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A Double-Blind Randomized Placebo-Controlled Pilot Study of Neuropsychiatric Adverse Events in Abstinent Smokers Treated with Varenicline or Placebo

Published:February 08, 2011DOI:https://doi.org/10.1016/j.biopsych.2010.12.005

      Background

      Varenicline is an α4β2 partial nicotinic agonist approved for smoking cessation. There have been spontaneous postmarketing reports of neuropsychiatric adverse events (NPAEs) in smokers without a history of psychiatric illness quitting with varenicline.

      Methods

      One hundred ten smokers without history of psychiatric illness (screened by Structured Clinical Interview for DSM-IV) were randomized to 12 weeks of varenicline 1 mg twice daily (n = 55) or placebo. Adverse events were solicited systematically. Depressive symptoms, anxiety, aggression, and irritability were measured at baseline and weekly using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Hamilton Anxiety Scale (HAM-A), and the Overt Aggression Scale—Modified (OAS-M). The Profile of Mood States (POMS) was administered daily. Mixed-model analysis of repeated measures was conducted to compare mean changes in scores between groups across study periods.

      Results

      Participants' mean baseline characteristics were 33 years of age, 22 cigarettes/day and Fagerström Test for Nicotine Dependence score > 7. Reported NPAEs were similar between groups. No suicidal events were reported. There were no significant differences between groups for the MADRS (treatment difference vs. placebo = .03, 95% confidence interval [CI] −.68–.73; NS), HAM-A (treatment difference [TD] = .14, 95% CI −.62–.90; NS), OAS-M Aggression subscale (TD = .5, 95% CI −1.18–2.18; NS), OAS-M Irritability subscale (TD = .08, 95% CI −.17–.34; NS), and the POMS total scores (TD = .5, 95% CI −.52–1.53; NS).

      Conclusions

      There were no significant differences between groups on measures of depressive symptoms, anxiety, or aggression/hostility. Systematically solicited NPAEs were similar between the varenicline and placebo groups.

