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Vol. LIX, No. 10
May 18, 2007

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Studies Examine Link Between Alcohol, Affective Disorders

  Drs. Bridget Grant and Markus Heilig of NIAAA  
  Drs. Bridget Grant and Markus Heilig of NIAAA  
Are the associations observed between alcohol abuse and dependence and mood and anxiety disorders the result of substance intoxication or withdrawal? That was the question before a well-attended Grand Rounds session recently in Lipsett Amphitheater.

A large and sophisticated national epidemiologic survey conducted by NIAAA suggests that very few people have substance-induced disorders.

Analyses also suggest that the associations between alcohol dependence and bipolar disorder, specific phobia and panic disorder without agoraphobia are due to both common and unique factors, said Dr. Bridget Grant, chief of NIAAA’s Laboratory of Epidemiology and Biometry.

Grant’s macro findings appear to agree with recent studies at the micro level, reported by her co-presenter Dr. Markus Heilig, NIAAA clinical director and chief of the Laboratory of Clinical and Translational Studies. To the conundrum of cause—does affective disorder lead to alcohol abuse or does heavy drinking prompt affective disorder?—he answered, “There is no universal truth that applies to all patients.”

He posited instead that “multiple trajectories lead to end-stage disease” and that an “overlapping genetic susceptibility” to both affective disorder and alcoholism is likely.

Citing new work by his team that has been published in 2006 and 2007, as well as work in press, Heilig described changes in the brain in response to a prolonged history of exposing it to cycles of intoxication and withdrawal, which he termed “a neuroadaptation story.” Put simply, either alcohol exposure or stress that an organism is exposed to during life interacts with its genetic endowment to determine the risk of depression or alcoholism. While in some individuals, a long exposure history is required to push the brain into a neuroadapted state, the gene set you are born with can also leave you “pre-kindled” for affective disorder or for alcoholism.

In an echo of the old Oliver Wendell Holmes axiom that the enlarged mind never again narrows, Heilig noted that the brain, once its stress thermostat has been elevated by events—or by alcohol use—remains at heightened sensitivity even in the post-dependent state, meaning relapse is always a threat.

How does medicine address a seemingly permanent “upregulated” sensitivity to stress? Heilig said it has been known since the mid-1980’s that the origin of anxiety symptoms within the brain is CRH—corticotropin-releasing hormone—but that attempts over the intervening decades to devise a chemical to block CRH receptors has proven devilishly difficult. One promising candidate blocked CRH receptors, but was toxic to the liver, he noted, and could therefore not be developed for clinical use.

Two new compounds—MTIP, developed by Lilly, and antalarmin, developed at NIH by Dr. Kenner Rice of NIDDK—show clinical promise in blocking CRH. “We should have one or two new compounds ready for testing in humans within the next 1½ years,” Heilig said. — NIH Record Icon

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