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
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
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.
United States: Federal Government
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