Effect of Varenicline on Cognitive Function in Cigarette Smokers With Schizophrenia

Schizophrenia is characterized by deficits in neurocognitive function, including executive function, attention, and spatial and verbal memory. Central nicotinic acetylcholine receptors (nAChR) are dysregulated in schizophrenia. It has been shown that neurocognitive deficits in schizophrenia improve by administration of nicotine, nicotinic agonists or cigarette smoking. Hence, it is believed that cigarette smoking may remedy cognitive deficits in schizophrenia and in fact some persons with schizophrenia may be "self-medicating" with tobacco to counter such cognitive problems. The prevalence rates of cigarette smoking in persons with schizophrenia are higher than in the general population (58-88% vs. 25% respectively). This population also has a nicotine dependence rate of around 80 % and a high relapse rate after smoking cessation. Additionally the leading cause of medical problems and death in people with schizophrenia is tobacco addiction. Research that addresses the problem of smoking in schizophrenia is of great importance. Varenicline (VAR), an α4β2 nAChR partial agonist, approved for smoking cessation, mimics the effect of nicotine by stimulating nAChRs, and releasing sufficient dopamine in order to reduce craving and withdrawal effects. This study will follow four groups of subjects (N=40) that will receive neuropsychological and psychiatric testing in three consecutive sessions (smoking satiation, abstinence and reinstatement) separated by at least one week over 3 weeks. The groups are: 1. cigarette smokers with schizophrenia (N=10), 2. non-smokers with schizophrenia (N=10), 3. healthy cigarette smoking controls (N=10), 4. non-smoking controls (N=10). All groups will be age- and sex- matched. Pre-treatment with varenicline (VAR) or placebo will start on Day 1 of each test session will be as follows: 1) 0.0 mg/day 2) 0.5 mg twice daily 3) or 1 mg twice daily for 3 days. Testing days will be separated by at least 1 week apart to rule out medication carry-over effects. If nicotinic acetylcholine receptors can be stimulated resulting in more dopamine release and improved neurocognitive function without inducing deleterious health effects it may be of benefit to persons with schizophrenia who smoke tobacco.