Pharmacogenetic Approach at the Serotonin Transporter Gene as a Method of Reducing the Severity of Alcohol Drinking

Johnson, Bankole A.; Ait-Daoud, Nassima; Seneviratne, Chamindi; Roache, John D.; Javors, Martin A.; Wang, Xin Qun; Liu, Lei; Penberthy, J. Kim; DiClemente, Carlo C.; Li, Ming D.

doi:10.1176/appi.ajp.2010.10050755

“…Specifi cally, in individuals with the L A L A genotype, sertraline decreased drinking signifi cantly in late-onset alcoholics, whereas in early-onset alcoholics, placebo treatment was associated with fewer drinking and heavy drinking days. Johnson et al (2011) subsequently found that variants in SLC6A4 infl uenced the response to ondansetron: The medication reduced drinking only in alcohol-dependent individuals with the 5-HTTLPR LL genotype. Further, a single nucleotide polymorphism in the 3´ untranslated region (3´UTR) of the serotonin transporter gene (Seneviratne et al, 2009) interacted with the 5-HTTLPR polymorphism to moderate the response to ondansetron.…”

Section: Pharmacogenetic Approachesmentioning

confidence: 99%

Pharmacotherapy of Alcohol Use Disorders: Seventy-Five Years of Progress

Zindel

¹

,

Kranzler

²

2014

J. Stud. Alcohol Drugs Suppl.

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ABSTRACT. Modern pharmacotherapy for alcohol dependence has its roots in the failure of National Prohibition in the United States and the rise of the disease model of alcoholism (embodied in Alcoholics Anonymous). In 1948, disulfi ram was the fi rst medication approved by the U.S. Food and Drug Administration (FDA) to treat alcohol dependence, but its effi cacy has not been supported by randomized controlled trials. In the 1960s, benzodiazepines replaced older treatments for alcohol withdrawal, but sedative and dependence-producing effects limit their utility in the postwithdrawal period. In the 1980s, the focus shifted to the treatment of co-occurring psychiatric disorders and medications that modify negative mood states, which contribute to relapse to heavy drinking. In the 1990s, developments in neurobiology implicated specifi c neurotransmitter systems underlying alcohol's effects, culminating in the 1994 approval by the FDA of the opioid antagonist naltrexone to treat alcohol dependence. In 2006, the FDA approved a long-acting formulation of naltrexone. Recently, nalmefene, another opioid receptor antagonist, was approved in Europe for as-needed use to reduce heavy drinking. Acamprosate, an amino acid derivative, fi rst approved in France in 1989, received FDA approval in 2004. However, the benefi cial effects of the approved medications are only modestly greater than those of placebo, and their use is limited. Topiramate, currently under investigation for alcohol dependence, has greater effi cacy but a variety of adverse effects. In addition to the identifi cation of novel compounds, the future of alcohol dependence pharmacotherapy will depend on developments in pharmacogenetics, in which genetic variation that moderates treatment effi cacy and adverse effects is used to personalize treatment. (J. Stud.

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“…Clinical studies, however, demonstrated that serotonergic medications-the most studied of which are the SSRIs-have only a modest, inconsistent effect on drinking behavior (Kranzler and Anton, 1994). The 5-HT 3 (5-hydroxytryptamine-3) antagonist, ondansetron, has also been studied for this purpose (Johnson et al, 2000(Johnson et al, , 2011.…”

Section: Medications That Directly Reduce Alcohol Consumptionmentioning

confidence: 99%

Pharmacotherapy of Alcohol Use Disorders: Seventy-Five Years of Progress

Zindel¹,

Kranzler²

2014

J. Stud. Alcohol Drugs Suppl.

View full text Add to dashboard Cite

ABSTRACT. Modern pharmacotherapy for alcohol dependence has its roots in the failure of National Prohibition in the United States and the rise of the disease model of alcoholism (embodied in Alcoholics Anonymous). In 1948, disulfi ram was the fi rst medication approved by the U.S. Food and Drug Administration (FDA) to treat alcohol dependence, but its effi cacy has not been supported by randomized controlled trials. In the 1960s, benzodiazepines replaced older treatments for alcohol withdrawal, but sedative and dependence-producing effects limit their utility in the postwithdrawal period. In the 1980s, the focus shifted to the treatment of co-occurring psychiatric disorders and medications that modify negative mood states, which contribute to relapse to heavy drinking. In the 1990s, developments in neurobiology implicated specifi c neurotransmitter systems underlying alcohol's effects, culminating in the 1994 approval by the FDA of the opioid antagonist naltrexone to treat alcohol dependence. In 2006, the FDA approved a long-acting formulation of naltrexone. Recently, nalmefene, another opioid receptor antagonist, was approved in Europe for as-needed use to reduce heavy drinking. Acamprosate, an amino acid derivative, fi rst approved in France in 1989, received FDA approval in 2004. However, the benefi cial effects of the approved medications are only modestly greater than those of placebo, and their use is limited. Topiramate, currently under investigation for alcohol dependence, has greater effi cacy but a variety of adverse effects. In addition to the identifi cation of novel compounds, the future of alcohol dependence pharmacotherapy will depend on developments in pharmacogenetics, in which genetic variation that moderates treatment effi cacy and adverse effects is used to personalize treatment. (J. Stud.

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“…Two important variants are long (insertion LL) and short (SS) version. It has been reported in a randomized clinical trial that individuals with LL genotype (Homozygous for the long version) of 5-HTT gene showed significant results in improvements of alcoholism with treatment of ondansetron as compared to LS and SS genotype (Johnson et al, 2011).…”

Section: Genetic Predictors Of Medication Responsementioning

confidence: 99%