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More than 430 psychiatrists, research donors and others gathered in late October for the National Alliance for Research on Schizophrenia and Depression (NARSAD)'s awards dinner in New York City. The black-tie fundraising event was held in conjunction with the organization's 10th annual scientific symposium at which 15 selected NARSAD grantees presented their ongoing research over two days of sessions devoted to basic science, schizophrenia and depression.

At the awards dinner, Mike Wallace and his wife Mary received NARSAD's 1998 Humanitarian Award for helping others understand psychiatric disorders. Wallace, co-editor of CBS television's "60 Minutes," is a diagnosed sufferer of depression.

Two $50,000 prizes for research also were awarded. George K. Aghajanian, M.D., professor of psychiatry and pharmacology at Yale University School of Medicine, was co-recipient of the Lieber Prize for Outstanding Research in Schizophrenia for his discoveries regarding neurotransmissions in the brain. These findings have been instrumental in furthering knowledge about schizophrenia.

Sharing the Lieber prize with Aghajanian was Sarnoff A. Mednick, Ph.D., Dr. Med., professor of psychology and director of the Social Science Research Institute at the University of Southern California. Mednick's research in the theory and epidemiology of schizophrenia has helped advance basic science relative to this disorder.

Martin B. Keller, M.D., professor and chair of the department of psychiatry and human behavior at the Brown University School of Medicine, was co-recipient of the Lieber Prize for Outstanding Research in Affective Illness (formerly known as the The Selo Prize). He and his colleagues developed a series of long-term studies using new methodological and statistical approaches to study the life course of depression and manic-depressive illness in adults and adolescents. Co-awardee for this prize was Julien Mendlewicz, M.D., Ph.D., professor of psychiatry at the Faculties of Medicine, Psychology and Law at the University of Brussels. Mendlewicz was recognized for his work in delineating pathophysiological mechanisms of unipolar and bipolar depression in terms of biochemistry, neuroendrocrinology, physiology and genetics.

A small dinner was held for the prize-winners the evening before the awards dinner. Each winner was given the opportunity to talk about their research. Taking the podium first, Aghajanian said that he was recently in Sweden to participate in a Nobel Foundation-sponsored meeting on schizophrenia, the first scientific conference on schizophrenia ever organized through those auspices.

"To see the Nobel Foundation recognize that schizophrenia is a problem that is akin to any other medical problem, that it can be approached scientifically, [and that] it's something that can be out in the open...was an important turning point in the emotional context in which we think of this disease," said Aghajanian.

He noted that while drugs now used in the treatment of schizophrenia are, in many cases, extremely helpful, there are still too many cases in which they are of limited benefit.

"The drugs that are now used, and have been used for many years, block certain kinds of messages that are transmitted through dopamine or serotonin," Aghajanian said. "At this [Nobel] conference, some of the work that was presented, including my own, went beyond that approach." He said that the particular target of all these new developments is the transmitter glutamate, through which serotonin and dopamine modulate excitatory messages in the brain.

"[Through] my work, and the work of several other investigators, we have reason to believe that in schizophrenia and drug models of schizophrenia, like the psychedelic hallucinogen model and the PCP ketamine model, the psychotic state may be ultimately a result of a disorder in glutamate transmission," Aghajanian said. "So this is a different twist on what you may have heard before."

Aghajanian next addressed the practical side of this approach, explaining that there are now tools-some of which have been developed in the pharmaceutical industry-whereby one can influence the type of messages transmitted through glutamate. "And some of the drugs that are able to modulate glutamate transmission can reverse the effects of drugs that we know can produce a psychosis," he added.

Aghajanian said his group and others are now in communication with pharmaceutical companies about the possibility of testing these new drugs in schizophrenic patients.

"I believe this will come about in the next year or so," he said. "Many new researchers are looking beyond the traditional transmitters and receptors at mechanisms that have not been considered in the past. And for me, this is a very exciting and really delightful new phase in trying to find new therapies for schizophrenia."

Following Aghajanian, Mednick discussed his past work and planned future work regarding the influence of teratogenic factors on later development of psychiatric disorders.

"Some years ago, I reported that if a woman suffers an influenza infection in the second trimester of gestation, that fetus has an increased risk of becoming schizophrenic," he said. "We later went back to the same population and looked for causes of affective disorders. And what we've now reported is that second-trimester infection also increases risk for affective disorders. This was puzzling because it removed the specificity of the influenza infection for the outcome of schizophrenia."

Therefore, said Mednick, his group then looked carefully at gestational ages of fetuses who later developed schizophrenia and affective disorders. They found that almost all fetuses who became schizophrenic came from mothers who had infections during the sixth month of gestation, whereas almost all the mothers of those with affective disorders had their influenza infection in the fifth month of gestation. Furthermore, in a later study of violent behavior using subjects from the same cohort, Mednick and colleagues found that a second-trimester influenza infection in the mother was also associated with an increased risk of violent behavior as an adult. In these cases, however, the maternal infections had occurred at the end of the sixth month and the beginning of the seventh month of gestation.

