Matching Genotypes and Serotonergic Medications for Alcoholism
Information source: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Information obtained from ClinicalTrials.gov on October 19, 2009
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Alcoholism
Intervention: ondansetron (Drug); sertraline (Drug)
Phase: Phase 1
Sponsored by: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Official(s) and/or principal investigator(s):
George A Kenna, PhD RPh, Principal Investigator, Affiliation: Brown University
George A Kenna, PhD, RPh, Phone: 401-456-4910, Email: George_Kenna@Brown.edu
The purpose the study is to investigate whether people with certain genetic traits who are
receiving treatment with ondansetron or sertraline will see a significant reduction in
alcohol consumption during an alcohol self-administration experiment (ASAE) and during the
period of treatment.
Official title: Matching 5-HT Genotypes to Serotonergic Medications for Alcoholism
Study design: Basic Science, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Safety/Efficacy Study
Primary outcome: The Primary aim of this study is to examine the efficacy of serotonergic treatment matching for alcohol dependence based on 5'-HTTLPR variant genotyping as matched with two medications: sertraline and ondansetron.
Secondary outcome: To examine the mechanism of action on subjective effects associated with alcohol use while taking serotonergic medication.
Abstract: DESCRIPTION (provided by applicant): Medications and genetics have been
identified as research priorities by NIAAA. The present application proposes to test two
genetic-drug matching hypotheses to better understand heterogeneity among alcoholics.
Previous basic science, treatment and genetic research suggests that active drinkers with
the LL genetic variant of the serotonin transporter 5'-HTTLPR (a hypothesized genetic risk
factor for early onset alcoholism) will respond better to ondansetron than sertraline or
placebo. Conversely, active drinkers with the SS or SL genetic variant of the serotonin
transporter 5'-HTTLPR (a hypothesized genetic risk factor for late onset alcoholism) will
respond better to sertraline than ondansetron or placebo. The objective of this research is
to match and mismatch serotonergic treatments to genetic polymorphic variants in a
double-blind placebo controlled 2 x 2 design laboratory study where the 2 arms will be
counterbalanced. The specific aims are to investigate: (1) whether LL-carriers receiving
ondansetron results in a significant reduction in alcohol consumption during an alcohol
self-administration experiment (ASAE) and during the period of treatment; (2) whether SL and
SS-carriers receiving sertraline will result in a significant reduction in alcohol
consumption during an ASAE and during the period of treatment; (3) examine mechanism of
action for craving and subjective effects during the ASAE sessions: (4) whether there is a
reduction in alcohol consumption during the ASAEs in the presence of the LG, and LA 5-HTTLPR
variants and when LL participants receive ondansetron or when LL participants receive
sertraline; (5) if the primary aims are moderated by the presence of the C (-1019) G
polymorphism of the 5-HT1A gene promoter. We propose to randomize 132 non-treatment-seeking
alcohol dependent participants based on their 5'-HTTLPR variant genotype (LL or SS/SL) into
one of two counterbalanced arms: e. g. subjects in the first arm will first receive one drug
(either 200mg/day of sertraline or ondansetron 0. 5mg/day) for three weeks followed by an
ASAE, then receive placebo for three weeks (this will be a single-blind portion to use as a
comparison group and to wash out the pharmacodynamic effects of the first drug) followed by
a second ASAE. Finally, participants will receive the second drug for three weeks followed
by a third ASAE. Volunteers in the second arm will receive the same medications in a
counter-balanced fashion. There will be a 1-week down titration after the first and third
segments for all subjects. The long-term objective of this proposed research is to examine
serotonergic treatment matching for alcohol dependence based on genotyping, and begin to
investigate patient variation when matched prospectively with one serotonoergic treatment or
Minimum age: 21 Years.
Maximum age: 65 Years.
1. Must be between 21 and 65 years old (inclusive).
2. Participants may be male or female and must be in good health as confirmed by medical
history, baseline physical examination, ECG, laboratory tests, urinalysis and vital
3. Female participants must be:
- Postmenopausal for at least one year, surgically sterile, or
- Practicing an effective method of birth control before entry and throughout the
study; have a negative urine pregnancy test at baseline screening and prior to
the alcohol challenge sessions.
4. Participants must understand that this is not a treatment study.
5. A diagnosis of Alcohol dependence using Module E of the structured clinical interview
for the DSM-IV (SCID). Alcohol dependent as defined by an AUDIT score ≥ 12 and men
must consume ≥ 35 and women ≥ 28 standardized alcoholic beverages a week.
6. Participants must be willing to take oral medication, adhere to the medication
regimen and be willing to return for weekly visits and the alcohol challenge
7. Participants must be able to read and comprehend written instructions and comprehend
and complete all scale and inventories required by the protocol.
8. Participants must have signed an informed consent indicating they understand the
purpose of and procedures required for the study and willingness to participate.
1. Pregnancy or breast feeding women.
2. Positive urine drug screen at baseline for any illegal substance other than
3. Participants will be excluded if they have: (a) clinically significant medical
abnormalities (i. e. ECG, hematological assessment, bilirubin > 150% of the upper
limit of normal or ALT or AST elevations >300% the upper limit of normal,
biochemistry including urinalysis, electrolytes,). (Persons with medical conditions
that are adequately controlled by their primary care physician will not be excluded.)
4. Current use of psychotropic medications that cannot be discontinued
5. Medical contraindications for use of sertraline or ondansetron
6. Taking drugs that interfere with the metabolism of either drug that cannot be stopped
per study physician.
7. Allergic to sertraline or ondansetron
8. Must have a breath alcohol concentration (BrAC) = 0. 000 at the beginning of the
alcohol challenge sessions.
9. Creatinine clearance ≤ 60 dl/min.
10. Individuals with a reasonable expectation of being institutionalized during the
course of the trial or pending legal charges.
11. Participants who have significant alcohol withdrawal symptoms (clinical institute
withdrawal assessment for alcohol revised (CIWA-Ar) >10.
12. lifetime depression or a history of suicide
13. history of seizures (e. g. epilepsy) or migraine headaches -
Locations and Contacts
George A Kenna, PhD, RPh, Phone: 401-456-4910, Email: George_Kenna@Brown.edu
Center for Alcohol and Addiction Studies, Providence, Rhode Island 02912, United States; Recruiting
Korto Tawse-Butha, BA, Phone: 401-863-6688, Email: Korto_Tawse-Butha@brown.edu
Blake Wilson, BS, Phone: (401) 863-6687, Email: Blake_Wilson@Brown.edu
George A Kenna, PhD, Principal Investigator
Robert M Swift, MD PhD, Sub-Investigator
John McGeary, PhD, Sub-Investigator
William Zywiak, PhD, Sub-Investigator
Alcohol and Addiction Studies at Brown University
Kenna GA, Zywiak WH, McGeary JE, Leggio L, McGeary C, Wang S, Grenga A, Swift RM. A within-group design of nontreatment seeking 5-HTTLPR genotyped alcohol-dependent subjects receiving ondansetron and sertraline. Alcohol Clin Exp Res. 2009 Feb;33(2):315-23. Epub 2008 Nov 19.
Starting date: September 2008
Ending date: December 2011
Last updated: March 4, 2009