Pharmacogenetic Response to Naltrexone For Alcohol Dependence

Despite the well established efficacy of naltrexone, there are significant variations in
individual responses to naltrexone. A critical question remains: under what circumstances
and for which patients will naltrexone (NTX) be most beneficial? Recent work at our center
provides evidence that the mu-opioid receptor (OPRM1) gene polymorphism A118G (Asn40Asp)
imparts a significant change in treatment response. We have shown that patients with 1-2
copies of the Asp40 variant have significantly better treatment responses than patients with
Asn40 variant (absence of heavy drinking -73.9% v/s 49% response). To further consolidate
our knowledge, we wish to test the relationship between A118G polymorphism and the response
to treatment with naltrexone. This work is focused on subjects of European or Asian descent
as the A118G polymorphism occurs in less than 1% of those of African descent.

The study consists of 12 weeks of outpatient treatment with 50mg/day of naltrexone or
placebo. Up to 340 subjects will be recruited across four sites. The inclusion criteria
include adult males and females of European or Asian descent with DSM-IV diagnosis of
alcohol dependence and heavy drinking per TLFB criteria. Patients with major psychiatric
disorders or on psychotropic medications, other substance dependence problems (except
nicotine), severe cognitive impairment, active suicidal/homicidal thoughts and serious
medical conditions (including liver disorders) will be excluded.

The ultimate aim of this line of investigation is to further establish a genetic link
between alcohol dependence and treatment by defining an endophenotype associated with
treatment response.

Based upon these very promising findings, the aim of this study is to examine prospectively
the interaction between a functional polymorphism of the mu-opioid receptor (A+118G
(Asn40Asp)) and response to treatment with naltrexone. A secondary aim of this study is to
examine the role of the Asp40 allele in alternating the subjective effects from alcohol use
in alcohol dependent individuals that have been demonstrated in human laboratory
experiments.

We hypothesize that naltrexone - but not placebo - will produce a greater clinical response
during the 12 weeks of the trial in subjects with one or two copies of the Asp40 variant
("Asp40 positives") than in subjects homozygous for the Asn40 allele. Response to
naltrexone will be measured by a reduction in the number of heavy drinking days (as defined
by >5 drinks/day for males; >4 for females) during the 12 weeks of the trial.

We also expect that there will be an interaction between medication and genotype such that,
as compared to the groups on placebo or homozygous for Asn40, Asp40 positive subjects
randomized to naltrexone will report less "high" from alcohol consumption (on the Biphasic
Alcohol Effects Scale), and the lowest levels of alcohol craving over time (on the Penn
Alcohol Craving Scale).

Inclusion Criteria:

1. Participant is male or female, 18 years of age or older, and of European or Asian
descent.

2. Participant has a current DSM-IV diagnosis of alcohol dependence using the SCID/MINI.

3. The participant has signed a witnessed informed consent form.

4. Participant meets the following drinking criteria as measured by the Timeline Follow
Back (TLFB): a. Drinks at least an average of 21 drinks/wk in the 60-day period
prior to intake and b. Has 2 or more days of heavy drinking (defined as 5 or more
drinks per day in males, 4 or more in females) in this same pre-treatment period.

5. Participant has at least 48 hours of abstinence, as determined by subject report and
breathalyzer measure immediately prior to randomization.

6. Participant scores below 8 on the Clinical Inventory of Withdrawal from Alcohol
(CIWA) prior to starting Naltrexone.

7. Participant has adequate vision, hearing and ability to communicate to allow study
participation.

8. Participant is able to speak, print and understand English.

Exclusion Criteria:

1. Participant meets DSM-IV criteria for dependence on any substance other than alcohol
or nicotine in the last 6 months.

2. Participant has tested positive on the urine drug screen for opioids,
benzodiazepines, or cocaine at the screening visit. Presence of THC is allowable.

3. Participant has a current or lifetime DSM-IV diagnosis of bipolar affective disorder,
schizophrenia, or any psychotic disorder.

4. Participant has presence of unstable or serious medical illness such as a recent
stroke, idiopathic seizure disorder, or cardiac disease.

5. Participant has severe liver disease (SGPT (ALT) or SGOT (AST) of at least 3 times
normal value at the time of randomization or an elevated Total Bilirubin level
without evidence of Gilbert's Syndrome.

6. Participant has taken any psychotropic medications (including disulfiram) regularly
within the last seven days (14 for fluoxetine) prior to randomization or needs
immediate treatment with a psychotropic medication (antidepressant, antipsychotic,
benzodiazepine, or mood stabilizing medication). EXCEPTIONS: Zolpidem and ramelteon
used sparingly if necessary for sleep; Oxazepam for alcohol detoxification; Seizure
disorder medications.

7. Participant is over the age of 64 and has evidence of severe cognitive impairment as
evidenced by a Mini-mental status exam (MMSE) score < 24.

8. Participant meets DSM-IV criteria for current major depression (non-substance
induced), PTSD, or panic disorder.

9. Participant has suicidal or homicidal ideation necessitating inpatient
hospitalization.

10. Participant is a pre-menopausal female who is pregnant, nursing, or not using a
reliable method of contraception.

11. Participant is over age 64 and has evidence of severe cognitive impairment as
evidenced by a Mini-mental status exam (MMSE) score less than 20.12. Participant is
of African descent.