"We interpret all these findings as suggesting that there is a disturbance in the development of the brain [that] occurs as a function of this maternal influenza infection," Mednick said. "We suggest that there exist periods of fetal neural development during which a te-ratogen such as an influenza infection may increase the risk specifically for brain areas relating to schizophrenia. If the teratogen strikes during a different period of neural development that is not related to schizophrenia, then some other brain region may be involved...and if that brain region is important to another mental disorder, then the risk for that [other] mental disorder will be increased."

Mednick said he is proposing a paradigm that encourages the study of the short- and long-term developmental effects associated with the timing, nature and severity of a teratogenic disturbance. To that end, he is now studying a cohort of young adults who were fetuses in Tangshan, China, during a very severe earthquake that killed 240,000 people on July 27, 1976.

"We know precisely when every pregnant woman in Tangshan felt this earthquake," he said. "We hope to narrow the window of vulnerability for schizophrenia and for other disorders by studying this cohort."

Following Mednick's presentation, Keller reviewed his 25-year career of research on the longitudinal course and neuropsychophar-macology of affective disorders and anxiety disorders. Included in this research, Keller said, is the ongoing National Institute of Mental Health (NIMH)-sponsored Collaborative Depression Study. Study investigators have conducted interviews with approximately 1,000 patients with affective disorders for over 20 years. The goal is to understand time to recovery, relapse and recurrence; levels of psychosocial functioning; and which clinical variables predict these outcomes. Keller has also designed and now directs several large-scale studies of patients with depression and manic-depressive illness, studies that examine acute-phase treatment and maintenance treatment using appropriate long-term pharmacological and psychotherapeutic interventions to prevent episode recurrence.

He focused on two ongoing studies regarding chronic depressive disorders being done in collaboration with a group of 10 medical centers across the country. In the first study of 635 people who had been suffering from chronic major depression or double depression for an average of 20 years, Keller said, it was found that over half also suffered from other psychiatric disorders, including anxiety disorders, substance abuse and personality disorders.

"When we brought them to a state of well-being for seven months, and then randomized them to either active treatment or placebo, there was a dramatic advantage to staying on active drug," he said. "This is the first study which has shown initially that drug alone for 12 weeks has, in a group of people ill with major depression for most of their lives...brought about a large enough response, and has also demonstrated the prophylactic benefit of 18 months of maintenance treatment."

Keller said he puts this finding in the context of a finding reported consistently since the mid-1980s: Despite the availability of effective treatments, less than 10% of people in the United States and worldwide suffering from depression today receive the right treatment in a high enough dose for a long enough period of time. Midway through the first study, Keller and colleagues were seeing the high response rates on drug alone, and that led to the second study.

"We decided to put to test what everyone thought was true-the best treatment to give people [is] a combination of psychotherapy and pharmacotherapy," he said. "Unfortunately, that belief had not yet been demonstrated in a randomized clinical trial."

In the first phase of this study, which looked at response after 12 weeks, it was shown that the combination of cognitive behavioral therapy with active medication therapy was significantly more effective than either therapy alone. Preliminary findings from the acute phase of the study show that 84% of patients receiving both therapies showed response, compared to 55% on active drug alone and 50% on psychotherapy alone.

"We have continuation, cross-over and maintenance phases yet to go, but we're heartened by these findings," Keller said.

Speaking of his contribution to the understanding of the pathophysiology of manic-depressive psychoses, Mendlewicz then noted achievements in biotechnology and molecular genetics, including the sequencing and cloning of more than 200 genes relevant to brain function, the development of transgenic animal models for behavioral and psychiatric disorders and, most recently, the construction of a human artificial chromosome.

"These breakthroughs will permit...the design of nonviral transfer vectors for gene therapy and genomic drug discovery for the treatment of various neurological and...mental disorders," he said.

After a review of evidence for genetic determination of manic depression, Mendlewicz described a program that his group developed in collaboration with other European groups. The European Program for Molecular Genetics in Affective Disorder is sponsored by the European Commission and now includes 12 centers.

"So far, we have collected data-clinical and genetic as well as psychological and social-on more than 1,600 subjects," he reported, adding that 600 of those patients have bipolar disorder. "We are also collaborating with the American NIMH program on linkage and genetics to make the results comparable and use similar methodologies."

Mendlewicz said it is his opinion that the challenge for future research will be identifying susceptibility genes, and learning how those can interact with other vulnerability factors.

"We will also develop genomic strategies to apply pharmacogenetics to the treatment of mental disorders, both schizophrenia and depression, which could lead to the discovery of new and more efficacious drugs acting at the molecular level in order to alleviate the enormous burden of mood disorder which, according to the World Bank, ranks first in terms of disability among 150 different diseases worldwide," Mendlewicz said, concluding: "There is still a lot to do, but we are making progress."

 
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