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Psychiatric Adverse Events in Randomized, Double-Blind, Placebo-Controlled Clinical Trials of Varenicline

A Pooled Analysis

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Abstract

Background: Varenicline (Chantix®, Champix®) has shown efficacy and tolerability as an aid to smoking cessation. In postmarketing surveillance, neuropsychiatric symptoms have appeared; however, their incidence and causal relationship to varenicline is not known.

Objective: We assessed the incidence and relative risk (RR) of psychiatric disorders in ten randomized, double-blind, placebo-controlled trials of varenicline for smoking cessation.

Methods: All smoking cessation phase II, III and IV randomized controlled clinical trials of varenicline versus placebo completed as of 31 December 2008, on file with the manufacturer (Pfizer, Inc.), were included. All studies have been published. All 3091 participants who received at least one dose of varenicline and all 2005 participants who received placebo were included in this analysis. These were men and women smoking ≥10 cigarettes/day, aged 18–75 years and without current psychiatric disease who received varenicline or placebo for 6 (one study), 12 (eight studies) or 52 (one study) weeks. Adverse events were recorded at each study visit and classified according to standard Medical Dictionary for Regulatory Activities (MedDRA®) terms (version 11.0).

Results: The incidence of psychiatric disorders other than solely sleep disorders and disturbances was 10.7% in subjects treated with varenicline and 9.7% in subjects treated with placebo, with an RR of 1.02 (95% CI 0.86, 1.22). The RRs (95% CI) versus placebo of psychiatric adverse events with an incidence ≥1% in the varenicline group were 0.86 (0.67, 1.12) for anxiety disorders and symptoms, 0.76 (0.42, 1.39) for changes in physical activity, 1.42 (0.96, 2.08) for depressed mood disorders and disturbances, 1.21 (0.79, 1.83) for mood disorders and disturbances not elsewhere classified and 1.70 (1.50, 1.92) for sleep disorders and disturbances. There were no cases of suicidal ideation or behaviour in varenicline-treated subjects in the ten placebo-controlled studies analysed. However, among three trials that were excluded from the analysis because of their open-label design, two cases of suicidal ideation and one completed suicide were reported in patients who had been treated with varenicline. With the exception of sleep disorders and disturbances, there was no evidence of dose-responsivity.

Conclusions: There was no significant increase in overall psychiatric disorders, other than sleep disorders and disturbances, in varenicline-treated subjects in this sample of smokers without current psychiatric disorders. Ongoing studies are testing the use of varenicline in psychiatric patients.

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References

  1. Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 2005 May 19; 48(10): 3474–7

    Article  PubMed  CAS  Google Scholar 

  2. West R, Baker CL, Cappelleri JC, et al. Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt. Psychopharmacology (Berl) 2008 Apr; 197(3): 371–7

    Article  CAS  Google Scholar 

  3. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2008; (3): CD006103

  4. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2007; (1): CD000031

  5. Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2008; (1): CD000146

  6. Gonzales D, Rennard SI, Nides M, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006 Jul 5; 296(1): 47–55 300

    Article  PubMed  CAS  Google Scholar 

  7. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006 Jul 5; 296(1): 56–63

    Article  PubMed  CAS  Google Scholar 

  8. Freedman R. Exacerbation of schizophrenia by varenicline [letter]. Am J Psychiatry 2007 Aug; 164(8): 1269

    Article  PubMed  Google Scholar 

  9. Kohen I, Kremen N. Varenicline-induced manic episode in a patient with bipolar disorder. Am J Psychiatry 2007 Aug; 164(8): 1269–70

    Article  PubMed  Google Scholar 

  10. Popkin MK. Exacerbation of recurrent depression as a result of treatment with varenicline [letter]. Am J Psychiatry 2008 Jun; 165(6): 774

    Article  PubMed  Google Scholar 

  11. Alhatem F, Black JE. Varenicline-induced mania in a bipolar patient. Clin Neuropharmacol 2009 Mar–Apr; 32(2): 117–8

    Article  PubMed  Google Scholar 

  12. Morstad AE, Kutscher EC, Kennedy WK, et al. Hypomania with agitation associated with varenicline use in bipolar II disorder. Ann Pharmacother 2008 Feb; 42(2): 288–9

    Article  PubMed  Google Scholar 

  13. Pirmoradi P, Roshan S, Nadeem SS. Neuropsychiatric disturbance after initiation of varenicline in a patient with a history of alcohol abuse and major depression. Am J Health Syst Pharm 2008 Sep 1; 65(17): 1624–6

    Article  PubMed  CAS  Google Scholar 

  14. Kutscher EC, Stanley M, Oehlke K. Chantix-induced mental status changes in a young healthy female. S D Med 2009 May; 62(5): 193, 195

