthy controls. They will not receive creatine treatment.
  • Experimental: Creatine
    20 adult male veterans with SSRI-resistant major depression will be treated with Creatine 5 grams per day for eight weeks.
    Intervention: Drug: Creatine

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
40
April 2014
April 2014   (final data collection date for primary outcome measure)

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)
Male
18 Years to 55 Years
Yes
Contact information is only displayed when the study is recruiting subjects
Not Provided
 
NCT01175616
00041936
Yes
Doug Kondo, University of Utah
University of Utah
Not Provided
Study Director: Perry Renshaw, MD, PhD, MBA University of Utah
University of Utah
May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP