Suicidal Behavior and Depression in Smoking Cessation Treatments

Institute for Safe Medication Practices, Alexandria, Virginia, United States of America.
PLoS ONE (Impact Factor: 3.53). 11/2011; 6(11):e27016. DOI: 10.1371/journal.pone.0027016
Source: PubMed

ABSTRACT 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, Aug 16, 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 · 3.99 Impact Factor
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    • "This would fit with associations of varenicline with depression and suicide reported in post-marketing surveillance studies (Moore et al. 2011). However, these studies could have been subject to several forms of biases (Moore et al. 2011). Furthermore, it may be that varenicline only has a depressogenic effect on the HPA axis in people with a high baseline cholinergic stimulation [e.g., current smokers, subjects with a (family) history of depression], which were excluded in the current study. "
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    ABSTRACT: Varenicline is the most effective drug for smoking cessation, but its use decreased because of reports of depressogenic side effects. However, because smoking and smoking cessation on their own are associated with depression, it remains unclear whether reported depressogenic effects are attributable to varenicline, or to smoking, and/or smoking cessation themselves. Previously, we observed no depressogenic effects of varenicline on a psychological level. In the present study, we aimed at investigating potential depressogenic effects of the partial nicotinergic acetylcholine receptor agonist varenicline on a biological level. A possible pathway would be an effect of varenicline on the hypothalamic-pituitary-adrenal (HPA) axis, considering the relation between the HPA axis and (1) the cholinergic system and (2) depression. In a randomized, double-blind design, we administered varenicline or placebo for 7 days (0.5 mg/day first 3 days, then 1 mg/day) to healthy never-smoking subjects, thereby eliminating bias by (previous) smoking status. We used repeated measures (before and after treatment) of the salivary free cortisol awakening response to measure HPA axis activity and flexibility. Salivary cortisol data of 34 subjects were included in the analysis. Results showed no effect of varenicline on height (F 1,32 = 0.405; P = 0.529) or shape (F 2,31 = 0.110; P = 0.164) of the cortisol awakening response. Results do not suggest depressogenic effects of varenicline on the HPA axis. Although this does not preclude other biological depressogenic effects of varenicline, it seems that concerns about effects of varenicline on the HPA axis should not limit its potential to treat nicotine and related addictions.
    Psychopharmacology 07/2013; 231(1). DOI:10.1007/s00213-013-3213-7 · 3.99 Impact Factor
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    • "It is a partial agonist at α4β2 nAChRs, and a partial to full agonist at β4 containing receptors and α7 receptors (Harpsoe et al., 2013; Rollema et al., 2010; Stokes and Papke, 2012; Tutka and Zatonski, 2006; Tzankova and Danchev, 2007). Cytisine use is associated with some of the same side effects as varenicline, but with notably decreased incidence of psychiatric symptoms (Moore et al., 2011; Tonstad et al., 2010; Tutka and Zatonski, 2006), possibly due to differential activation of the α3β4 nAChR receptor subunit (Stokes and Papke, 2012). "
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    ABSTRACT: Increased appetite and weight gain after cessation is a deterrent for quitting smoking. Pharmacotherapies that can reduce this weight gain in ex-smokers would be invaluable, and yet are not well studied in this context. To examine the effects of extended daily exposure to intravenous cytisine, an alpha4beta2 nAChR partial agonist used for smoking cessation in some European countries, on body weight and patterns of food intake in rats. In the first experiment, programmed infusions of cytisine were administered over 15 h per day. Food intake, meal patterns, and weight change were examined relative to a vehicle-infused group during treatment, and in a post-cytisine phase. The second experiment examined the effects of cytisine on food intake, meal patterns, and weight change when substituted for nicotine in a self-administration protocol. Rats self-administered nicotine and cytisine during alternating four day periods, and changes in body weight, drug infusions, and meal patterns were compared between drugs and during an extinction phase. In the first experiment, cytisine-treated rats ate less and gained less weight than those that received the vehicle. This occurred primarily by a reduced frequency of meals. In the 12 day post-cytisine phase, animals maintained a lower body weight relative to controls throughout. In the second experiment, total pellet intake increased during cytisine substitution relative to nicotine and animals self-administered cytisine significantly less than nicotine. However, cytisine substitution maintained decreases in food intake and weight gain compared to baseline via decreases in total pellet intake and meal size. Cytisine administration results in decreased weight gain and changes in meal patterns dependent upon mode and pattern of administration and a previous history of nicotine administration.
    Pharmacology Biochemistry and Behavior 07/2013; 110. DOI:10.1016/j.pbb.2013.07.012 · 2.82 Impact Factor
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