    PubMed  Google Scholar 

  15. Cahill K, Stead L, Lancaster T. A preliminary benefit-risk assessment of varenicline in smoking cessation. Drug Saf 2009; 32(2): 119–35

    Article  PubMed  CAS  Google Scholar 

  16. US FDA. Early communication about an ongoing safety review of varenicline (marketed as Chantix). US FDA, 2007 Nov [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070765.htm [Accessed 2010 Jan 26]

  17. US FDA. Public health advisory: important information on Chantix (varenicline). US FDA, 2008 May [online]. Available from URL: http://www.fda.gov/drugs/drugsafety/publichealthadvisories/ucm051136 [Accessed 2010 Jan 26]

  18. US FDA. Information for healthcare professionals: varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics) [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm169986.htm [Accessed 2009 Jul 10]

  19. Kasliwal R, Wilton LV, Shakir SA. Safety and drug utilization profile of varenicline as used in general practice in England: interim results from a prescription-event monitoring study. Drug Saf 2009; 32(6): 499–507

    Article  PubMed  CAS  Google Scholar 

  20. Nakamura M, Oshima A, Fujimoto Y, et al. Efficacy and tolerability of varenicline, an alpha4beta2 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 Jun; 29(6): 1040–56

    Article  PubMed  CAS  Google Scholar 

  21. Niaura R, Hays JT, Jorenby DE, 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 May 29; 24(7): 1931–41

    Article  PubMed  CAS  Google Scholar 

  22. Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med 2006 Aug 14–28; 166(15): 1561–8

    Article  PubMed  Google Scholar 

  23. Oncken C, Gonzales D, Nides M, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med 2006 Aug 14–28; 166(15): 1571–7

    Article  PubMed  CAS  Google Scholar 

  24. Tsai ST, Cho HJ, Cheng HS, et al. A randomized, placebo-controlled trial of varenicline, a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist, as a new therapy for smoking cessation in Asian smokers. Clin Ther 2007 Jun; 29(6): 1027–39

    Article  PubMed  CAS  Google Scholar 

  25. Williams KE, Reeves KR, Billing Jr CB, et al. A double-blind study evaluating the long-term safety of varenicline for smoking cessation. Curr Med Res Opin 2007 Apr; 23(4): 793–801

    Article  PubMed  CAS  Google Scholar 

  26. Wang C, Xiao D, Chan KP, et al. Varenicline for smoking cessation: a placebo-controlled, randomized study. Respirology 2009 Apr; 14(3): 384–92

    Article  PubMed  Google Scholar 

  27. Rigotti N, Pipe A, Benowitz NL, et al. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation 2010 Jan; 19(121): 221–9

    Article  Google Scholar 

  28. Tonstad S, Tonnesen P, Hajek P, et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA 2006 Jul 5; 296(1): 64–71

    Article  PubMed  CAS  Google Scholar 

  29. Aubin HJ, Bobak A, Britton JR, et al. Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax 2008 Aug; 63(8): 717–24

    Article  PubMed  Google Scholar 

  30. Pfizer Inc. A3051048: a double-blind, placebo-controlled, multicenter study evaluating the safety of repeated use of varenicline in smokers who failed to remain abstinent in study A3051046 [online]. Available from URL: http://pdf.clinicalstudyresults.org/documents/company-study_2500_0.pdf [Accessed 2009 Jul 10]

  31. Clinical study results for protocol no. A3051046 and A3051048 [online]. Available from URL: http://www.clinicalstudyresults.org/drugdetails/?inn_name_id=494&sort=c.company_name&page=1&drug_id=2500 [Accessed 2009 Apr 7]

  32. MedDRA, Maintenance and Support Services Organization [online]. Available from URL: http://www.meddramsso.com/MSSOWeb/index.htm [Accessed 2008 Aug 21]

  33. Pfizer Inc. US prescribing information: CHANTIX (varenicline) tablets [online]. Available from URL: http://www.pfizer.com/files/products/uspi_chantix.pdf [Accessed 2009 Jul 10]

  34. Agresti A, Hartzel J. Strategies for comparing treatments on a binary response with multi-centre data. Stat Med 2000 Apr 30; 19(8): 1115–39

    Article  PubMed  CAS  Google Scholar 

  35. Heatherton TF, Kozlowski LT, Frecker RC, et al. The Fagerström test for nicotine dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict 1991 Sep; 86(9): 1119–27

    Article  PubMed  CAS  Google Scholar 

  36. Faessel HM, Gibbs MA, Clark DJ, et al. Multiple-dose pharmacokinetics of the selective nicotinic receptor partial agonist, varenicline, in healthy smokers. J Clin Pharmacol 2006 Dec; 46(12): 1439–48

