Applying Molecular Approaches to Understand the Etiology and Treatment of Bipolar Disorder

Abstract

Bipolar disorder is characterized by episodes of mania and depression that are frequently acute, debilitating, and conducive to gross social dysfunction and an elevated suicide rate.1-4 While often lifelong and affecting about 1.5% of the population, the condition responds to, and in some cases is controlled by, pharmacologic treatment-particularly with mood-stabilizing agents. Although there is a clear consensus on the importance of factors in the development of bipolar disorder, and a substantial quantity of scientific investigation has been undertaken, the etiology and operative pathophysiologic processes are still unclear. Early research attention focused on monoaminergic neurotransmitter systems distributed in various brain regions, but the corresponding development of novel or improved treatments for bipolar disorder based on this research has not occurred. Long-term administration of mood stabilizers has for many years been used both for treatment of acute manic and depressive episodes and for prophylaxis against future episodes. Mood stabilizers such as lithium and valproate are among the most common treatments with the emergence of secondgeneration antipsychotics. While these treatments have made a vast improvement in our patients' lives, there is room for more effective treatment with even fewer side effects. Understanding the etiology and the specific pathophysiologic processes of bipolar disorder is critical to the development of such new treatment approaches. Among the strongest clues to the basis of bipolar disorder is the large body of evidence suggestive of genetic predisposition. Recent findings indicate that the pathologic process of this disorder is involved in complex interactions between multiple susceptibility genes and environmental factors.5,6 Recent advances in genetics, and cellular biology, neuroscience, and imaging technology have provided a variety of new and sophisticated approaches to evaluate the complex features of this disease. These new genetic, pharmacologic, and and cellular approaches to the study of the etiology of disorders and the mechanism of action of psychotropic drugs have been very instructive in refining our understanding. Given the many widely used advances in investigative approaches and technologies, the term molecular psychiatry has been readily adopted to replace the older biological psychiatry. Important among these advances, high density DNA expression microarray technology has recently been widely adapted by scientists in the search for susceptibility genes for bipolar disorder.7-9 The great advantage of this technology is that it allows us to monitor, on a genomic level, the expression of hundreds of known and unknown genes simultaneously.10-12 In this issue's In Review section, Dr Tadafumi Kato and coauthors13 review recent findings in bipolar disorder studies using DNA microarray analysis. Gene candidates coding for proteins related to mitochondrial function and apoptosis, glutamate receptors, markers of GABAergic neurons, chaperones, and oligodendrocyte proteins are differentially expressed in postmortem brain tissue, peripheral blood cells, and olfactory neuroepithelium between control and bipolar disorder subjects. The next steps are to determine the role these gene candidates played in the pathophysiology of bipolar disorder and to identify which, if any, of these candidates are targeted by mood-stabilizing treatment. As mentioned, mitochondria-related genes are one of the candidate groups revealed by DNA microarray analysis to be abnormally expressed in bipolar disorder. Increasing evidence has shown the presence of mitochondrial dysfunctions such as deletion, mutation and abnormal expression of mitochondria-related genes, increased anaerobic glycolysis, and impaired phospholipid metabolism. Because mitochondrial oxidative phosphorylation is the major resource for the generation of reactive oxygen species, mitochondrial dysfunction indicates that oxidative stress may occur in bipolar disorder and that oxidative stress-induced damage may be prevented by mood-stabilizing treatment. …