Protocol Number: 06-M-0162

Title:

An Investigation Examining the Evidence for Mitochondrial Dysfunction in the Pathophysiology and Treatment of Bipolar Disorder

Number:

06-M-0162

Summary:

This study will examine whether mitochondrial function is impaired in patients with bipolar disorder. Mitrochondria are small organelles inside the cell that are responsible for energy production. Recent studies in animals and humans suggest that abnormalities of mitrochondria may be involved in bipolar depression. The study will also examine whether the food supplement Coenzyme Q10 (CoQ10) improves mitochondrial function and symptoms such as depressed mood, low energy, anxiety or slowness in thinking and movements in bipolar patients. CoQ10 has been used to increase cell energy production and as an antioxidant. It has had some benefit in patients with Parkinson's disease and migraine and in prolonging survival in patients with cancer and heart failure.

Patients 18-65 years of age with bipolar disorder who are currently in a depressive episode of at least 4 weeks duration may be eligible for this study. The study has four phases, as follows:

Phase I: Medication Withdrawal

Patients taper off all psychotropic medications, usually over 1 to 2 weeks.

Phase II: Baseline Evaluation

After being off all medication for about 2 weeks, patients undergo the following procedures:

-Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). The two procedures are performed in an MRI scanner. Both tests use a strong magnetic field and radio waves to obtain images that provide information on brain anatomy and chemistry.

-Blood tests to assess mitochondrial function isolated from blood cells.

-Skin biopsy for tests of mitochondria. A small sample of skin tissue 5 x 5 millimeters is surgically removed.

Phase III: Administration of CoQ10 or Placebo

Participants are randomly assigned to take either CoQ10 or placebo (an inactive look-alike substance) twice a day by mouth. While taking the study medication, patients have the following procedures periodically:

-Rating scales for anxiety and depression and adverse events.

-Check of vital signs.

-Blood and urine sample collections.

Phase IV: Study Completion

At the end of the 8 weeks of treatment, patients have a physical examination and electrocardiogram, and the procedures in phase II are repeated. Participants may then receive short-term treatment (up to 12 weeks) with medications for bipolar depression, followed by referred to a community physician for long-term treatment.

Sponsoring Institute:

National Institute of Mental Health (NIMH)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

- Male or female subjects, 18 to 65 years of age.

- Female subjects of childbearing potential must be using a medically accepted means of contraception.

- Each subject must understand the nature of the study and must sign an informed consent document.

- Subjects must fulfill the criteria for Bipolar disorder depressed without psychotic features including rapid cycling as defined in DSM-IV based on clinical assessment and confirmed by structured diagnostic interview SCID-P.

- Subjects must have an initial score at Visit 1 and Visit 2 of at least 16 on the MADRS

- In bipolar II disorder, subjects must have experienced, in the opinion of the investigator, at least two previous hypomanic and two major depressive episodes as defined in DSM-IV.

- Current major depressive episode at least 4 weeks in duration.

EXCLUSION CRITERIA:

- Subjects who are currently on a mood stabilizer for maintenance treatment and are benefiting from it.

- Current diagnosis of primary anxiety disorder necessitating treatment (subjects with OCD will be excluded).

- Presence of psychotic features

- Participation in a clinical trial of another investigational drug within 1 month prior to study entry (Visit 1).

- Female subjects who are either pregnant or nursing.

- Serious, unstable illnesses including hepatic, renal, gastroenterological, respiratory, cardiovascular (including ischemic heart disease), endocrinology, neurological, immunologic, or hematological disease.

- Subjects diagnosed with a mitochondrial disorder.

- Subjects taking other putative mitochondrial enhancers (e.g., vitamin E, carnitine, creatine, Vit complex B, pramipexole; see Appendix B) by the time of randomization (Visit 2).

- Subjects taking Statins

- Subjects with Diabetes Mellitus (Type I and Type II)

- Subjects with a history of clotting disorders or needing anticoagulants e.g. warfarin.

- Subjects with history of deep vein thrombosis or the following risk factors for DVTs, smoking and/or contraceptives (30 days before Visit 2).

- Subjects with uncorrected hypothyroidism or hyperthyroidism.

- Subjects with one or more seizures.

- Documented history of hypersensitivity or intolerance to CoQ10.

- DSM-IV substance abuse (except caffeine) within the past 12 months, 1 month for nicotine.

- DSM-IV lifetime substance dependence (except caffeine).

- Treatment with an injectable depot neuroleptic within less than one dosing interval prior to Visit 2.

- Treatment with a reversible MAOI, guanethidine, or guanadrel within 1 week prior to Visit 2.

- Treatment with fluoxetine within 6 weeks prior to Visit 2.

- Treatment with any other concomitant medication 1 day prior to Visit 2.

- Treatment with clozapine or ECT within 1 month prior to Visit 2.

- Judged clinically to be at serious suicidal risk.

Healthy Control Sample: Twenty-six subjects (ages 18-65) who do not meet criteria for any major medical or psychiatric disorder (using SCID -NP) will undergo imaging and mitochondrial assay part of the study and serve as control group. Control subjects will be matched to bipolar subjects for age, gender, Body Mass Index (BMI) plus or minus 2.

Special Instructions:

Currently Not Provided

Keywords:

Depression

Magnetic Resonance Spectroscopy

Mitochondrial Enhancer

Manic Depressive

Bioenergetics

Recruitment Keyword(s):

Bipolar Disorder

Manic Depression

Condition(s):

Bipolar Affective Disorder

Depression

Investigational Drug(s):

Coenzyme Q10

Investigational Device(s):

None

Intervention(s):

Drug: Coenzyme Q10

Supporting Site:

National Institute of Mental Health

Contact(s):

Libby Jolkovsky
National Institutes of Health
Building 10
Room 7-5563
10 Center Drive
Bethesda, Maryland 20892
Phone: (877) 646-3644
Fax: (301) 402-9360
Electronic Address: libby_jolkovsky@nih.gov

Citation(s):

Arias-Mendoza F. In vivo magnetic resonance spectroscopy in the evaluation of mitochondrial disorders. Mitochondrion. 2004 Sep;4(5-6):491-501. Epub 2004 Sep 30.

Baker SK, Tarnopolsky MA. Targeting cellular energy production in neurological disorders. Expert Opin Investig Drugs. 2003 Oct;12(10):1655-79. Review.

Bertolino A, Frye M, Callicott JH, Mattay VS, Rakow R, Shelton-Repella J, Post R, Weinberger DR. Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry. 2003 May 15;53(10):906-13.

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