Varenicline Adjunctive Treatment in Schizophrenia

This is a double-blind, placebo controlled clinical trial in schizophrenia patients. Outcome
measures include biomarkers and clinical symptoms and functions, and smoking cessation.
Neurobiological and cognitive markers will be measured for short term (2 weeks) and
longer-term (8 weeks). Current schizophrenia treatments are mostly ineffective against
primary negative symptoms and the cognitive and information processing deficits associated
with the disorder. Previous research has identified several neurophysiological deficits in
schizophrenia that are enduring, frequently occurring before psychosis, and mark the disease
liability. These schizophrenia endophenotypes provide important targets for novel treatment
development as they represent the core deficits of the disorder. We hypothesize that
sustained nicotinic and dopaminergic modulation by varenicline may ameliorate the core
neurobiological deficits seen in schizophrenia patients, which would lead to subsequent
clinical improvement. Neurobiological and neurocognitive markers and clinical and functional
measures will be obtained to determine 1) short-term effect of varenicline on biomarkers; and
2) longer-term improvement in clinical symptoms, smoking cessation, and functions; and how
biomarker changes predict these improvements.

Inclusion Criteria:

- Age 18-60

- DSM-IV Diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform
disorder

- Clinically stable with no change in antipsychotic medications and increase of daily
dose for 4 weeks prior to enrollment

- Sufficient understanding of the study and risks (ESC score 10 or above)

Exclusion Criteria:

- Major medical illness history including, but not limited to, history of heart attack,
stroke, TIA (transient ischemic attack)

- History of organic brain disorders that may affect neurophysiological measurements,
including seizure disorder, brain tumor, head injury with evidence of significant
cognitive deterioration

- DSM-IV diagnosis of substance dependence within 6 months except nicotine and marijuana

- On nicotine replacement therapy (nicotine patch, gum, or nasal spray)

- Uncontrolled blood pressure (persistent systolic above 155 or diastolic above 95)

- EKG of second or third degree atrioventricular (AV) block

- Renal insufficiency with estimated creatinine clearance <40 ml/min

- Women who have positive urine pregnancy tests

- Women who are pregnant, plan to become pregnant, or in breastfeeding