A Study of Varenicline for Prevention of Relapse to Smoking in Patients With Schizophrenia or Bipolar Disorder

Varenicline (Chantix) is a smoking cessation treatment that was approved in 2006 by the FDA for treatment of nicotine dependence and may be particularly beneficial in smokers with schizophrenia or bipolar disorder. Early experience with varenicline indicates that it will be effective for smoking cessation in schizophrenia and in addition, has the potential to be therapeutic for cognitive dysfunction in this population. In addition, more data is needed to evaluate the safety, tolerability and effectiveness of Varenicline in people with bipolar disorder.

To assess this possibility, we will evaluate the safety and efficacy of 12 months of varenicline in schizophrenia or bipolar disorder patients who are able to quit smoking in the short term with this treatment. To do so, we will enroll 324 smokers with schizophrenia or bipolar disorder from 6 mental health clinics in Massachusetts, New Hampshire, Michigan and Minnesota into an open, 12-week smoking cessation program that includes varenicline added to weekly group cognitive behavioral therapy (CBT). Those who achieve at least 2 weeks of continuous abstinence during the last 2 weeks of the open intervention will be randomized to the relapse prevention phase: a 40-week, double blind, placebo-controlled trial of varenicline at the dose used to quit smoking added to a tapering CBT schedule. Participants will then discontinue study medications and behavioral treatment and enter a 3-month follow up phase.

Participants will be moderate to heavy smokers, aged 18-70, who have smoked an average of ≥10 cigarettes/day for the past year and who have not quit during the past year for a period \>1 month.

During a 12-week open phase smoking cessation program, eligible subjects will be given active varenicline in addition to a 13-session weekly cognitive behavioral therapy program for smoking cessation. Dr. Evins (Principal Investigator) or a co-investigator will meet with subjects individually at Baseline of the Smoking Cessation Program to assess their medical eligibility for varenicline. A chart review will also be conducted by a research physician or psychiatrist.

Dr. Evins or another prescribing co-investigator will write a prescription for varenicline for each medically eligible subject. Subjects will receive their study medication at the end of each weekly group meeting. Any subject who experiences a serious side effect to the medication will meet with Dr. Evins or another medical co-investigator individually.

Subjects will set quit dates between the fourth and fifth CBT session weeks. Self-reports and exhaled carbon monoxide (CO) levels will be used to assess smoking status. Those subjects who have been abstinent for ≥2 weeks at the end of the 12th session group will be eligible for a 40-week relapse prevention program. After enrolling in the Relapse Prevention Program, subjects will be randomized to receive varenicline or placebos in addition to CBT for relapse prevention.

At Week 12 (the week before the end of the Smoking Cessation Program), Dr. Evins or another prescribing co-investigator will write prescriptions for subjects eligible for the randomized Relapse Prevention phase (i.e. successful quitters); these prescriptions will be sent to the Massachusetts General Hospital Research Pharmacy, where they will be filled according to the randomization code that the a research pharmacist will create.

When subjects come for the CBT orientation group session of the Relapse Prevention Program (Week 13), they will receive a 1-month supply of varenicline or placebo pill. During this randomized Relapse Prevention phase, medication compliance will be assessed at every group meeting by pill-count. Subjects will be asked about medication compliance and side effects at each group by the CBT group leaders and staff.

Any subject who experiences a serious side effect to the medication will meet with Dr. Evins or another medical co-investigator individually. In addition, Dr. Evins or a medical co-investigator will review the adverse events forms for each subject every week. Again, self-report and CO levels will be used to monitor smoking status.

Before and during both the open and randomized relapse prevention phases, subjects will be periodically assessed for cognitive performance, clinical characteristics, and adverse events in order to evaluate effects of withdrawal, predictors of cessation and relapse, and medication side effects. Following the completion of the 40-week relapse prevention phase, 3 follow-up assessments will be performed over a 3-month period to evaluate smoking status, cognitive functioning, and clinical effects.

Eligibility Criteria:
Inclusion Criteria:

* Women and men aged 18-70
* DSM-IV diagnosis of schizophrenia, schizoaffective disorder or bipolar disorder by diagnostic interview and chart review
* Smoke at least 10 cigarettes per day
* Clinically stable, on a stable dose of antipsychotic (schizophrenia) or mood stabilizer (bipolar) medication for at least 1 month
* No current active suicidal ideation
* Expired air carbon monoxide (CO) concentration \>9 ppm
* Willing to take study medications and set a quit date within 2-3 weeks of beginning treatment and be willing to participate in the relapse prevention and follow-up portions of the study
* Women of childbearing potential must have a negative urine pregnancy test at baseline and agree to use an approved form of contraception during the study.

Exclusion Criteria:

* DSM-IV diagnosis of dementia, neurodegenerative disease, or other organic mental disorder
* Substance use disorder other than nicotine or caffeine in the last 6 months
* Major depressive disorder within the last 6 months
* Serious unstable medical illness including, cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease such that hospitalization for treatment of that illness is likely within the next 2 months
* Life-threatening arrhythmia or cerebro-vascular event within 6 months, cardiovascular event within 2 months or uncontrolled hypertension
* History of multiple head injuries with neurological sequelae, a single severe head injury with lasting neurological sequelae, or current CNS tumor
* Liver function tests elevated over twice normal
* Renal insufficiency with estimated creatinine clearance \<40 ml/min
* Plan to continue use of tobacco products othe than cigarettes (e.g., cigar, pipe)
* Use of an investigational medication or device in the past 30 days
* Current suicidal or homicidal ideation