Matching Genotypes and Serotonergic Medications for Alcoholism

Condition(s) targeted: Alcoholism

Intervention: ondansetron (Drug); sertraline (Drug)

Phase: Phase 1

Status: Recruiting

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

Overall contact:
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.

Detailed description: 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 the other.

Minimum age: 21 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

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 signs.

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 sessions.

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.

Exclusion Criteria:

1. Pregnancy or breast feeding women.

2. Positive urine drug screen at baseline for any illegal substance other than marijuana.

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 -

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

Related publications:

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