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Volume 19, Number 2, June 2008
Clinician Scientist Garbutt Translates Animal Research to Advances in Clinical Medicine
One in ten Americans grapples with alcoholism at some time during their life. Alcohol-dependent individuals face a challenge notoriously difficult to overcome, and more than 75% of alcoholics who seek treatment relapse to drinking within the first year. Dr. James C. Garbutt of the University of North Carolina’s Department of Psychiatry, the Alcohol and Substance Abuse Program, and the Bowles Center for Alcohol Studies, is working to improve this statistic. Both a psychiatrist and a scientist, Garbutt is adept at identifying potential clinical applications of findings from animal models. Likewise, he is skilled in planning and implementing studies that translate concepts gleaned from basic research into clinical advances.
Garbutt’s work with the drug baclofen illustrates his facility in these regards. Baclofen acts on the brain’s GABAergic system, which is important in mediating alcohol intake and mood, among other functions. Garbutt was motivated to investigate the effects of baclofen on drinking in alcoholics by basic research showing that baclofen reduces alcohol intake in several animal models and attenuates the anxiety induced by repeated exposure to alcohol in alcohol-dependent animals. Based on these findings, Garbutt, in collaboration with Dr. Barbara Flannery of Research Triangle International, surmised that baclofen may be useful in reducing drinking and symptoms, such as anxiety, that lead to drinking in human alcoholics. Garbutt and Flannery showed in a preliminary study that baclofen decreased alcohol drinking, craving for alcohol, and anxiety among 12 alcohol-dependent men and women and that baclofen appeared safe. Based on this pilot work, Garbutt and Flannery obtained funds from the NIAAA and completed a randomized, double-blind, placebo-controlled, 12-week study that compared the effects of baclofen with those of placebo on drinking in 80 alcoholics. They found that patients treated with baclofen did indeed drink less while taking baclofen. However, the placebo-treated group also drank less while taking the inactive placebo pill. In fact, the baclofen-treated group and the placebo-treated group showed similar reductions in the percentage of heavy drinking days relative to the pretreatment baseline. To demonstrate efficacy of baclofen, the baclofen group would have needed to improve significantly more than the group given inactive placebo with respect to the percentage of heavy drinking days. Because both groups demonstrated similar improvement, the efficacy of baclofen in reducing heavy drinking cannot be concluded on the basis of this investigation.
(Left to Right): Alexei Kampov-Polevoy, MD, PhD, Linda Kalka-Juhl,
JC Garbutt, MD, Olivera Pluzarev, PhD, and Mark Tommerdahl, PhD,
and Amy Ford (not pictured).
Garbutt is not discouraged by these results. He notes that placebo-treated patients often improve during the course of a clinical trial. This phenomenon, known as the “placebo effect,” is thought to be related partly to the increased medical attention patients receive by virtue of their participation in a study. Garbutt cites as reason for continued optimism the recent demonstration by Addolorado’s group in Italy that baclofen was more effective than placebo at enhancing abstinence from alcohol among alcoholics with liver cirrhosis. In these severely ill patients, the placebo effect was not as marked as it is in patients who are less ill. “Considering the evidence in aggregate, we are seeing a signal that baclofen is working,” says Garbutt. “We need to work to define the circumstances and patient types that might be most appropriate for baclofen treatment. It could be that there are subtypes of alcoholics who are particularly responsive to baclofen. For example, based on the animal work from the Breese laboratory, we predict that baclofen might be particularly effective in alcoholics who have anxiety as a prominent component of their illness.
We now want to examine whether baclofen is more effective for some subtypes of alcoholics than others.”
