Varenicline Treatment for Smoking Cessation in Patients With Bipolar Disorder

OBJECTIVE:

Our primary objective is to determine if adjunctive varenicline will be efficacious (vs.
placebo) in initiating abstinence from smoking cigarettes in subjects with stable bipolar
disorder who are motivated to quit smoking during a 12-week treatment phase. A secondary
outcome is to determine whether those who initiated abstinence during the 12-week treatment
phase will maintain abstinence in the subsequent three-month follow-up period off study
medications.

Additional outcomes: we plan to test the effectiveness of varenicline in reducing nicotine
withdrawal symptoms or urges to smoke, as well as its safety for use in stable bipolar
patients when used as an adjunctive treatment for smoking cessation.

RESEARCH PLAN:

We plan to test these hypotheses by conducting a randomized, placebo-controlled, treatment
trial of Chantix. Measures of CO levels in expired air (10 ppm or lower), self-reported
abstinence, and psychopathology ratings will be used to evaluate primary and secondary
outcomes along with safety assessments. Smoking abstinence is defined as 7-day point
prevalence of self-reported no smoking verified objectively by expired CO levels of 10 ppm or
less, and will be assessed at 12-weeks (or end of treatment phase) as the primary outcome.
The same criterion will be used to assess maintenance of abstinence in the non-treatment
phase, i.e. at 24 weeks or end of study.

METHODS:

Seventy-six subjects with DSM-IV bipolar disorder will be recruited from Western Psychiatric
Institute and Clinic and Dubois Regional Medical Center. Using a 1:1 Randomization, which
also takes into account gender, subjects who sign an informed consent document will be
randomized to receive Chantix or placebo.

It is expected that 16 of the 76 may not meet inclusion/exclusion criteria, leaving 60
consenting adults aged 18-65 years with DSM-IV bipolar disorder, which will be confirmed by
the MINI (Sheehan et al.) Subjects must meet smoking inclusion criteria of smoking 10 or more
cigarettes per day. Motivation to quit smoking (score of at least 7 on the Contemplation
Ladder Scale) as well as stable mood status (Young Mania Rating Scale score of eight or less,
Montgomery Asberg Depression Rating Scale Score of eight or less, with low scores on suicide
aggression and psychotic items over a four-week period required. Subjects who have received
pharmacological agents for smoking cessation such as bupropion, nicotine replacement
treatment, or who have participated in behavioral treatment for smoking cessation more than
three months before beginning the study will be permitted to enroll in the study. Anyone
experiencing serious side-effects from varenicline in the past or who has already
participated in a smoking cessation study with varenicline will be excluded.

Chantix or placebo will be administered using random assignment at a dose of 0.5 mg by mouth
for three days, followed by 0.5 mg twice per day for four days. After the first week, the
dose will be increased to 1 mg twice daily for 11 weeks. Subjects must be able to tolerate a
minimum of 1 mg per day to continue in the study.

Subjects will pick a target date between visit 3 (to permit titration to the target dose of 2
mg per day) and visit 4 to quit smoking. There needs to be at least 24 hours (preferably 48)
between the time of the last cigarette usage and visit 4, where a CO measurement will be
taken.

Those who are unable to quit at this time will be given an opportunity to pick additional
quit dates. All visits will be scheduled a week apart and subjects will continue to take
their double-blind medication and receive counseling sessions for smoking cessation. Study
medication will be stopped after 12 weeks, and there will be weekly visits to evaluate
abstinence.

Some standard psychopathology rating scales and smoking rating scales will be administered to
evaluate secondary aims such as the degree of nicotine withdrawal symptoms and the impact of
residual symptoms on bipolar disorder. Safety will be assessed through the administration of
specific mania and depression rating scales including and the Columbia -Suicide Severity
Rating Scale, as well as a comprehensive health assessment. This includes a medical history
and evaluation of laboratory measures. Any adverse effects of medication will be assessed by
asking questions at each visit and if necessary, contacting the subject by phone outside the
scheduled visits.

