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

• SCID for DSM-IV diagnoses of bipolar I or bipolar II disorder, and nicotine dependence.
• Young Mania Rating Scale Total Score <12 at study entry.
• BPRS Total Score < 20 at study entry
• 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.
• Fagerstrom Test for Nicotine Dependence (FTND) score of 4 or more.
• Smoking at least 15 cigarettes per day, and have expired breath CO level >10 ppm and plasma cotinine level >150 ng/ml at baseline.
• 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.
• 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

• Meet criteria for current abuse or dependence for any other alcohol or illicit substance within the past 3 months of study enrollment.
• Current evidence by SCID-IV and clinical evaluation of suicidality, homocidality or psychosis.
• Meet DSM-IV criteria for current major depression at the time of baseline evaluation.
• A history of hypersensitivity or other known adverse reactions (e.g. hyperstimulation, severe agitation) to bupropion.
• 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).
• 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.
• Prescription of monoamine oxidase inhibitors or the Wellbutrin® formulation of bupropion.
• The presence of manic, mixed manic or hypomanic symptoms in the past one (1) month prior to study enrollment.
• A lifetime history of antidepressant-induced mania or hypomania.
• A history of suicidal ideation while taking antidepressants.