Name: James C. Garbutt Birth: October 24, 1949, in Carbondale, Ill. Education: B.A. in Biology, University of Illinois, 1971; M.D., University of Illinois Medical Center, 1975; Psychiatry Resi-dency, University of North Carolina at Chapel Hill, 1975-78; Clinical Associate Fellowship, National Institute of Mental Health, 1978-80. Experience: Staff Psychiatrist, National Institute of Mental Health, 1978-80; Research Psychiatrist, Dorothea Dix Hospital, 1980-83; Clinical Assistant Professor of Psychiatry, UNC-CH, 1981-83; Director of the Clinical Research Unit, Dorothea Dix Hospital, 1983-94; Assistant Professor of Psychiatry, UNC-CH, 1983-86; Faculty Member of the Neurobiology Curriculum, UNC-CH, 1984-present; Research Associate, Center for Alcohol Studies, UNC-CH, 1986-present; Associate Professor of Psychiatry, UNC-CH, 1986-present; Director of the Division of Clinical Research Services, Dorothea Dix Hospital, 1994-present. Honors and Awards: Phi Eta Sigma Freshman Honorary Society, 1968; Alpha Omega Alpha Medical Honorary Society, 1973; Sandoz Award in Psychiatry for Medical Students at the University of Illinois, 1975; Eugene A. Hargrove Mental Health Research Award, 1989; Teaching Award, Fourth Year Psychiatric Residents at UNC-CH, 1990. Family: Married Sharon Gray in 1973. Two children: Carter, 12, and Taylor, 13.

For years communities have whispered about it.

It's a fact backed both by folklore and statistics: Tommy's dad is an alcoholic so it's likely that Tommy will be one too.

Today, alcoholism researchers are confronting this observation head on. But they are going far beyond numbers and community folklore.

They're identifying biological differences between alcoholics and nonalcoholics, and between young people with a family history of alcoholism and those without that history. If they learn enough about the factors that set these groups apart, those who might be susceptible to the illness could be warned that if they start drinking, they might develop alcoholism. Alternatively, a greater understanding of these differences might lead to the development of medications that reduce craving or risk of relapse, such as the recently introduced naltrexone (ReVia®).

"Some offspring are at greater risk than others because they inherit different genetic factors from their parents," says Dr. James C. Garbutt, a psychiatrist and clinical researcher. "Vulnerability markers could be utilized to let someone know they're at higher risk for the development of alcoholism - above and beyond whether they have a positive family history of alcoholism."

Garbutt has spent the last 16 years trying to identify some of these inherited differences. "We know alcoholism has a genetic component," he says. "The question is, what is the expression of that genetic component biologically?" Further, how does that contribute to the development of alcoholism?

As director of clinical research at Dorothea Dix Hospital in Raleigh and a member of the Center for Alcohol Studies' clinical research team, Garbutt has access to laboratory animals bred to consume alcohol and to people who have alcoholism or who are at risk for alcoholism.

Because of the many challenges of working with human subjects, most experimentation begins in the lab. If the initial experiments in animals are successful, the long process of human testing begins.

Looking for a biological indicator of alcoholism sounds relatively easy, that is, until you realize that alcoholism is an umbrella term for what may be more accurately call the alcoholisms.

"People don't realize there's more than one type of alcoholism," says Linda Powell, a clinical research associate who has worked with Garbutt since 1987. "That may be why it is so hard to treat some people. Like cancer, some types are much more treatable."

The illnesses' biological features are thought to include alterations in neurophysiological, neurochemical, neuroendocrinological and temperamental patterns.

One avenue of Garbutt's research involves studying subjects' hormonal response to thyrotropin-releasing hormone (TRH). This response is part of the thyroid axis beginning in the brain with the release of TRH. This hormone stimulates the release of thyrotropin from the pituitary, which then leads to the release of thyroid hormone by the thyroid gland. Measuring this response may provide insight into the activity of TRH within the brain; TRH being of interest to alcoholism because it can modify the behavioral actions of alcohol.

Early research indicated that alcoholics have a reduced response to TRH. Because depressed patients were known to exhibit the same phenomenon, Garbutt looked at whether the response of depressed and alcoholic patients to TRH was similar. He found, however, that the neuroendocrine thyroid axis abnormality was different in the two types of patients. Depressed patients not only had a decreased TRH-response to multiple doses of TRH, but their prolactin response was lower as well. Alcoholic patients, in contrast, retained a normal prolactin response to TRH.

This suggested that the TRH-response abnormality observed in alcoholics might be unique to their condition and represent a possible vulnerability factor.

Garbutt then looked at the TRH-response of young men with alcoholic fathers compared to those who have no close relatives with alcoholism. The results showed that young men with fathers whose alcoholism began later in life had the same decreased TRH response. The others - those with no family history of alcoholism or fathers with an early onset of alcoholism - did not exhibit this phenomenon.

Staff of the Division of Clinical Research Services, Dorothea Dix Hospital. Left to right: Bess Dew, RN; Georgia Stephens, RN; Linda Powell, MSW; JC Garbutt, MD; Debbie Randall, RN; Linda Page, LPN; and Rosalind Thompson, CCSW.

"Blunted TRH may be tapping a genetic difference between a subgroup of people at risk for alcoholism and those not at risk for alcoholism," Garbutt says. "It may provide another means to define and to describe this population which may have relevance for prevention and treatment."

A collaboration with Ron Thurman, professor and director of the Laboratory of Hepatobiology and Toxicology at UNC-Chapel Hill, has provided clues to another possible vulnerability marker: different ethanol metabolism rates.

In this study, nonalcoholic young men were given a priming dose of alcohol and then a second dose. Thurman's lab first noticed that about 20 percent of those tested had a rate of ethanol metabolism that increased by at least 40 percent after the second dose. The individuals with this response, called Swift Increase in Alcohol Metabolism or SIAM, reported little or no problems with alcohol.

A second study confirmed this finding and made another discovery. The ethanol metabolism rate of some young men with a positive family history (FHP) of alcoholism decreased 20 percent or more after the second dose of alcohol. "What this means is some FHP men show rates of alcohol metabolism that decrease during drinking, and this could lead to a greater exposure to alcohol and a more rapid development of tolerance," Garbutt says. "One of the things we know is that individuals who develop alcoholism generally develop tolerance faster than people who aren't at risk."

In another collaboration with two UNC scientists, Alexey Kampov-Polevoy and David Janowsky, a possible diagnostic test is being investigated.

This project grew out of the recognition that recovering alcoholics often crave sweets. Crunching M&Ms, munching a candy bar or eating ice cream are reported by many patients during recovery.

The test is simple: subjects are given sugar solutions of differing sweetness and asked to rank the relative sweetness of each solution and their preference for each one.

So far, the results confirm the research team's expectations: About 65 percent of alcoholics prefer the sweetest solution, compared to only about 16 percent of the nonalcoholic subjects.

"Again, one thing that's exciting about this work is that sweet preference may be associated with a subtype of alcoholism," Garbutt says.

Beyond a diagnostic tool, further investigation of this phenomenon might lead to the development of a drug that activates the brain system stimulated by sweets. This drug could potentially be used to decrease craving in alcoholics.

Garbutt hopes the results of these clinical experiments will lead to solutions that will help more alcoholics achieve long-term sobriety

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From: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill

Center Line
Volume 8, No. 1, 1996