SANTA FE, N.M.--Mitochondrial dysfunction plays a role in recurring mood disorders, and might help explain why most treated patients eventually have relapses or recurrences, according to a leading investigator in psychiatry and pharmacology.
Unipolar and bipolar disorder are not mitochondrial diseases, but both appear to involve mitochondrial dysfunction. Dr. Richard C. Shelton told attendees at an annual psychiatric symposium sponsored by the University of Arizona.
The evidence is strong in bipolar disorder, and emerging in major depressive disorder, he said. Moreover, patients with mitochondrial diseases, such as certain forms of Parkinson's, might be at increased risk of depressive disorders.
"Future treatment development may involve modulation of mitochondrial function," said Dr. Shelton, James G. Blake-more Research Professor of Psychiatry and professor of pharmacology at Vanderbilt Medical Center in Nashville, Tenn.
Lithium and valproate--two agents commonly used in bipolar disorder--interact with mitochondria, he noted. In addition, some mitochondrial-targeted antioxidants in drug development for mitochondrial diseases "may be useful for bipolar disorder." One investigational agent, triacetyluridine, significantly reduced depressive symptoms of 11 bipolar disorder patients in a 6-week trial (Exp. Clin. Psychopharmacol. 2008;16:199-206). "We can say with reasonable confidence that bipolar disorder is a condition of mitochondrial dysfunction," Dr. Shelton said, citing molecular and magnetic resonance spectroscopy studies, including a meta-analysis of the latter in bipolar disorder (Mol. Psychiatry 2005;10:900-19).
As an example of the more recent evidence in unipolar depression, he described a postmortem brain tissue study conducted in his laboratory. The investigators compared brain tissue from 20 deceased patients known to have been depressed at the time of death to tissue from 20 nondepressed controls.
Microarray analysis found three genes were upregulated only in the depressed patients: YBX1, COP1, and FKSG2. All three are known to be upregulated under oxidative stress, he said, after tying mitochondrial dysfunction to the release of harmful reactive oxygen species and free radicals.
All the samples from depressed patients had low levels of metallothionine, with the reduction from normal levels ranging from 60% to 99% and averaging 90%. This "strongly suggests" depression involves suppression of a major buffer to reactive oxygen species, Dr. Shelton said.
In another study that compared plasma from patients with major depression with and without melancholia to the plasma of healthy controls, depressed patients had significantly higher antioxidative enzyme and lipid peroxidation levels, he added (J. Affect. Disord. 2001;64:43-51).
As outlined by Dr. Shelton, the relationship between depressive disorders and mitochondrial dysfunction can be traced to the electron transport chain located in the inner membrane of mitochondria. A series of protein complexes, the chain synthesizes adenosine triphosphate. The number of proteins involved and the complexity of the process create "unfortunately lots of places to have problems along the way," he said. …