After many years of struggling to identify the genetics of major psychiatric disorders, researchers are reporting major progress in identifying areas involved in bipolar disorder. The findings will hopefully lead to innovative therapies for people suffering from the disorder.

One of the leading experts in the field, John Nurnberger, Jr., M.D., director of the Institute for Psychiatric Research at Indiana University School of Medicine, is the national coordinator of a new study that will include 5,000 participants with bipolar I disorder. He is also conducting an investigation targeting vulnerable adolescents in the hope that early detection may prevent the overwhelming and often tragic con sequences of bipolar illness.

Indiana University School of Medicine is the coordinating site for the National Institute of Mental Health study that will involve 11 other major research sites. Post readers have been particularly helpful by participating in familial studies. Researchers now hope that volunteers will step forward to enroll in the new trial that needs an additional 2,500 participants. To learn more about the emerging science and the Collaborative Genomics Study of Bipolar Disorder, the Post spoke with Dr. Nurnberger.

Post: Could you discuss the latest research on bipolar disorder?

Dr. Nurnberger: Over the past 15 years, we have been trying to identify the biochemical pathways--the neuronal pathways--involved in bipolar illness. This work has been in the theoretical stage for a long time and now is becoming much more concrete. The findings bring us from the abstract world of genetics to the concrete world of the brain and show us where in the brain and on which subcellular structures and pathways we need to concentrate to find the therapies. Some of the new findings are targeting the brain-signaling system that uses the chemical glutamate.

Post: Are you collaborating with other universities?

Dr. Nurnberger: Other universities around the country are contributing to this project, including Howard, Johns Hopkins, University of Pennsylvania, University of California at San Diego and San Francisco, University of Chicago, Rush, University of Michigan, Iowa, Washington University at St. Louis and the National Institute of Mental Health Intramural Research Program, Indiana University School of Medicine is the coordinating center for the collection efforts, Over the past two years, we have collected DNA samples from individuals with bipolar illness who are unrelated to each other. We are proceeding with detailed genetic studies (genome-wide association, or GWA) in the first 1,200 cases and a large set of controls. This is a new technique that allows us to test approximately one million DNA markers in each subject and screen for association with illness. It has been difficult to locate as many patients as we need. We know many people are out there and that they would want to participate. Post readers can hopefully help us,

Post: Who might be eligible?

Dr. Nurnberger: We are looking for individuals who are 16 or older with bipolar I disorder, If persons have been hospitalized or incapacitated with a manic episode, they will meet our criteria. Participants will be asked to give a DNA sample for analysis and undergo an interview. If it's not convenient for them to go to one of our centers, we can conduct the interview over the phone and send the blood kit to his or her doctor's office. We also pay people for their time.

Post: Are you also working on a project dealing with adolescents who have bipolar disorder?

Dr. Nurnberger: This investigation flows from the project we are discussing in that we are studying adolescents at risk for bipolar disorder. The population includes 12- to 18-year-olds with parents who have bipolar I illness. In this case, we are looking for familial illness, ideally, the parent is enrolled in a genetic study already, because an important part of this investigation is to use available genetic information to identify risk and protective factors in the adolescent. We hope that the study provides a way for early identification and, ultimately, prevention of these disorders. We want to see the earliest phases of illness among those who are genetically vulnerable and to see what we can do to intervene.

Post: Do you regard current progress in genetics as a promising step?

Dr. Nurnberger: It is a major stride. This is a very exciting time in genetic studies of psychiatric disorders. The next decade or two will change our whole way of thinking about menial illness and put us on a much firmer footing because we will know the neurobiology of the disorders. It really is a critical time.

Post: Has the publicity to raise awareness and the fact that well-known individuals are going public about their disorders helped decrease the stigma associated with them?

Dr. Nurnberger: There already has been a major impact of educational efforts by the NIMH, the World Health Organization (WHO), and other entities over the past decade. The general public is much more willing to recognize that bipolar illness is real: it's not an excuse for bad behavior or a personality weakness. It's a brain disorder that involves particularly the frontal lobes and the limbic (emotion processing) system. From the work of the WHO, we also understand more about the tremendous disability associated with these disorders. It's becoming clear that depression, bipolar illness and related disorders are some of the most disabling conditions for people worldwide.

Post: Is any ethnicity or group of individuals at higher risk for bipolar disorder?

Dr. Nurnberger: These disorders are widely distributed through all populations. However, the genetic markers are not necessarily the same for ethnic groups, which speaks to the complexity of the disorders. Take one gene--for example, the serotonin transporter gene on chromosome 17 that controls the uptake of serotonin in the synaptic cleft between neurons. It works the same way in everyone. But there are many different ways that this gene can vary in its sequence. The variations that have been studied differ tremendously among African-Americans, Americans of European ancestry, and persons of East Asian extraction. The vulnerability indicators may be different in ethnic groups, even though they may indicate the same problem at the level of the neuron.

Post: What's the latest news about treatment?

Dr. Nurnberger: The one new medication that I would emphasize the most for bipolar disorder is lamotrigine, a mood stabilizer that was developed originally as an anti-seizure medication. It is similar to lithium in that it is a maintenance medication serving as a foundation for people with bipolar disorder. It prevents both the high and low episodes from occurring over time. However, it is better for the lows than for the highs, which is the opposite of lithium. We have had much experience and good results with lamotrigine now. Sometimes we use both medications (lamotrigine and lithium). However, some patients are well suited for lamotrigene by itself. For example, bipolar Il patients are perfectly matched with the profile of lamotrigine.

Post: Is lamotrigine safer than lithium?

Dr. Nurnberger: The side effect profile is very favorable; it is easier to take than lithium. It doesn't re quire blood levels. There can be a rare hypersensitivity reaction that manifests as a generalized skin rash, so we adjust the dose slowly over a period of several months. If we use the suggested protocol, there is very little problem with anyone getting the hypersensitivity reaction.

Post: How can people learn more about participating in the genetic study?

Dr. Nurnberger: The toll-free number is 1-888-750-2201. There is also a website: www.iupui.edu/%26sim;bipolar. Our e-mail is bipolar@iupui.edu.