      Key Words

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      References

        • Gonzales D.
        • Rennard S.I.
        • Nides M.
        • Oncken C.
        • Azoulay S.
        • Billing C.B.
        • et al.
        varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial.
        JAMA. 2006; 296: 47-55
        • Jorenby D.E.
        • Hays J.T.
        • Rigotti N.A.
        • Azoulay S.
        • Watsky E.J.
        • Williams K.E.
        • et al.
        Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial.
        JAMA. 2006; 296: 56-63
        • Nides M.
        • Oncken C.
        • Gonzales D.
        • Rennard S.
        • Watsky E.J.
        • Anziano R.
        • Reeves K.R.
        Smoking cessation with varenicline, a selective α4β2 nicotinic receptor partial agonist: Results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up.
        Arch Intern Med. 2006; 166: 1561-1568
        • Oncken C.
        • Gonzales D.
        • Nides M.
        • Rennard S.
        • Watsky E.
        • Billing C.B.
        • et al.
        Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation.
        Arch Intern Med. 2006; 166: 1571-1577
        • Nakamura M.
        • Oshima A.
        • Fujimoto Y.
        • Maruyama N.
        • Ishibashi T.
        • Reeves K.R.
        Efficacy and tolerability of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, in a 12-week, randomized, placebo-controlled, dose–response study with 40-week follow-up for smoking cessation in Japanese smokers.
        Clin Ther. 2007; 29: 1040-1056
        • Niaura R.
        • Hays J.T.
        • Jorenby D.E.
        • Leone F.T.
        • Pappas J.E.
        • Reeves K.R.
        • et al.
        The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers: A randomized controlled trial.
        Curr Med Res Opin. 2008; 24: 1931-1941
        • Tonstad S.
        • Tønnesen P.
        • Hajek P.
        • Williams K.E.
        • Billing C.B.
        • Reeves K.R.
        • Varenicline Phase 3 Study Group
        Effect of maintenance therapy with varenicline on smoking cessation: A randomized controlled trial.
        JAMA. 2006; 296: 64-71
        • Tsai S.T.
        • Cho H.J.
        • Cheng H.S.
        • Kim C.H.
        • Hsueh K.C.
        • Billing Jr, C.B.
        • Williams K.E.
        A randomized, placebo-controlled trial of varenicline, a selective α4β2 nicotinic acetylcholine receptor partial agonist, as a new therapy for smoking cessation in Asian smokers.
        Clin Ther. 2007; 29: 1027-1039
        • Wang C.
        • Xiao D.
        • Chan K.P.
        • Pothirat C.
        • Garza D.
        • Davies S.
        Varenicline for smoking cessation: A placebo-controlled, randomized study.
        Respirology. 2009; 14: 384-392
        • Pfizer Inc
        Chantix (varenicline) Tablets [U.S. Precribing Information].
        (Accessed March 8, 2010)
        • Tonstad S.
        Psychiatric adverse events in randomized, double-blind, placebo-controlled clinical trials of varenicline: A pooled analysis.
        Drug Saf. 2010; 33: 289-301
        • Gunnell D.
        • Irvine D.
        • Wise L.
        • Davies C.
        • Martin R.M.
        Varenicline and suicidal behaviour: A cohort study based on data from the General Practice Research Database.
        BMJ. 2009; 339: b3805
        • Hatsukami D.K.
        • Hughes J.R.
        • Pickens R.W.
        • Svikis D.
        Tobacco withdrawal symptoms: An experimental analysis.
        Psychopharmacology (Berl). 1984; 84: 231-236
        • Hughes J.R.
        Measurement of the effects of abstinence from tobacco: A qualitative review.
        Psychol Addict Behav. 2007; 21: 127-137
        • Hughes J.R.
        Effects of abstinence from tobacco: Valid symptoms and time course.
        Nicotine Tob Res. 2007; 9: 315-327
        • Hughes J.R.
        Effects of abstinence from tobacco: Etiology, animal models, epidemiology, and significance: A subjective review.
        Nicotine Tob Res. 2007; 9: 329-339
        • Hughes J.R.
        • Hatsukami D.
        Signs and symptoms of tobacco withdrawal.
        Arch Gen Psychiatry. 1986; 43: 289-294
        • Hemenway D.
        • Solnick S.J.
        • Colditz G.A.
        Smoking and suicide among nurses.
        Am J Public Health. 1993; 83: 249-251
        • Hughes J.R.
        Smoking and suicide: A brief overview.
        Drug Alcohol Depend. 2008; 98: 169-178
        • Miller M.
        • Hemenway D.
        • Bell N.S.
        • Yore M.M.
        • Amoroso P.J.
        Cigarette smoking and suicide: A prospective study of 300,000 male active-duty Army soldiers.
        Am J Epidemiol. 2000; 151: 1060-1063
        • Miller M.
        • Hemenway D.
        • Rimm E.
        Cigarettes and suicide: A prospective study of 50,000 men.
        Am J Public Health. 2000; 90: 768-773
        • World Medical Association
        World Medical Association Declaration of Helsinki—Ethical principles for medical research involving human subjects 2008.
        (Accessed December 23, 2009)
        • International Conference on Harmonisation
        The ICH process for harmonisation of guidelines.
        (Accessed December 23, 2009)
        • Heatherton T.F.
        • Kozlowski L.T.
        • Frecker R.C.
        • Fagerström K.O.
        The Fagerström Test for Nicotine Dependence: A revision of the Fagerström Tolerance Questionnaire.
        Br J Addict. 1991; 86: 1119-1127
        • First M.B.
        • Gibbon M.
        • Spitzer R.L.
        • Williams J.B.W.
        • Benjamin L.S.
        User's Guide for the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II).
        American Psychiatric Publishing, Washington, DC1997
        • First M.B.
        • Spitzer R.L.
        • Gibbon M.
        • Williams J.B.W.
        User's Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders: SCID-1 Clinician Version.
        American Psychiatric Publishing, Washington, DC1997
        • Posner K.
        • Oquendo M.A.
        • Gould M.
        • Stanley B.
        • Davies M.
        Columbia Classification Algorithm of Suicide Assessment (C-CASA): Classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants.
        Am J Psychiatry. 2007; 164: 1035-1043
        • Osman A.
        • Bagge C.L.
        • Gutierrez P.M.
        • Konick L.C.
        • Kopper B.A.
        • Barrios F.X.
        The Suicidal Behaviors Questionnaire—Revised (SBQ-R): Validation with clinical and nonclinical samples.
        Assessment. 2001; 8: 443-454
        • Montgomery S.A.
        • Asberg M.
        A new depression scale designed to be sensitive to change.
        Br J Psychiatry. 1979; 134: 382-389
        • Hamilton M.
        The assessment of anxiety states by rating.
        Br J Med Psychol. 1959; 32: 50-55
        • Faessel H.M.
        • Gibbs M.A.
        • Clark D.J.
        • Rohrbacher K.
        • Stolar M.
        • Burstein A.H.
        Multiple-dose pharmacokinetics of the selective nicotinic receptor partial agonist, varenicline, in healthy smokers.
        J Clin Pharmacol. 2006; 46: 1439-1448
        • Levine J.
        • Schooler N.R.
        SAFTEE: A technique for the systematic assessment of side effects in clinical trials.
        Psychopharmacol Bull. 1986; 22: 343-381
        • Price B.B.
        • Moran S.
        • Crunican M.A.
        • Rothenberg S.
        • Cutter H.S.
        Mood, primary heroin withdrawal, and acute methadone administration.
        Int J Addict. 1975; 10: 613-631
        • Dyer K.R.
        • White J.M.
        • Foster D.J.
        • Bochner F.
        • Menelaou A.
        • Somogyi A.A.
        The relationship between mood state and plasma methadone concentration in maintenance patients.
        J Clin Psychopharmacol. 2001; 21: 78-84
        • Coccaro E.F.
        • Harvey P.D.
        • Kupsaw-Lawrence E.
        • Herbert J.L.
        • Bernstein D.P.
        Development of neuropharmacologically based behavioral assessments of impulsive aggressive behavior.
        J Neuropsychiatry Clin Neurosci. 1991; 3: S44-S51
        • McNair D.M.
        • Lorr M.
        • Droppleman L.
        EITS Manual for the Profile of Mood States.
        Educational and Industrial Testing Service, San Diego, CA1992
        • Cappelleri J.C.
        • Bushmakin A.G.
        • Baker C.L.
        • Merikle E.
        • Olufade A.O.
        • Gilbert D.G.
        Revealing the multidimensional framework of the Minnesota Nicotine Withdrawal Scale.
        Curr Med Res Opin. 2005; 21: 749-760
        • Nyenhuis D.L.
        • Yamamoto C.
        • Luchetta T.
        • Terrien A.
        • Parmentier A.
        Adult and geriatric normative data and validation of the profile of mood states.
        J Clin Psychol. 1999; 55: 79-86

      Linked Article

      • Varenicline and the Evaluation of Neuropsychiatric Adverse Events in Smokers
        Biological PsychiatryVol. 69Issue 11
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          Varenicline, a selective partial agonist of α4β2 subunits of nicotinic acetylcholine receptors, has been shown to be efficacious relative to placebo as summarized in a meta-analysis of clinical trials of smokers without significant psychiatric comorbidities (1). In these studies, neuropsychiatric adverse events (NPAEs) on varenicline were infrequent and comparable to placebo. In the postmarketing period, however, various NPAEs have been reported to occur in individuals taking varenicline.
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