A Preliminary Study of Sustained-Release Bupropion for Smoking Cessation in Bipolar Affective Disorder

The purpose of this pilot study is to determine the safety and potential efficacy of
sustained-release bupropion (Zyban®) for the treatment of nicotine dependence in patients
with bipolar affective illness. we propose to conduct a preliminary study of the safety and
efficacy of bupropion SR (with flexible dosing up to 300 mg/day) in comparison to placebo in
medication-maintained and stabilized outpatients with bipolar I and II disorder who are
currently depressed despite mood-stabilizing medication and who are also nicotine-dependent
cigarette smokers, and who are motivated to quit smoking. Subjects will be n=32 subjects
between 18 and 65 years of age who meet DSM-IV criteria for bipolar disorder (either Type I
or II), and nicotine dependence, and smoke at least 15 cigarettes per day, with an FTND
score at baseline >5, expired breath CO >10, and plasma cotinine >150 ng/ml, and are
motivated to quit smoking within thirty days of the initial intake. Subjects must be on a
stable dose of a mood stabilizer (e.g. lithium, valproate, carbamezepine, topiramate,
gabapentin or atypical antipsychotic), and be in complete remission from active manic or
hypomanic and psychotic symptoms as judged by a psychiatric evaluation. Subjects will be
recruited through outpatient departments at Connecticut Mental Health Center (CMHC) and its
satellite clinics. Study medications will be given for 9 weeks duration, beginning at 1 week
prior to the "quit date". Bupropion [as the intermediate-release (IR) formulation] will
begin at 75 mg po qd x 3days, then increase to 150 mg [as bupropion SR formulation] qd x 4
days, and then increased to a final dose of up to 150 mg po bid (300 mg/day) by Day 15 (the
target quit date; TQD) as tolerated, and this dose will be continued for an additional eight
(8) weeks at up to 150 mg po bid. We will allow flexible dosing above 150 mg/day to allow
for adjustments needed if a bipolar subject does not tolerate the full dose of Zyban at 300
mg/day. Zyban will then be discontinued at the end of Week 10. Primary outcome measures are
endpoint (7-day) smoking abstinence and adverse events.

Inclusion Criteria:

1. SCID for DSM-IV diagnoses of bipolar I or bipolar II disorder, and nicotine
dependence.

2. Young Mania Rating Scale Total Score <12 at study entry.

3. BPRS Total Score < 20 at study entry

4. HAM-D 17-Item Score >12 and <25 at study entry. NB: We have set an upper limit for
allowable HAM-D 17-item scores since higher scores would typically trigger the
initiation of an antidepressant trial, and this study involves a placebo-controlled
augmentation of existing medication therapies with bupropion.

5. Fagerstrom Test for Nicotine Dependence (FTND) score of 4 or more.

6. Smoking at least 15 cigarettes per day, and have expired breath CO level >10 ppm and
plasma cotinine level >150 ng/ml at baseline.

7. Be on a stable dose of a mood stabilizer for at least 1 month (e.g. lithium,
valproate, carbamazepine, atypical antipsychotic) as judged by the study
psychiatrists (T. George, M.D. and H. Blumberg, M.D.), and judged by well-trained
trained psychiatric clinicians (e.g. J. Vessicchio, M.S.W. or K. Sacco, Psy.D.) to be
in remission from active manic, hypomanic, major depression and psychotic symptoms
based on a clinical interview and SCID-IV.

8. Be able to provide informed consent to participate in this study as judged by
clinical evaluation, and scoring at least 80% on a post-consent "test".

Exclusion Criteria:

1. Meet criteria for current abuse or dependence for any other alcohol or illicit
substance within the past 3 months of study enrollment.

2. Current evidence by SCID-IV and clinical evaluation of suicidality, homocidality or
psychosis.

3. Meet DSM-IV criteria for current major depression at the time of baseline evaluation.

4. A history of hypersensitivity or other known adverse reactions (e.g.
hyperstimulation, severe agitation) to bupropion.

5. Any serious documented medical disorders which might be contraindicated with
bupropion (i.e. anorexia or bulimia nervosa, history of seizure disorder, history of
major head injury with loss of consciousness for a period greater than five minutes),
or if the results of psychiatric/medical screening suggest reason concern of a trial
of bupropion (e.g., a history of severe cardiac, renal or hepatic disease, diabetes
mellitus or thyroid abnormalities which in the opinion of the study internist Dr.
Lynn Sullivan would preclude participation in this study).

6. Evidence of clinically significant EKG abnormalities as judged by the study
internist, Lynn E. Sullivan, M.D. (Department of Internal Medicine, YUSM), or her
designate.

7. Prescription of monoamine oxidase inhibitors or the Wellbutrin® formulation of
bupropion.

8. The presence of manic, mixed manic or hypomanic symptoms in the past one (1) month
prior to study enrollment.

9. A lifetime history of antidepressant-induced mania or hypomania.

10. A history of suicidal ideation while taking antidepressants.