Garbutt has also worked extensively with long-acting injectable naltrexone, a medication shown to reduce alcohol consumption when injected only once a month. Long-acting injectable naltrexone (Vivitrol®) was approved by the US Food and Drug Administration in April 2006 for the treatment of alcohol dependence and is now available in the United States. Like baclofen, naltrexone first became a candidate as an intervention for alcoholics after animal research showed that the drug could modify drinking in animal models. Naltrexone is thought to reduce craving for alcohol by binding to the brain’s opioid receptors—a mechanism different from that of baclofen, which acts on the GABAergic system. Garbutt was intimately involved in the research that led to approval of Vivitrol® and was lead author of the 2005 paper published in the Journal of the American Medical Association that described the results of a large, Phase III clinical trial of the drug. Garbutt and his col-leagues are now inves-tigating the possibility that tar-geting two systems putatively involved in alcoholism—the GABAergic system and the opioid system—might yield better efficacy than targeting these systems individually. In a 40-patient pilot study sponsored by the Bowles Center for Alcohol Studies, alcoholics are receiving one of four treatments: naltrexone+baclofen, baclofen alone, naltrexone alone, or placebo. Garbutt hypothesizes that baclofen may counteract the dysphoric/anxious component of alcoholism that is prominent in early recovery whereas naltrexone counteracts the rewarding response if alcohol is consumed and may also reduce craving for alcohol. Together, they may complement one another and lead to improved outcomes. The results of this study are expected to be
available next year.
In collaboration with Dr. Mark Tommerdahl of Bioengineering, Garbutt and colleagues are investigating a non-invasive sensory device that probes cortical glutamate and GABA function in real time. Early findings suggest that patients with alcohol dependence have deficits in their sensory responses that may indicate dysfunction in GABAergic/glutamatergic systems. Intriguingly, in some patients these deficits improve with time in recovery. Garbutt and Tommerdahl are extending this work in more patients and examining whether cerebral recovery can indeed be documented. If so, this method could provide a tool to provide patients with feedback to see progress as they recover. This method could also have relevance to predicting response to medications such as acamprosate that is thought to modulate glutamate hyperactivity.
In addition to drawing upon findings from animal models to identify drug candidates for the treatment of alcohol dependence, Garbutt uses animal findings to point him to leads in the quest to discover the causes and consequences of excessive alcohol intake in humans. Recently, Garbutt was motivated to investigate whether cytokine concentrations are abnormal in alcoholics’ blood. This study is based on findings from Dr. Fulton Crews’ laboratory at the Bowles Center that excessive alcohol drinking causes activation of cytokines and consequent brain damage in animal models. Cytokines are a diverse group of proteins that regulate immune responses, inflammation, and communication among cells in the brain. Although the action of pro-inflammatory cytokines is crucial for defending the body against infections and other challenges, excessive cytokine-mediated pro-inflammatory activity can cause cell damage. Garbutt and Crews are exploring the possibility that cytokines may be elevated in alcoholics and that they may contribute to some of alcohol’s detrimental effects in humans. Preliminary data from blood samples from patients enrolled in the baclofen study show a relationship between patients’ baseline level of drinking during the period before the study and the blood concentrations of inflammatory cytokines.
Besides exploring consequences of and treatments for alcohol dependence, Garbutt is interested in identifying predictors of alcohol dependence. If risk factors that predict a tendency to consume excessive alcohol can be identified, then alcoholism could potentially be prevented through behavior modification among individuals having the risk factor. With UNC Psychiatry Department researchers Drs. Alexei Kampov-Polevoy and David Janowsky, Garbutt showed in research conducted more than a decade ago that alcoholics express a preference for much stronger sweet solutions than do nonalcoholics. Additional studies demonstrated that preference for stronger sweet solutions appears to be associated with heightened genetic risk for alcoholism. This research, like Garbutt’s work on pharmacotherapies for alcohol dependence and the cytokine work, was stimulated by earlier animal research indicating that rats genetically bred for high alcohol intake had a much greater preference for highly concentrated sweet solutions than did their non-alcohol-preferring counterparts. Garbutt has recently extended the work on sweet preference to show, in a preliminary human study, that the sweet-liking phenotype interacts with high novelty-seeking interact to greatly increase risk for alcohol-related problems. The two risk factors appear to synergize such that the risk of excessive alcohol consumption is much higher when both are present than when one is present alone. In a study of individuals who at study entry did not meet diagnostic criteria for alcoholism, problems with alcohol were two times more likely to develop in high novelty-seekers (identified using a personality questionnaire) than in low novelty-seekers and three times more likely to develop in sweet-likers than in sweet-dislikers. In individuals who were both high novelty-seekers and sweet-likers, the risk of alcohol problems was markedly elevated: those with both characteristics were 17 times more likely to develop alcohol problems than individuals who were both low novelty-seekers and sweet-dislikers.
“Every day the basic research findings give us a new lead to follow.” Garbutt remarks. “Our research initiatives show how animal research has pointed the way to some significant clinical advances that can make a difference in patients’ lives.”