J. Raymond DePaulo, Jr., M.D., is Professor of Psychiatry and the Director of the Affective Disorders Clinic at the Johns Hopkins University School of Medicine.

Bipolar disorder is an episodic disorder primarily affecting moods, emotions, self-attitude, energy, and concentration. It typically occurs in manic and depressive episodes, and the severe form of the disorder, classical manic-depressive illness, or bipolar type I illness, affects about 1 percent of the American population. A milder form of the disorder, bipolar II, is characterized by severe depressive episodes but less intense manic periods; we do not know its prevalence.

Bipolar type I can be a severely disabling illness, and even lethal; a high percentage of people with manic-depressive illness commit suicide. A Swedish study shows that the rate of suicide for people with depression or manic-depressive illness is 650 per 100,000 per year, compared with 8 per 100,000 per year in the general population.

Studies of twins conducted since the 1930s show that monozygotic (genetically identical) twins tend to share the disorder (are concordant) more frequently than dizygotic, or fraternal (nonidentical) twins. Genes thus play an important role in this disorder; and since the concordance never reaches 100 percent, we know there also are significant non-genetic factors involved.

In approaching this mysterious disorder from the genetic perspective, researchers have pursued two strategies in the last decade to search for genes involved in its cause. One strategy is to collect a few large pedigrees or families in which several members, through several generations, have the disorder. The other strategy is to collect a large number of small families in which multiple siblings have the disorder.

We chose to collect small pedigrees, gathering about sixty pedigrees in one study and seventy pedigrees in another. Most of our pedigrees had at least two siblings with the disorder. We interviewed all siblings, their parents, and, if possible, some aunts and uncles, and we collected blood samples to obtain their DNA or genetic material.

My role in this research as a clinician is to describe the phenotype so that the geneticists can compare variations in the phenotype to variations in the DNA. By examining and interviewing patients, we diagnose the severity of the disorder and classify it.

We found one pedigree that had six siblings with severe manic-depressive illness and neither parent with affective disorder. Given this, our geneticist colleagues thought that finding the relevant gene would occur quickly. Unfortunately in the ten years since then, we have found only one other family like this.

In most of the families there is a mixture of phenotypes: bipolar I, bipolar II, and unipolar disorder, which is severe recurrent depression. Clinically diagnosing an affective disorder can be difficult. Out of the 500 people we interviewed for this study, there were 150 about whom we were not sure. We considered them as "unknown" rather than guess whether they were affected or not.

What we found was a surprising number of bipolar IIs; in fact bipolar II seemed the most frequent phenotype in the relatives of the bipolar I patients. Based on this, we hypothesized that bipolar II is a simpler form of the disorder. We also observed that in our pedigrees the maternal relatives were more likely to be affected than the paternal relatives.

When the DNA was studied, we and others found some evidence for linkage of bipolar disorder to markers on chromosome 18. In the two analyses we have done, bipolar II/bipolar II sibling pairs shared 82 percent of alleles at six consecutive markers on the long arm of chromosome 18. And in our studies and those of Wade Berrettini and colleagues, the sharing seems greatest on the paternal copy of chromosomes 18. That is, the smaller fraction of families appear to have evidence for linkage on this particular chromosome, while the larger group of maternally transmitting families appear to have some other genetic form of the illness.

Exciting as this is, we still have not found any of the genes that confer vulnerability to these disorders. We can treat mood disorders today with a number of pharmacological preparations, but we do not know why they work or why they fail when they fail. Identifying the genes involved would help us begin to understand how the illness occurs (for example, what are the key effects in the brain) and give us a chance to design rational treatments.

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