DESCRIPTION (provided by applicant): Between 72% and 90% of schizophrenia patients smoke cigarettes, compared with 24% in the general population. Mortality from coronary disease, pulmonary disease and cancer is 2-6 times higher in schizophrenia patients than age matched controls. Although patients with schizophrenia can be both highly motivated and persistent in attempts to quit smoking, they have had relatively low smoking cessation rates of approximately 20% during treatment and high relapse rates of approximately 75% with standard treatments. We have found that a combined regimen of bupropion and dual nicotine replacement therapies (NRT) is well tolerated and associated with a 52% abstinence rate, a cessation rate comparable to that seen in the general population. While this cessation rate is excellent, 31% of those who were abstinent during treatment relapsed during NRT dose reduction and 77% relapsed by 12 months. Our hypothesis is that decreased nicotinic responsiveness underlies the high rates of relapse to smoking observed in schizophrenia. Because schizophrenia patients have reduced nicotinic responsiveness that is not expected to return to normal after smoking cessation, continuation of a nicotinic agonist may reduce rates of relapse to smoking. Standard treatment for smoking cessation in the general population involves 8-12 weeks of therapy. It is our hypothesis, based on the high rate of relapse to smoking during taper and immediately after discontinuation of pharmacotherapy, and on convincing evidence for a nicotinic receptor dysfunction in schizophrenia, that longer duration of pharmacotherapy is needed to prevent relapse to smoking in patients with schizophrenia. To assess this possibility, we propose to evaluate the safety and efficacy of 12 months of bupropion combined with dual NRT in schizophrenia patients who are able to quit smoking with open treatment. To do so, we will enroll 260 smokers with schizophrenia into an open, 8-week smoking cessation program that includes bupropion, NRT patch, prn NRT nasal spray and group cognitive behavioral therapy. Those who are abstinent at the end of the open intervention (n=91-104) will be randomized to a 44 week, double blind, placebo-controlled trial of bupropion, NRT patch and prn NRT nasal spray at the dose used to quit smoking. Participants will then discontinue study medications and enter a 3-month follow up. The primary outcome measure will be 7-day point prevalence abstinence rate at 12 months in the intervention vs. placebo groups.