Approximately 60 chronic smokers with bipolar disorder, schizophrenia or schizoaffective disorder who are motivated to try to quit smoking will be randomized to receive smoking cessation treatment with the FDA-approved medication, varenicline, delivered either a) at its standard dose and titration schedule (half of the participants) versus b) at a lower dose and slower titration schedule (the other half), for 12 weeks. All smokers will choose a target quit date sometime between 8 to 35 days after starting the medication. All participants will receive ten 30-minute sessions of a behavioral treatment called Acceptance and Commitment Therapy (ACT). Participants will be followed for an additional 12 weeks off study medication. The major endpoint is the feasibility of combining ACT with the different dosing strategies. Investigators will also conduct a blood test that measures the breakdown of nicotine in the body to explore whether that measure influences treatment response and side effects.

This pilot feasibility trial is a Phase IV, 12-week, single center, randomized, double blind, parallel group comparison of low (0.5 mg twice daily with slower titration over one full week) versus standard dose (1.0 mg twice daily with standard titration) varenicline in individuals with DSM-V Bipolar Disorder (BD) or Schizophrenia Spectrum Disorders (SSD) with a 12-week, post-treatment follow-up. The 16 visits after screening (Weeks 0-24) include 11 in-person (with medications dispensed at weeks 0, 2, 4, 6, 8 and 10] and 5 via telephone. Plasma will be obtained at baseline to measure participants' Nicotine Metabolite Ratio (NMR) and to identify slow versus normal nicotine metabolisers. A flexible quit date (between days 8-35) will be employed allowing varenicline preloading to occur prior to the Target Quit Date. Ten sessions of Acceptance & Commitment Therapy (ACT) for smoking cessation will be delivered by trained counselors.

Inclusion Criteria:

• 18-70 years of age
• Outpatients with a DSM-V diagnosis of Bipolar Disorder or Schizophrenia Spectrum Disorder
• Smoke at least 10 cigarettes per day and have an expired carbon monoxide (CO) breathalyzer of ≥ 10 ppm at screening and baseline visits
• Are motivated to quit smoking
• Have access to a mental health provider

Exclusion Criteria:

• Females who are pregnant, planning to become pregnant, or lactating
• Test positive for any non-prescribed medications or illicit drugs
• Have made a suicide attempt or engaged in self-mutilatory behavior in the past year
• Meet criteria for another Substance Use Disorder in the past month
• In the investigators' judgement, are either psychiatrically or medically unstable to safely participate
• Are currently using any other form of treatment for smoking cessation

Adverse events were monitored throughout the 12 week active treatment phase and for one month after treatment discontinuation (i.e. through week 16).

Everyone, with the exception of the study pharmacist, will be blinded to which arm participants will be randomized into.