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. Blakemore 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.
When the process goes awry, electron leakage can generate reactive oxygen species, which in turn may cause DNA damage, inactivation of proteins through amino acid oxidation, and fatty acid oxidation, said Dr. Shelton. Accordingly, the body has multiple mechanisms to buffer reactive oxygen species: among them, antioxidants, superoxide dismutases, catalases, glutathione/glutathione perioxidases, and metallothionines.
According to Dr. Shelton, among the possible causes of mitochondrial dysfunction in mood disorders are increased rate of oxygen consumption, reduced effects of specific neurotransmitters, alterations in “antioxidant potentials” (as might occur with low metallothionine), changes in certain metals (iron, copper, and zinc), and alterations in the sequences and/or expression of mitochondrially related DNA.
Dr. Shelton urged study of agents that target mitochondrial dysfunction either as monotherapy or as adjuncts to established therapies. New targets are necessary in depressive disorders, he said; improving on old ideas does not go far enough in overcoming the shortcomings of current therapies.
Dr. Shelton disclosed grant/research support from eight pharmaceutical companies, and said he serves on the speakers bureau for five companies.
Supplements Can Act as Modulators
Some common nutritional supplements sold on the Internet and in health food stores are mitochondrial modulators that might help patients who are being treated with common therapies for depressive disorders, Dr. Shelton advised.
Two supplements that he recommends to his own patients are N-acetyl cysteine (NAC) at a dose of 2 g per day and acetyl-l-carnitine (ALCAR) at a dose of 500 mg twice a day. His patients have benefited from adjuvant use, he said, with the caveat that such evidence is anecdotal.
N-acetyl cysteine did improve symptoms of bipolar depression in a double-blind study of 75 patients (Biol. Psychiatry 2008;64:468-75) cited by Dr. Shelton. He noted that given at a dose of 1 g twice a day in this trial, it was slow to accumulate, producing a statistically significant benefit at 20 weeks. Withdrawal at 24 weeks led to “a dramatic return” of symptoms, he said.
ALCAR has been studied as well, mostly in elderly patients, for depression, he said.
Also on his list of mitochondrial modulators to consider from the health food store were coenzyme Q10 (CpQ10) at 300 mg per day, alpha lipoic acid (ALA) at 600 mg twice a day, and creatine monohydrate at 3-5 g per day. While ALA has been studied in numerous clinical trials, none has been in unipolar or bipolar disorder, he said.
Multiple trials have shown benefit from another supplement, S-adenosylmethionine (SAMe), in major depressive disorder, but Dr. Shelton discouraged its use. SAMe helps form glutathione, a buffer to reactive oxygen species, he said. The hitch is that homocysteine is formed in an intermediate step.
“There is a strong literature on the relationship between accumulation of homocysteine and increase of cardiovascular disease …. This leads me to concern that you might develop elevated homocysteine levels,” he said.
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