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Abstract
BackgroundTwo treatments for smoking cessation—varenicline and bupropion—carry Boxed Warnings from the U.S. Food and Drug Administration (FDA) about suicidal/self-injurious behavior and depression. However, some epidemiological studies report an increased risk in smoking or smoking cessation independent of treatment, and differences between drugs are unknown.MethodologyFrom the FDA's Adverse Event Reporting System (AERS) database from 1998 through September 2010 we selected domestic, serious case reports for varenicline (n = 9,575), bupropion for smoking cessation (n = 1,751), and nicotine replacement products (n = 1,917). A composite endpoint of suicidal/self-injurious behavior or depression was defined as a case with one or more Preferred Terms in Standardized MedDRA Query (SMQ) for those adverse effects. The main outcome measure was the ratio of reported suicide/self-injury or depression cases for each drug compared to all other serious events for that drug.ResultsOverall we identified 3,249 reported cases of suicidal/self-injurious behavior or depression, 2,925 (90%) for varenicline, 229 (7%) for bupropion, and 95 (3%) for nicotine replacement. Compared to nicotine replacement, the disproportionality results (OR (95% CI)) were varenicline 8.4 (6.8–10.4), and bupropion 2.9 (2.3–3.7). The disproportionality persisted after excluding reports indicating concomitant therapy with any of 58 drugs with suicidal behavior warnings or precautions in the prescribing information. An additional antibiotic comparison group showed that adverse event reports of suicidal/self-injurious behavior or depression were otherwise rare in a healthy population receiving short-term drug treatment.ConclusionsVarenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-injurious behavior. Bupropion for smoking cessation had smaller increased risks. The findings for varenicline, combined with other problems with its safety profile, render it unsuitable for first-line use in smoking cessation.
Highlights
Treatments for smoking cessation include counseling without pharmacological intervention (‘‘cold turkey’’) and a variety of nicotine replacement products, bupropion, and varenicline
Source Data Case reports for this study were extracted from a database of all adverse drug event reports received by the Food and Drug Administration (FDA) since 1998 into its Adverse Event Reporting System (AERS), and released for research use [17]
Patient and Event Characteristics We identified 17,290 case reports meeting the study criteria for all types of serious adverse events, including 13,243 cases in the smoking cessation population and 4,047 in the antibiotic comparison group
Summary
Treatments for smoking cessation include counseling without pharmacological intervention (‘‘cold turkey’’) and a variety of nicotine replacement products, bupropion (an antidepressant), and varenicline (a partial agonist of a4b2 nicotinic acetylcholine receptors). While ‘‘dysphoria and depressed mood’’ is listed among eight possible nicotine withdrawal symptoms in the current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), [7] little supporting evidence could be found in clinical studies and reviews. These reports provided stronger evidence for other withdrawal symptoms such as irritability, insomnia, and weight gain, [8,9,10] which suggests that depression is not common in nicotine withdrawal. Two treatments for smoking cessation—varenicline and bupropion—carry Boxed Warnings from the U.S Food and Drug Administration (FDA) about suicidal/self-injurious behavior and depression. Some epidemiological studies report an increased risk in smoking or smoking cessation independent of treatment, and differences between drugs are unknown
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