Neuropsychiatric Safety and Efficacy of Varenicline, Bupropion, and Nicotine Patch in Smokers With Psychotic, Anxiety, and Mood Disorders in the EAGLES Trial

Abstract

Background-Neuropsychiatric safety and relative efficacy of varenicline, bupropion, and transdermal nicotine patch (NRT) in those with psychiatric disorders is of interest. Methods-We performed secondary analyses of safety and efficacy outcomes by psychiatric diagnosis in EAGLES, a 12-week, randomized, double-blind, triple-dummy, placebo-and active-(NRT)-controlled trial of varenicline and bupropion with 12-week follow-up, in a subset population, n=4092, with a primary psychotic (n=390), anxiety (n=792) or mood (n=2910) disorder. Primary endpoint parameters were incidence of pre-specified moderate and severe neuropsychiatric adverse events (NPSAEs) and week 9-12 continuous abstinence rates (9-12CAR). Results-The observed NPSAE incidence across treatments was 5.1-6.3% in those with a psychotic disorder, 4.6-8.0% in those with an anxiety disorder, and 4.6-6.8% in those with a mood disorder. Neither varenicline nor bupropion were associated with significantly increased NPSAEs relative to NRT or placebo in the psychiatric cohort or any psychiatric diagnostic sub-cohort.

Achieving Smoking Cessation in Individuals with Schizophrenia: Special Considerations

“…Articles were identified in a Pubmed literature search of English language manuscripts and a search of the citations in each identified manuscript (see Table 1 for a summary of study methodologies and outcomes). Because clinical practice guidelines recommend use of a combination of medication and counseling in all individuals making a smoking cessation attempt [47], and because the abstinence rate with behavioral treatment alone is approximately 4% across smoking cessation trials randomizing one group to behavioral treatment and placebo [30, 31], this review focuses on trials of combined pharmacotherapy and behavioral treatment. Biochemically verified self report of prolonged or continuous abstinence is the outcome of interest where available.…”

“…Since the revised PORT guidelines were published, evidence has emerged consistently and strongly supporting the safety and efficacy of varenicline for smoking cessation and maintenance of abstinence in schizophrenia [44–46, 54–56]. Varenicline in combination with behavioral support has been found to be efficacious in promoting abstinence in smokers with schizophrenia interested in quitting [37, 44] and maintenance treatment with varenicline among successful quitters has been shown to protect against relapse in those with schizophrenia and bipolar disorder [42, 56].…”

“…Contrary to anecdotal reports of serious neuropsychiatric adverse events with pharmacotherapeutic cessation aids, particularly varenicline, and particularly in those with psychiatric illness, much emphasized in the press, and highlighted in a boxed warning for neuropsychiatric adverse events for both bupropion and varenicline, no controlled trial to date, alone or in aggregate, in smokers with psychiatric illness in general or schizophrenia in particular has shown a signal for increased neuropsychiatric adverse events other than sleep disturbance with varenicline or bupropion compared to placebo or NRT [37, 42, 44–46, 54, 57–61]. …”

“…In the psychotic disorders subgroup in Eagles, the rate of moderate to severe neuropsychiatric adverse events was 6.3% in the varenicline, bupropion, and placebo arms and 5.1% in the nicotine patch arm [54]. The finding that neuropsychiatric adverse events are not more common with varenicline or bupropion than placebo or nicotine patch led to the removal of the boxed warning for bupropion and varenicline from both FDA and European Medicines Agency (EMA) prescribing instructions.…”

“…Reluctance to prescribe cessation aids, particularly non-nicotine pharmacotherapies, to aid smoking cessation, may be due to continuing concerns about safety of the pharmacotherapy itself, low expectancies regarding patient follow-through or success with quit attempts, or simply lack of knowledge about the evidence base for smoking cessation pharmacotherapies for smokers with schizophrenia. Although a recent meta-analysis reported that smokers with schizophrenia are as likely as those without schizophrenia to receive physician advice to quit smoking [29], cessation advice or even behavioral therapy alone alone has a low success rate with this population [11, 30, 31], and effective pharmacotherapies, particularly varenicline, are less likely to be prescribed to smokers with schizophrenia than to smokers without psychiatric illness [32]. Reluctance by treaters to recommend and prescribe effective smoking cessation therapies may contribute to the disparity in the rates of successful cessation in smokers with schizophrenia at the population level [33].…”