Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: a randomized clinical trial

Abstract

Importance: It is estimated that more than half of those with serious mental illness smoke tobacco regularly. Standard courses of pharmacotherapeutic cessation aids improve short-term abstinence, but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy.

Objective: To determine whether smokers diagnosed with schizophrenia and bipolar disease have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with standard treatment.

Design, setting, and participants: Randomized, double-blind, placebo-controlled, parallel-group, relapse-prevention clinical trial conducted in 10 community mental-health centers. Of 247 smokers with schizophrenia or bipolar disease recruited from March 2008-April 2012, 203 received 12-weeks' open-label varenicline and cognitive behavioral therapy and 87 met abstinence criteria to enter the relapse prevention intervention.

Interventions: Participants who had 2 weeks or more of continuous abstinence at week 12 of open treatment were randomly assigned to receive cognitive behavioral therapy and double-blind varenicline (1 mg, 2 per day) or placebo from weeks 12 to 52. Participants then discontinued study treatment and were followed up to week 76.

Main outcomes and measures: Seven-day rate of continuous abstinence at study week 52, the end of the relapse-prevention phase, confirmed by exhaled carbon monoxide. Secondary outcomes were continuous abstinence rates for weeks 12 through 64 based on biochemically verified abstinence and weeks 12 through 76, based on self-reported smoking behavior.

Results: Sixty-one participants completed the relapse-prevention phase; 26 discontinued participation (7 varenicline, 19 placebo) and were considered to have relapsed for the analyses; 18 of these had relapsed prior to dropout. At week 52, point-prevalence abstinence rates were 60% in the varenicline group (24 of 40) vs 19% (9 of 47) in the placebo group (odds ratio [OR], 6.2; 95% CI, 2.2-19.2; P < .001). From weeks 12 through 64, 45% (18 of 40) among those in the varenicline group vs 15% (7 of 47) in the placebo group were continuously abstinent (OR, 4.6; 95% CI, 1.5-15.7; P = .004), and from weeks 12 through 76, 30% (12 of 40) in the varenicline group vs 11% (5 of 47) in the placebo group were continuously abstinent (OR, 3.4; 95% CI, 1.02-13.6; P = .03). There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events.

Conclusions and relevance: Among smokers with serious mental illness who attained initial abstinence with standard treatment, maintenance pharmacotherapy with varenicline and cognitive behavioral therapy improved prolonged tobacco abstinence rates compared with cognitive behavioral therapy alone after 1 year of treatment and at 6 months after treatment discontinuation.

Trial registration: clinicaltrials.gov Identifier: NCT00621777.

Figure 1. Study Flow Chart

The reasons patients withdrew include that they did not want to attend or take placebo, they moved, or no reason was provided. The reasons for administrative withdrawal include poor medication adherence, poor attendance, medical instability, or site closure. Four participants who were considered withdrawn for adverse-events during the open-phase segment gave more than 1 reason for withdrawing. ^a Data from 7 participants, 1 of whom had relapsed and 6 of whom had been continuously abstinent, were included in the primary analysis measured by imputation as relapsed at the time they dropped out. ^bData from these 19 participants, 17 of whom had relapsed and 2 of whom had been continuously abstinent, were included in the primary analysis by imputation as relapsed at the time of dropout.

Figure 2. Point-Prevalence and Continuous Abstinence Rates During Study Treatment and Follow-up Phases

At week 16, cognitive behavioral therapy sessions were tapered to twice a month; at week 20, to once a month. P values are based on Fisher exact tests. Seven-day point-prevalence was higher for those assigned to varenicline at week 52 (P < .001) and at week 64 (P < .01). Continuous abstinence was higher for those assigned to the varenicline group from weeks 12 through 52 (P < .01), weeks 12 through 64 (P < .01), and weeks 12 through 76 (P < .05). There were 40 participants in the varenicline and 47 in the placebo group throughout the relapse-prevention and follow-up phases, and there were 203 participants in the open-label phase.

Figure 3. Clinical Outcomes During the Open-Label, Randomized, Follow-up Phases

At week 16, cognitive behavior therapy sessions were tapered to twice a month; at week 20, to once a month. Data presented are raw means. Error bars represent 95% confidence intervals. The 12-Item Short Form Health Survey is scored via a standard algorithm, with higher scores indicating better patient self perception of health, with a mean score of 50 and a standard deviation of 10 in a representative sample of the US population. See the legend in Table 1 for score definitions for Brief Psychiatric Rating Scale, and the Calgary Depression Scale for Schizophrenia.