NARSAD Honors Three Pioneering Researchers

The National Alliance for Research in Schizophrenia and Depression (NARSAD) awarded the 2000 Nola Maddox Falcone Prize for Outstanding Achievement in Affective Disorders Research to three pioneering researchers. The co-awardees for the $50,000 prize were Robert H. Belmaker, M.D., Hoffer-Vickar professor of psychiatry at Ben Gurion University and director of the Stanley International Research Center in Beersheva, Israel, for his work on the neurobiology and therapeutics of bipolar illness; Kay Redfield Jamison, Ph.D., professor of psychiatry at Johns Hopkins School of Medicine, for her seminal writings on suicide and manic depression; and A. John Rush Jr., M.D., professor and vice-chair of research and Betty Jo Hay Distinguished Chair in Mental Health in the department of psychiatry at the University of Texas Southwestern Medical Center, for his work on guidelines for the treatment of unipolar depression and development of the Texas Bipolar Algorithm project.

In New York City, the night before the October award ceremony, NARSAD held a gathering of scientists and board members, at which Belmaker and Jamison spoke about their careers. Rush, who was unable to attend, was represented at the gathering by Harold Sackeim, M.D., chair of the department of biological psychiatry at the New York State Psychiatric Institute of Columbia University College of Physicians and Surgeons.

Belmaker, who has lived in Israel since 1974, told attendees that one of the joys of research is its international aspect. "All over the world, there are people who see each other once or twice at meetings but who feel very much part of an effort to try to reduce the burden of suffering of human beings," he said. "There is a sense of camaraderie in that effort."

Belmaker said that in medical school, he had a "burning desire" to help psychiatric patients. "But I naively thought that what the world needed to help patients was a good five-dollar-an-hour psychotherapist," he said. "When I got to [the National Institute of Mental Health in the 60s], I realized that health care delivery isn't enough. [Rather,] we have to really know what we want to deliver and what we have to deliver, and to a large extent what we have to deliver isn't really enough for our patients' needs. And along with health care delivery, we need to make those advances in research that will allow us to have more and more to deliver."

Belmaker said he has always retained some skepticism of the pharmaceutical companies' role in new treatment development. "There's no question that we need them [and] need to be partners with them-they've done a lot of good. But I think an organization like NARSAD is absolutely essential to make sure there is funding for ideas that won't necessarily make a profit," he said, reporting that his early funding proposals for work on transcranial magnetic stimulation were rejected until he applied for a NARSAD senior investigator award, which finally enabled him to do the first psychiatric study of that technique.

Belmaker-whose research has suggested that a component of lithium's antimanic activity may be based on its ability to inhibit adenylate cyclase-said he has always seen himself as an unorthodox thinker. "One of my early studies was the first controlled study of lithium in a spectrum of affective symptoms...[from] patients with schizophrenia to patients with pure bipolar illness," he said. "At that time, people were very interested in developing-as they still are today-diagnostic systems in psychiatry. And our finding was that there was no diagnostic border that could predict on [which] side...lithium helped and on which side it didn't. We had a lot of trouble getting that published, although today I think it would be rather well accepted that whatever diagnostic systems we have now don't really clearly predict drug response."

Continued Belmaker, "That's been another theme of my research and career the difficulty in making sense of the fact that on one hand we so strongly need controlled clinical trials of homogeneous populations that give, in the end, a statistically significant result on the average. On the other hand, as clinicians we know that individual patients very often, more often than not, respond according to the results of the controlled studies, which only give you a mean. And since we don't have good enough diagnostic systems, often the process of finding the best treatments for patients is a trial-and-error phenomenon that requires the physician not believing too much in those very same controlled studies."

Belmaker next noted that dietary manipulations were very popular in psychiatry a century ago but went out of fashion because they were not based on controlled scientific evidence. "They've come back into medicine because we know now that...in many illnesses diet is a key risk factor," he said. "Several dietary constituents are key precursors for brain metabolism. And to the extent that there are scientific data showing that these metabolic substances and diets are not present in excess, we ought to look at adding or subtracting them in terms of their potential role in treating mental illness." To that end, his group has been examining the sugar-like substance of inositol both for depression and as a method of enhancing lithium effects. Belmaker proposed, "Psychiatry again ought to follow medicine and go back to looking at diet, something that 20 or 30 years ago we would've been running away from."

Following Belmaker, Jamison, who has a history of manic depression, told attendees that before she had her first "flaming" psychotic mania, she was doing "all sorts of things in zoology and mathematical psychology and so on." She added that while there were not many advantages to her first breakdown, one advantage was that it quickly channeled her intellectual interests.

