In the US, cigarette smoking causes 480,000 premature deaths annually, due mainly to a twofold increased risk of cardiovascular disease and a 20-fold increased risk of lung cancer.1 Public health efforts and effective cessation treatments–including behavioral counseling and medications–have decreased US rates to approximately 14%; they are markedly increasing in most developing countries.2 Smoking and the emerging pandemic of obesity are the leading avoidable cause of premature deaths in most developed countries and rapidly becoming so in developing countries. Smoking and obesity are the major contributors to the worldwide increase in mortality from cardiovascular disease from #5 to #1.3
In people with serious mental illnesses such as schizophrenia, smoking rates reach 75%. Smoking is the chief contributor to these individuals dying, on average, about 20 years earlier than the general population. Although the risk of suicide is about 10-fold higher in people with serious mental illnesses than the general population rate of 1%, the majority of premature deaths are due to cardiovascular disease because it is so much more common.4
Smoking cessation significantly reduces risks of cardiovascular disease, beginning within a matter of months and reaching the nonsmoker within a few years, even among older adults. For lung and other cancers, however, reductions are not observable for several years after quitting, and by 10 years achieve death rates only midway between the continuing smoker and the nonsmoker. Thus, to reduce risks of cardiovascular disease, it is never too late to quit, but to reduce risks of cancer, it is never too early.5
In 2006, varenicline, a selective α4β2 nicotinic acetylcholine receptor partial agonist, was approved by the US Food and Drug Administration (FDA), producing long-term cessation rates of approximately 20%, significantly greater than the other approved smoking cessation aids such as bupropion or nicotine replacement therapy.6 In 2009 the FDA issued a black box warning for varenicline, resulting in a 76% decrease in the number of prescriptions dispensed, from a peak of approximately 2 million in the fourth quarter of 2007 to approximately 531,000 in the first quarter of 2014.7 The black box warning was based on reports to the Adverse Event Reporting System, useful to formulate, but not test, hypotheses. They included serious neuropsychiatric symptoms (NPSs) of aggression, depression, suicidal ideation, and agitation. Interestingly, those with psychiatric histories comprised about half of the cases of suicidal ideation and behavior change, those taking psychotropic drugs approximately 42%, and those with depression approximately 42%.7 Thus, plausible alternative explanations for these uncontrolled, and not unexpected, case reports include prior psychiatric conditions as well as psychiatric correlates of smoking cessation, which are independent of varenicline usage.8
The reliable detection of small-to-moderate risks and benefits of drug therapies requires cogent data from large-scale randomized trials designed a priori to test the hypothesis.9 Until recently, the totality of randomized evidence on varenicline safety was restricted to 8 small trials. Two included patients with psychiatric conditions such as schizophrenia and schizoaffective disorder or major depressive disorder, and only 5 used the validated Columbia-Suicide Severity Rating scale for assessing suicidal ideation and behavior. All showed no significant association between varenicline and NPSs. In a meta-analysis of 18 small randomized trials, there was no significant association between varenicline and serious NPSs.10 In 2011, the FDA sponsored 2 analyses of existing data sets containing information on varenicline use, both focusing on psychiatric hospitalizations. One was derived from the Department of Veterans Affairs Center for Medication Safety and the other from the Department of Defense’s US Army Medical Commands Pharmacovigilance Center. Although also useful to formulate, not test, hypotheses, both demonstrated no statistically significant association between varenicline and psychiatric hospitalizations.11
At the request of the FDA and with their consultation, a large, 8000-subject, randomized, double-blind, triple-dummy, placebo-controlled, and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) was conducted for 12 weeks.12 Participants were long-term smokers and included equal subgroups of those with and without psychiatric disorders. The primary safety endpoint was a composite of moderate and severe NPSs. The primary efficacy endpoint was biochemically confirmed continuous abstinence for 12 weeks.
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-Dianna Gaballa, BS, MS, Joanna Drowos, DO, MBA, Charles H. Hennekens, MD, DrPH
This article originally appeared in the April 2017 issue of The American Journal of Medicine.