SIGNIFICANCE The rate of cigarette smoking among people with psychiatric disorders remains
exceedingly high; nearly two to four times as high as those in the general population.
Patients with bipolar disorder may have the highest rates of smoking as compared with people
with other psychiatric diagnoses. To date, there have been no treatment trials of adequate
size to measure smoking cessation rates in people with bipolar disorder. If varenicline
proves to be an effective in helping people with bipolar disorder to stop smoking, or even to
reduce their smoking rates, this could play an important role in improving their health.

Subject inclusion criteria

1. DSM IV-TR Bipolar I or II or Bipolar NOS Disorder

2. Ability to provide written informed consent

3. Male or Female patients, all races, ages 18 to 65 years inclusive

4. Negative serum pregnancy test for females of child-bearing potential. Patients must
agree to one of the following birth control methods: an oral contraceptive agent, an
intrauterine device (IUD), an implantable contraceptive (e.g., Norplant), or an
injectable contraceptive (e.g., Depo Provera) for at least 1 month prior to entering
the study and will continue its use through at least 30 days after the last dose of
study medication or a barrier method of contraception, e.g., condom and/or diaphragm
with spermicide while participating in the study through at least 30 days after the
last dose of study medication or abstinence.

5. MADRS total scores ≤ 8 (past 4 weeks) (suicidal item, score ≤ 1, past 4 weeks).

6. Y-MRS scores ≤ 8 (past 4 weeks) irritability, speech content, disruptive, or
aggressive behavior items score ≤ 3, past 4 weeks)

7. Stable doses of primary bipolar maintenance medication for at least 8 weeks prior to
randomization

8. No psychiatric hospitalization or Emergency Room Visits for psychiatric issues in the
6-month period prior to randomization

9. No suicidal attempts or behavior history past 6 months

10. No aggressive or violent acts or behavior by history past 6 months

Subject exclusion criteria

1. Uncontrolled seizure disorders and other neurological disorders including Huntington's
Chorea, Multiple Sclerosis, Cerebral Palsy, and stroke (cerebrovascular accident,
CVA).

2. Current alcohol or other substance abuse or dependence within the last 3 months
(caffeine will be permitted, nicotine dependence is part of inclusion criteria),
including a case-by-case evaluation of those who meet remission criteria and who are
on long-term substance abuse and/or alcohol abuse treatment.

3. Female patients who are pregnant, lactating or likely to become pregnant in next 6
months

4. Uncontrolled diabetes mellitus, asthma, seizure disorder, uncontrolled hypertension,
(uncontrolled hypertension is defined as Systolic BP > 150 mm or Hg or diastolic BP >
95 mm or Hg on 2 consecutive BP readings 15 minutes apart at the time of screening) or
unstable medical illness. Moderate to severe renal disease - moderate renal failure is
defined as serum Creatinine >1.3 mg/dl in women and > 1.5 mg/dl in men, at the time of
screening.

5. Severe dizziness or fainting due to orthostatic blood pressure changes

6. Known hypersensitivity to varenicline

7. Current use of cimetidine

8. Current treatment with heparin, warfarin, or lidocaine

9. Comorbid psychiatric condition diagnosed within the last three months.

Subject smoking inclusion criteria

1. Score of 7 or greater on the Contemplation Ladder, and willing to pick a target quit
date within the next 4 weeks.

2. Smoke > 10 cigarettes per day.

3. Expired breath CO level > 10 ppm at screening and randomization.

4. No use of smoking cessation medication and/or behavioral treatment for smoking
cessation in the past three months.

5. No current use of any nicotine replacement treatment.

6. Not using any tobacco products other than cigarettes.

7. No current treatment for smoking cessation (hypnosis, acupuncture, others).

8. No current use or past treatment failure with varenicline.

9. No current treatment with bupropion for smoking cessation.