Oxidative Stress May Be Culprit When Bipolar Illness Damages DNA

Brazilian scientists have made a tantalizing discovery about bipolar disorder. It looks as if bipolar disorder can damage DNA, and thus the pathophysiology of bipolar disorder is not confined to the brain.

The lead researcher was Flavio Kapczinski, M.D., Ph.D., a professor of psychiatry and director of the Bipolar Disorders Program and Molecular Psychiatry Unit at Hospital de Clinicas & Federal University of Rio Grande do Sul in Porto Alegre, Brazil. Their results are in press with Psychiatry Research.

Kapczinski and his colleagues took peripheral blood cells from 32 bipolar subjects without any comorbid medical illnesses and from 32 mentally and physically healthy volunteers. The bipolar subjects used no medications except for those prescribed for their bipolar illness. The control subjects were not on medication. None of the subjects smoked.

The researchers assessed DNA damage in cells from the two groups of subjects. They found that the damage was markedly greater in the cells from the bipolar illness group than in those from the controls; the difference was highly significant statistically.

Since the bipolar-illness subjects had no other medical illnesses, Kapczinski and his colleagues thought it unlikely that the excess of DNA damage in the subjects' cells was due to comorbid medical conditions. The scientists also conducted an in vitro assay to determine whether the medications used by the patients could induce DNA damage. The answer was no—the psychotropic medications the bipolar subjects were taking did not seem to explain the excess DNA damage in their cells. Thus the researchers concluded that the damage was due to the subjects' bipolar disorder.

Kapczinski told Psychiatric News that he and his colleagues believe that bipolar illness damages DNA by causing oxidative stress—that is, oxidative damage—to cells in the body.

Their reasoning goes as follows. In this study, they found that the extent of DNA damage in bipolar subjects' peripheral blood cells correlated with the severity of the subjects' mania and depression as assessed by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. And in an earlier study they found that oxidative stress in bipolar subjects' peripheral blood cells increased during mania and depression. Thus it is logical that bipolar disorder, especially during active illness phases such as mania and depression, could trigger oxidative stress in cells and that this stress in turn could damage DNA in those cells. Moreover, in an animal experiment, they found that levels of DNA damage in both nerve cells and peripheral blood cells correlated with increased oxidative stress.

But how might bipolar illness unleash oxidative stress in body cells in the first place? By causing mitochondria in those cells to malfunction, Kapczinski proposed. Not long ago, he said, researchers found that white blood cells taken from bipolar subjects had abnormal mitochondrial electron transport, which is the mechanism whereby cells deal with oxidative stress.

“Altogether, our findings of DNA damage in bipolar disorder seem to be related to increased oxidative stress due to mitochondrial dysfunction,” Kapczinski said. “It is reasonable to suppose that if mitochondrial dysfunction and consequently increased oxidative stress are present in bipolar disorder, such changes would not be confined to the central nervous system and would therefore be expressed in peripheral blood cells.”

Persons with bipolar disorder often have multiple chronic medical illnesses, spanning nearly every organ system in the body (Psychiatric News, November 17, 2006). An emerging body of evidence has linked DNA damage with various medical conditions. Thus, these findings “provide an important clue as to why patients with bipolar disorder have increased rates of physical comorbidities,” Kapczinski noted.

The results also have implications for psychiatrists, he suggested.“ Clinically, this emerging body of evidence shifts the paradigm of intervention in bipolar disorder. Treatment should be provided as early and effectively as possible to avoid the detrimental effects of cumulative mood episodes. Treating bipolar disorder effectively would not only improve the lives of patients but also reduce their overall morbidity and mortality rates. The investigation of new interventions using antioxidant agents as adjunct therapy in bipolar disorder is warranted.”

“Another intriguing possibility,” he said, “is that in the future the severity of bipolar disorder would be assessed not only clinically, but also by means of lab tests such as levels of DNA damage and oxidative stress.”

The study was funded by Fundacao de Amparo a Pesquisa do Rio Grande do Sul, Conselho Nacional de Pesquisa, Hospital de Clinicas de Porto Alegre, Federal University of the Rio Grande do Sul, and the University of Caxias do Sul.

An abstract of “DNA Damage in Bipolar Disorder” can be accessed at<www.sciencedirect.com> by clicking on “P” under “Browse by Title,” then“ Psychiatry Research,” then “Articles in Press.” ▪