"Everything else that I had been studying elephant behavior at the zoo, you name it went out the window and I got very focused on the study of manic depression," she said. Her particular interest is studying intense moods. "When I was an undergraduate I had read Varieties of Religious Experiences by William James [Penguin Putnam, 1982] and it really completely changed my career choice around because the focus of that book, in many respects, is exactly that," she said. "I have continued with the interest of intense moods in the lives of individuals and societies in which individuals live."

Jamison who with Frederick K. Goodwin, M.D., wrote the textbook Manic-Depressive Illness (Oxford University Press, 1990), which is now being updated said the borders between intense, expansive and high-energy states and psychopathological ones are permeable, mutable and important.

"They're extremely damaging states destructive, painful, devastating, potentially lethal states but they're interesting states," she said. "These borderlines have within them a volatility and a flux, and on occasion the capacities which move our societies forward, inspiring some great poets and some great musicians. But they also create a dangerous undertow of seduction and deadliness," she said, adding that one area that is the least studied in psychiatry is the fact that although there are effective medications for manic depression, too often, people will not take them. "You may as well not have the medications if people don't take them," she said. "One of the problems with mania is that for the 50% of people who have expansive and euphoric manias, they are deeply and profoundly addictive not only at a psychological level, but I believe at a biological level as well."

Noncompliance needs to be addressed in adolescents, Jamison stressed. "One of the things that we know about manic depression, and depression and schizophrenia, is that people kill themselves...young. They kill themselves early on in the course of the illness, and that means they're killing themselves at a time when they're least likely to comply with treatment." Jamison said that her decision six years ago to go public with her own illness was not easy and is one that she has had a lot of time to regret in some ways. Still, she said she would do it again in a heartbeat, because she claims that one problem with mental illnesses is that most professionals keep their own suffering a secret.

"As a result, people have a very skewed notion of what severe mental illness is all about. A lot of professionals have severe mental illnesses, but because they don't talk about them...people have the notion that they're untreatable." Jamison, who is also an honorary professor of English at the University of St. Andrews in Scotland, has written, or been co-author of, fivebooks, including the New York Times bestsellers An Unquiet Mind: A Memoir of Moods and Madness (Random House, 1996) and Night Falls Fast: Understanding Suicide (Random House, 1999). She is now working on a book about exuberance.

"I'd like to make a pitch for the importance of books and high passion," she said. "And I say this in the context of being a great respecter of basic science, a total respecter both as loving it and loving the elegance that's coming out of genetics and all of the great neuroscience that's being done, and believing that that's where lives are saved. But I think there's been a tendency, perhaps, to undervalue the importance of books in the intellectual life of a society. So if there are any of you who really love to write and want to write, keep that going. Don't be persuaded by the conformity of a field that says 'article after article after article.' Keep publishing the articles, but also keep the possibility alive of writing books."

Following Jamison, Sackeim talked about Rush's contributions to the development of new treatments for depression.

"As a resident, he was mentored by Aaron Beck [M.D.] at the University of Pennsylvania, where he conducted the first prospective controlled trial of outpatients of the use of a modularized cognitive-behavioral therapy to treat depression," Sackeim reported. "[Rush has] gone on to extend the use of cognitive therapy not just to adults with major depression, but also to adolescents and individuals with bipolar disorder. This is clearly an alternative to some of our somatic treatments."

Sackeim said that Rush was also critical in the evaluation of sodium valproate (Depakene, Depakote Sprinkles) in mania treatment, which is now standard treatment, and, with colleagues, conducted the first study showing that Prozac (fluoxetine) worked in depressed adolescents. Furthermore, Rush and colleagues, including Sackeim, are studying the use of vagus nerve stimulation, a promising and moderately invasive treatment for refractory unipolar and bipolar depressions. "Currently, much of the biological mechanisms work that John is doing is focused on a totally different area, which is, 'What's wrong in the brain before you get depressed?'" said Sackeim. "What are the factors that are going to, in essence, let us know that one year or two years or 10 years later a major depression will develop? And there's been very promising work using sleep abnormality indexes and the sleep [electroencephalogram] as predictors of the onset of depression."

Another pioneering area of Rush's work has been developing and testing algorithms for treating major mental illness. The most recent component of that work is his role as principal investigator for an NIMH-supported study that aims to define empirically which of several different treatments are most effective for treatment-refractory depression. That $27 million study, called STAR*D (Sequenced Treatment Alternatives to Relieve Depression), will include 4,000 patients.

"So I think you've gotten the flavor of John's work," Sackheim said. "It's extended from the development of new treatments, to the investigation of biological mechanisms, to going into the services arena and asking, 'How can we bring this work to the public in a way that helps?'"