Smoking Cessation With Varenicline in Schizophrenia: Antipsychotic-Induced Neurological Symptoms as Correlates

1. Objectives(s): To study whether smoking cessation with varenicline treatment will be
associated with a significant reduction in symptoms of antipsychotic-induced tardive
dyskinesia without worsening acute extrapyramidal symptoms.

2. Research Design: To test the feasibility of studying effects of smoking cessation with
varenicline on antipsychotic drug-induced neurological side effects, we propose a 12
week exploratory, open-label, proof-of-concept, pilot study of smoking cessation
treatment with varenicline in 10 schizophrenia or schizoaffective disorder patients who
are actively smoking and have pre-existing TD while receiving stable doses of
antipsychotics. Subjects will be followed after a 2 week baseline period to assess
changes in smoking status and neurological symptoms using standardized rating scales.
The aim is to examine clinically significant effects on antipsychotic-induced
neurological side effects that may warrant further investigation.

3. Methodology: Patients will be evaluated at a Screening Visit 1 (Week 0) and at a
Baseline Visit 2 (Week 2) two weeks apart. After the Baseline Visit, subjects will be
asked to cease smoking completely by the target date four weeks after the baseline visit
(Week 6) and will attend a clinic Cessation Visit 4 (Week 6) for medication check and
resupply. Treatment with varenicline will start at Baseline Visit 2 (Week 2) with 0.5mg
hs x 3 days, 0.5mg bid x 4 days, then start 1mg bid at Visit 3 (Week 3) for the
remaining 9 weeks of the study.

At the Screening and Baseline Visits, and at study visits thereafter (Visit 3-7), subjects
will be evaluated for efficacy and safety, and changes in smoking or other tobacco use since
the last visit. The following measures will be taken; Fagerstrom Test for Cigarette
Dependence (FTCD) at screening only; Cigarette smoking will be assessed by a structured
questionnaire of time-line follow-back (TLFB) usage; Expired carbon using a hand-held carbon
monoxide monitor; Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BAS), and the Abnormal
Involuntary Movement Scale (AIMS); Global Clinical Impression Scale (CGI-S at baseline, CGI-I
at final visit) for TD; C-SSRS; Brief Psychiatric Rating Scale (BPRS), Mini-Mental Status
Examination (MMSE) and Hospital Anxiety and Depression Scale (HADS) at baseline and the final
visit only; Brief smoking cessation counseling; Laboratory measures; Urine toxicology sample
at the screening and final visits only, serum pregnancy test (women) at screening visit only;
Changes in psychotropic medications; Varenicline compliance by pill counts; Adverse events.

Inclusion Criteria:

- DSM 5 criteria for schizophrenia or schizoaffective disorder and stable disease

- Glazer-Morgenstern-Doucette criteria for TD

- Smoking at least 5 cigarettes on average daily for at least 30 days prior to screening

- An exhaled carbon monoxide concentration greater than 5 parts per million (ppm) at
screening

- Agree to stop smoking by the target date (four weeks after baseline

- Concurrence for varenicline treatment from the patient's mental health provider if the
patient is under mental health care; OR, if the patient is not under mental health
care, the prescribing clinician should consult with a mental health provider to
evaluate the patient for appropriateness to receive varenicline

Exclusion Criteria:

- Have untreated or unstable acute medical or psychiatric illnesses

- Have a history of seizures

- History of somnambulism

- Have chronic degenerative neurological illnesses (e.g., Parkinson's disease)

- Have a history of active substance abuse (including marijuana abuse) in the 3 months
prior to screening or a positive toxicology screen

- Are receiving clozapine or cholinesterase inhibitors

- Had a change in dosing or medication type of antipsychotic or anti-muscarinic for one
month prior to enrollment (two months for long-acting antipsychotics)

- Are unable to remain on a stable dose of antipsychotic or anti-muscarinic during the
study period

- Have acute suicidal ideation, intent or behavior within 12 months or risk based
assessed on the C-SSRS or depression/anxiety score ≥ 8 on the HADS.

- Female subjects of childbearing age will have a negative pregnancy serum test at
screening and are required to use approved methods of birth control

- Use of an investigational drug within 30 days of screening

- Use of other smoking cessation aids (bupropion, nicotine replacement products)

- Use of other tobacco products

- History of allergic reactions to varenicline

- Lack capacity to provide informed consent