An Investigation Examining the Evidence for Mitochondrial Dysfunction in the Pathophysiology and Treatment of Bipolar Disorder
18 Years
65 Years
Both
Bipolar Affective Disorder, Depression
Trial Information
An Investigation Examining the Evidence for Mitochondrial Dysfunction in the Pathophysiology and Treatment of Bipolar Disorder
Bipolar affective disorder is a common, severe, chronic and often life-threatening illness.
The depressive phase contributes to the majority of morbidity and mortality in this illness.
Impairments in physical and social functioning resulting from depression are often as severe
as other chronic medical illnesses. Few of the treatments in use have resulted from an
understanding of the pathophysiology of bipolar disorder. Undoubtedly, a greater
understanding of the pathophysiology of bipolar disorder will lead to improved treatments.
Current theories of depression suggest that mood disorders are associated with impairments
of cellular resilience and structural plasticity possibly a result of abnormal cellular
energy metabolism. Studies with Magnetic Resonance Spectroscopy (MRS) in bipolar subjects
show reduced brain intracellular pH and reduced ATP. Cellular energy generated by
mitochondrial oxidative phosphorylation from glucose via the electron transport chain is
stored as ATP, which provide neurons and glia with energy required to maintain their
function. Mitochondrial dysfunction and its inability to compensate for increase in ATP
demand might lead to impaired cellular resilience believed to be involved in the
pathophysiology of bipolar disorder. Abnormal regulation of nuclear genes coding for
mitochondrial proteins in the hippocampus of bipolar subjects provides further evidence of
mitochondrial dysfunction in bipolar disorder.
Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial electron transport chain
necessary for cellular energy generation. Exogenous administration of CoQ10 attenuates ATP
depletion and has anti-oxidant properties. In light of the above evidence, we hypothesize
that bipolar disorder is associated with mitochondrial dysfunction as evidenced by impaired
brain energy metabolism and that administration of CoQ10, a mitochondrial enhancer, will
restore mitochondrial function. To accomplish these objectives, we will compare
mitochondrial functions in bipolar depressed subjects to 26 healthy controls matched for
age, gender and BMI. Measures of mitochondrial function will include brain lactate levels (a
product of anaerobic glycolysis) with H+ MRS, 2) assays of mitochondrial function in
cultured fibroblasts and platelets, and 3) gene expression of mitochondrial and nuclear
genes using a cDNA Microarray. Further, subjects with bipolar depression, ages 18 to 65 will
be randomized to either CoQ10 (300-1200 mg/day) or placebo in a double-blind placebo
controlled trial for a period of 8 weeks. Measures of mitochondrial function will be
compared between subjects randomized to placebo or CoQ10 at baseline and at the end of the
8-week trial.
Inclusion 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.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Outcome Measure:
Compare brain lactate levels between healthy controls and subjects with bipolar depression and assess in subjects w/bipolar depression the effect of of CoQ10 admin compared to placebo on the brain lactate signal obtained w/MRS w/photic stimulation.
Outcome Time Frame:
8 weeks
Safety Issue:
No
Authority:
United States: Federal Government
Study ID:
060162
NCT ID:
NCT00327756
Start Date:
May 2006
Completion Date:
Related Keywords:
- Bipolar Affective Disorder
- Depression
- Depression
- Magnetic Resonance Spectroscopy
- Mitochondrial Enhancer
- Manic Depressive
- Bioenergetics
- Bipolar Disorder
- Manic Depression
- Bipolar Disorder
- Depression
- Depressive Disorder
- Mood Disorders
Name | Location |
|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |
