Adjunctive Topiramate for Treatment of Alcohol Dependence in Patients With Bipolar Disorder

Alcohol and substance use disorders are more common in bipolar disorder bipolar disorder
than in any other DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) Axis I
disorder, estimated to occur in up to 60% of patients with bipolar disorder. Alcohol use is
associated with poor outcome in bipolar disorder, and yet these co-occurring conditions are
understudied. To date, there is only one published placebo-controlled trial of an agent for
the treatment of alcohol dependence alcohol dependence in bipolar disorder. The purpose of
the proposed study is to evaluate the efficacy of a topiramate as a treatment for alcohol
dependence in patients with bipolar disorder. This is a 12-week, randomized,
placebo-controlled study of the efficacy of topiramate adjunctive to standard treatment for
bipolar disorder in patients with alcohol dependence and bipolar disorder. Additional aims
of the study are to document the safety and tolerability of topiramate in this population,
and to evaluate to effect of decreased drinking on mood symptoms. The study involves the
enrollment of a total of 80 patients with co-occurring alcohol dependence and bipolar
disorder over the course of 40 months at the Massachusetts General Hospital (MGH) Bipolar
Clinic and Research Program (BCRP) (www.manicdepressive.org). With a conservative estimate
of a 30% dropout rate, approximately 56 of the 80 patients with these two comorbid
conditions will complete 12 weeks treatment with either topiramate or placebo.

Inclusion Criteria:

1. Age 18+

2. Written informed consent.

3. Meet DSM-IV criteria (by SCID) for alcohol dependence.

4. Meet DSM-IV criteria (by SCID) for bipolar disorder I or II disorder.

5. ≥ 8 heavy drinking days (defined as ≥ 5 standard drinks per day for men, ≥ 4 standard
drinks per day for women) in the prior 4 weeks.

6. During the baseline visit, patients must be on a stable dose of accepted maintenance
treatment for bipolar disorder for the past 4 weeks. If the subject is on more than
one agent, at least one agent must be adequately dosed.

7. Antidepressant treatment is permitted if the dose has been stable for the past 4
weeks.

Exclusion Criteria:

1. Pregnant women or women of child bearing potential who are not using a medically
accepted means of contraception (condom, diaphragm, spermicide, intrauterine device,
tubal ligation, or partner with vasectomy). Because of the risk of the lowering of
oral contraceptive blood levels with topiramate, women whose sole means of
contraception is oral contraceptives or hormonal implants will be asked to use an
additional barrier method of birth control during treatment with the study drug.

2. Women who are lactating.

3. Age under 18.

4. Patients who do not have ≥ 8 heavy drinking days in the 4 weeks prior to the baseline
visit.

5. Important alcohol withdrawal symptoms (Clinical Institute Withdrawal Assessment for
Alcohol-Revised, CIWA-Ar, score > 15)

6. Urine toxicological screen positive for amphetamines or cocaine.

7. Meets DSM-IV criteria for current substance dependence for drugs other than cannabis
or nicotine.

8. Currently meets full DSM-IV criteria for manic, hypomanic, or mixed episode.

9. Serious suicide or homicide risk, as assessed by evaluating clinician.

10. Unstable medical illness including cardiovascular, hepatic, renal, respiratory,
endocrine, neurological, or hematological disease or uncontrolled seizure disorder.

11. History of nephrolithiasis, or treatment with any drug associated with
nephrolithiasis.

12. Current treatment with zonisamide.

13. Current treatment with any carbonic anhydrase inhibitors, including acetazolamide,
dorzolamide, and methazolamide.

14. Current treatment with any drug known to decrease drinking.

15. Subjects who have begun a new psychosocial treatment within 12 weeks of study
enrollment. Subjects receiving psychosocial treatment that has been stable for at
least 12 weeks prior to study entry, however, will be permitted to enroll in the
study.

16. Any psychotic disorder, including schizoaffective disorder (current or past).

17. Clinical or laboratory evidence of untreated hypothyroidism.

18. Patients with a diagnosis or history of glaucoma

19. Patients requiring excluded medications (see table below for details).

20. Psychotic features in the current episode or a history of a psychotic disorder, as
assessed by SCID.

21. Past intolerance to topiramate.

22. Any use of topiramate in the past 12 months.

23. Any investigational psychotropic drug within the last 3 months.