Suicidal Behavior and Depression in Smoking Cessation Treatments

Institute for Safe Medication Practices, Alexandria, Virginia, United States of America.
PLoS ONE (Impact Factor: 3.23). 11/2011; 6(11):e27016. DOI: 10.1371/journal.pone.0027016
Source: PubMed


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. However, some epidemiological studies report an increased risk in smoking or smoking cessation independent of treatment, and differences between drugs are unknown.
From 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.
Overall 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.
Varenicline 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.

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Available from: Curt D Furberg, Oct 06, 2015
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    • "It acts on β2-containing receptors and induces the release of mesolimbic dopamine, which counteracts withdrawal symptoms and reduces smoking satisfaction (Foulds 2006; Mihalak et al. 2006; Rollema et al. 2007). Clinical trials indicate that VAR is effective in decreasing relapse to smoking in humans (Cahill et al. 2011; Gonzales et al. 2006; Jorenby et al. 2006; Tonstad et al. 2006; Zierler-Brown and Kyle 2007), but adverse cardiovascular effects and/or neuropsychiatric events have recently been reported including (but not limited to) depression, suicidal ideation, suicide attempts , and completed suicide (Freedman 2007; Moore et al. 2011; Singh et al. 2011). It is possible that at least some of these are related to VAR acting on subtypes other than these β2-containing subtypes. "
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    ABSTRACT: Rationale Cigarette smoking is one of the most serious health problems worldwide and people trying to stop smoking have high rates of relapse. Zebrafish (Danio rerio), by combining pharmacological and behavioral assays, is a promising animal model for rapidly screening new compounds to induce smoking cessation. Objectives This study aims to identify possible acetylcholine nicotinic receptors (nAChRs) involved in mediating nicotine (NIC)-induced conditioned place preference (CPP) in zebrafish and investigate the effect of the CC4 and CC26 cytisine derivatives in reducing NIC-induced CPP. Methods CPP was evaluated using a two-compartment chamber, and the zebrafish were given CC4 (0.001–5 mg/kg), CC26 (0.001–1 mg/kg), cytisine (0.1–2.5 mg/kg), and varenicline (1–10 mg/kg) alone or with NIC (0.001 mg/kg). Swimming activity was evaluated using a square observational chamber. The affinity of the nicotinic ligands for native zebrafish brain nAChRs was evaluated by binding studies using [3H]-Epibatidine (Epi) and [125I]-αBungarotoxin (αBgtx) radioligands, and their subtype specificity was determined by means of electrophysiological assay of oocyte-expressed α4β2 and α7 subtypes. Results CC4 and CC26 induced CPP with an inverted U-shaped dose–response curve similar to that of NIC. However, when co-administered with NIC, they blocked its reinforcing or slightly aversive effect. Binding and electrophysiological studies showed that this effect was due to binding to high-affinity heteromeric but not α7-containing receptors. Conclusions We have further characterized CC4 and identified a new compound (CC26) that may be active in inducing smoking cessation. Zebrafish is a very useful model for screening new compounds that can affect the rewarding properties of NIC.
    Psychopharmacology 05/2014; 231(24). DOI:10.1007/s00213-014-3619-x · 3.88 Impact Factor
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    • "Although previous data mainly addressed specifically misperceptions regarding NRT, similar misperceptions may also be attached to other medications and treatments [8]. While few data are available regarding smokers’ perception of bupropion SR and varenicline, publicity on the recent debate regarding potential risk of suicide [15], and cardiovascular events [16], [17] may discourage smokers not to seek assistance in their attempt to quit smoking. "
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    ABSTRACT: In Korea, nicotine replacement therapy (NRT) has been widely used in government-led, public health center-based smoking cessation services since 2004 and varenicline has become available from 2007 but without reimbursement. In this study which used a series of nationwide cross-sectional surveys in Korea performed from 2005 to 2011, we examined the prevalence of smoking cessation medication use and factors associated with it. We analyzed data from the third to fifth waves of Korean National Health and Nutrition Examination Survey (2005-2011). Prevalence of each smoking cessation method use was calculated for each year, and its secular trend was tested by multivariate logistic regression. Among smokers who made quit attempt during the previous year, 15.7% had used smoking cessation medications,15.3% had used NRT, and 0.7% had used prescription medication. There was a significant increasing trend for NRT use (P<0.001) during the study period, but use of prescription medication did not show any increase over time (P = 0.654) Education on smoking prevention and cessation was associated with smoking cessation medications use (OR 2.08, 95% CI 1.58-2.75). While the use of NRT has increased over years through government-sponsored smoking cessation programs, use of prescription drugs remained very low and flat probably due to lack of reimbursement. Education of smokers about effective smoking cessation methods and change in reimbursement policy are suggested to stimulate evidence-based smoking cessation practice.
    PLoS ONE 10/2013; 8(10):e74904. DOI:10.1371/journal.pone.0074904 · 3.23 Impact Factor
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    • "Poluzzi et al. [7] detected drug-induced torsades de pointes (TdP) signals of linezolid, caspofungin, posaconazole, indinavir, and nelfinavir using ROR. However, most of existing studies on the AERS were carried out for a small number of drugs [6,8-10], and few studies were focused on large-scale mining or on detecting the etiology of ADE signals in terms of mechanism of action, physiologic effect, or molecular structure of drugs [11]. We realize that potential of the AERS has not been fully utilized, and one of main reasons for this is because there is a lack of standardization among drug names. "
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    ABSTRACT: Background The Adverse Event Reporting System (AERS) is an FDA database providing rich information on voluntary reports of adverse drug events (ADEs). Normalizing data in the AERS would improve the mining capacity of the AERS for drug safety signal detection and promote semantic interoperability between the AERS and other data sources. In this study, we normalize the AERS and build a publicly available normalized ADE data source. The drug information in the AERS is normalized to RxNorm, a standard terminology source for medication, using a natural language processing medication extraction tool, MedEx. Drug class information is then obtained from the National Drug File-Reference Terminology (NDF-RT) using a greedy algorithm. Adverse events are aggregated through mapping with the Preferred Term (PT) and System Organ Class (SOC) codes of Medical Dictionary for Regulatory Activities (MedDRA). The performance of MedEx-based annotation was evaluated and case studies were performed to demonstrate the usefulness of our approaches. Results Our study yields an aggregated knowledge-enhanced AERS data mining set (AERS-DM). In total, the AERS-DM contains 37,029,228 Drug-ADE records. Seventy-one percent (10,221/14,490) of normalized drug concepts in the AERS were classified to 9 classes in NDF-RT. The number of unique pairs is 4,639,613 between RxNorm concepts and MedDRA Preferred Term (PT) codes and 205,725 between RxNorm concepts and SOC codes after ADE aggregation. Conclusions We have built an open-source Drug-ADE knowledge resource with data being normalized and aggregated using standard biomedical ontologies. The data resource has the potential to assist the mining of ADE from AERS for the data mining research community.
    Studies in health technology and informatics 08/2013; 192(1):1101. DOI:10.1186/2041-1480-5-36
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