Relapse to alcoholism remains a vexing clinical and national health problem. Efforts to match alcohol dependent patients to specific treatments based on their clinical characteristics have produced mixed results. Pharmacogenetics (the study of genetic influences on therapeutic response to drugs) offers a powerful new tool to match specific elements of an individual patient's complex genetic blueprint with targeted pharmacotherapies to which that individual may optimally respond. The purpose of this proposed research is to apply pharmacogenetic techniques to predict which alcohol dependent patients will respond favorably to a trial of a selective serotonin re-uptake inhibitor (SSRI) for the prevention of alcoholism relapse. Our central hypothesis is that genetic differences affecting serotonin transporter function will influence an alcohol dependent individual's treatment response to the SSRI, citalopram. To test this hypothesis, we will perform a 14-week, randomized, double blind, parallel group comparison of citalopram and placebo in treatment seeking outpatients who meet DSM-IV criteria for alcohol dependence. All subjects will receive a single Motivational Interview and 9 brief sessions of a manual-guided Compliance Enhancement Therapy designed to promote treatment adherence and enhance motivation to quit or cut down on drinking. Post-treatment follow-up assessments will be conducted at 4, 12 and 24 weeks. Subjects' DNA will be genotyped to determine allelic variants in the promoter region of the serotonin transporter gene that have been found to markedly affect serotonin re- uptake and influence treatment responsiveness to SSRIs. We predict that individuals who carry two long variant alleles (1/1 homozygotes) of this polymorphism will exhibit a significant reduction in drinking days in response to citalopram compared with patients homozygous for the short variant allele (s/s homozygotes). To our knowledge, this will be the first study conducted in alcohol dependent patients to test whether pharmacogenetic differences in the function of the serotonin transporter (the site of action of these medications) influence the treatment response to a SSRI in nondepressed women and men. The study is designed to maximize the likelihood of finding treatment efficacy for citalopram over placebo by excluding subjects with severe alcohol dependence and marked impulsive traits in which SSRIs have not been found to be effective, controlling the exposure to the concomitant psychosocial intervention to minimize a psychotherapy ceiling effect, and by controlling the potential moderating effects of sex and cigarette smoking. The successful completion of this single center study may lead to future multicenter trials in more heterogeneous populations, and to studies using serotonin receptor subtype-specific medications.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZAA1-HH (21))
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Fertig, Joanne
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University of Cincinnati
Schools of Medicine
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Mingione, Carolyn J; Heffner, Jaimee L; Blom, Thomas J et al. (2012) Childhood adversity, serotonin transporter (5-HTTLPR) genotype, and risk for cigarette smoking and nicotine dependence in alcohol dependent adults. Drug Alcohol Depend 123:201-6
Heffner, Jaimee L; DelBello, Melissa P; Anthenelli, Robert M et al. (2012) Cigarette smoking and its relationship to mood disorder symptoms and co-occurring alcohol and cannabis use disorders following first hospitalization for bipolar disorder. Bipolar Disord 14:99-108
Heffner, Jaimee L; Blom, Thomas J; Anthenelli, Robert M (2011) Gender differences in trauma history and symptoms as predictors of relapse to alcohol and drug use. Am J Addict 20:307-11
Heffner, Jaimee L; Mingione, Carolyn; Blom, Thomas J et al. (2011) Smoking history, nicotine dependence, and changes in craving and mood during short-term smoking abstinence in alcohol dependent vs. control smokers. Addict Behav 36:244-7
Johnson, Candace S; Heffner, Jaimee L; Blom, Thomas J et al. (2010) Exposure to traumatic events among treatment-seeking, alcohol-dependent women and men without PTSD. J Trauma Stress 23:649-52
Anthenelli, Robert M (2010) Focus on: Comorbid mental health disorders. Alcohol Res Health 33:109-17
Heffner, Jaimee L; Tran, Giao Q; Johnson, Candace S et al. (2010) Combining motivational interviewing with compliance enhancement therapy (MI-CET): development and preliminary evaluation of a new, manual-guided psychosocial adjunct to alcohol-dependence pharmacotherapy. J Stud Alcohol Drugs 71:61-70
Thompson, Rachel D; Heffner, Jaimee L; Strong, Judith A et al. (2010) Relationship between the serotonin transporter polymorphism and obsessive-compulsive alcohol craving in alcohol-dependent adults: a pilot study. Alcohol 44:401-6
Heffner, Jaimee L; Johnson, Candace S; Blom, Thomas J et al. (2010) Relationship between cigarette smoking and childhood symptoms of inattention and hyperactivity/impulsivity in alcohol-dependent adults without attention-deficit hyperactivity disorder. Nicotine Tob Res 12:243-50
Heffner, Jaimee L; Lee, Theodore C; Arteaga, Carmen et al. (2010) Predictors of post-treatment relapse to smoking in successful quitters: pooled data from two phase III varenicline trials. Drug Alcohol Depend 109:120-5

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