    Article  PubMed  CAS  Google Scholar 

  37. Rollema H, Chambers LK, Coe JW, et al. Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor 301 partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology 2007 Mar; 52(3): 985–94

    Article  PubMed  CAS  Google Scholar 

  38. Charney D, Nestler E, editors. Neurobiology of mental illness. 2nd ed. New York: Oxford University Press, 2005

    Google Scholar 

  39. Parrott AC. Cigarette-derived nicotine is not a medicine. World J Biol Psychiatry 2003 Apr; 4(2): 49–55

    Article  PubMed  Google Scholar 

  40. Markou A, Kenny PJ. Neuroadaptations to chronic exposure to drugs of abuse: relevance to depressive symptomatology seen across psychiatric diagnostic categories. Neurotox Res 2002 Jun; 4(4): 297–313

    Article  PubMed  Google Scholar 

  41. Olausson P, Engel JA, Soderpalm B. Involvement of serotonin in nicotine dependence: processes relevant to positive and negative regulation of drug intake. Pharmacol Biochem Behav 2002 Apr; 71(4): 757–71

    Article  PubMed  CAS  Google Scholar 

  42. Kamali M, Oquendo MA, Mann JJ. Understanding the neurobiology of suicidal behavior. Depress Anxiety 2001; 14(3): 164–76

    Article  PubMed  CAS  Google Scholar 

  43. George TP, Sacco KA, Vessicchio JC, et al. Nicotinic antagonist augmentation of selective serotonin reuptake inhibitor-refractory major depressive disorder: a preliminary study. J Clin Psychopharmacol 2008 Jun; 28(3): 340–4

    Article  PubMed  Google Scholar 

  44. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed., text revision. Washington, DC: American Psychiatric Association, 2000

    Google Scholar 

  45. Hughes JR. Depression during tobacco abstinence. Nicotine Tob Res 2007 Apr; 9(4): 443–6

    Article  PubMed  Google Scholar 

  46. Evins AE, Goff DC. Varenicline treatment for smokers with schizophrenia: a case series [letter]. J Clin Psychiatry 2008 Jun; 69(6): 1016

    Article  PubMed  Google Scholar 

  47. McClure JB, Swan GE, Jack L, et al. Mood, side-effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline. J Gen Intern Med 2009 May; 24(5): 563–9

    Article  PubMed  Google Scholar 

  48. Stapleton JA, Watson L, Spirling LI, et al. Varenicline in the routine treatment of tobacco dependence: a pre-post comparison with nicotine replacement therapy and an evaluation in those with mental illness. Addiction 2008 Jan; 103(1): 146–54

    Article  PubMed  Google Scholar 

  49. Gunnell D, Irvine D, Wise L, et al. Varenicline and suicidal behaviour: a cohort study based on data from the General Practice Research Database. BMJ 2009; 339: 1072

    Google Scholar 

  50. FDA drug safety newsletter. Vol. 2, No. 1. 2009 Oct 8 [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm110235.htm [Accessed 2010 Feb 10]

  51. Ziedonis D, Hitsman B, Beckham JC, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res 2008 Dec; 10(12): 1691–715

    Article  PubMed  Google Scholar 

  52. Anthonisen NR, Skeans MA, Wise RA, et al. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med 2005 Feb 15; 142(4): 233–9

    PubMed  Google Scholar 

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Acknowledgements

Serena Tonstad is currently employed at the School of Public Health, Loma Linda University, Loma Linda, CA, USA.

The studies included in this analysis were funded by Pfizer, Inc. All authors, including those employed by Pfizer, Inc. (Simon Davies, Martina Flammer and Cristina Russ), were involved in the design and conduct of this study, the collection, management, analysis and interpretation of data, the preparation and review of the report, and the decision to submit the study for publication. Serena Tonstad has received honoraria from Pfizer for lectures, and consulting fees and honoraria for lectures and/or consulting from Abbott, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, MSD, Novartis, Novo Nordisk, Roche, sanofi-aventis and Schering-Plough. John Hughes is an employee of The University of Vermont and Fletcher Allen Health Care. He has received research grants from the National Institute of Health, Pfizer and sanofi-aventis, and consulting fees from multiple other for-profit and non-profit organizations that develop, sell or promote smoking cessation services, products or medications, including Pfizer.

Editorial support for this manuscript was funded by Pfizer and provided by Giles Brooke, PhD, Joanne Cowan, PhD, Christopher Grantham, PhD, Brenda Smith, PhD, and Abegale Templar, PhD, of UBC Scientific Solutions, none of whom were involved in the interpretation of data.

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Tonstad, S., Davies, S., Flammer, M. et al. Psychiatric Adverse Events in Randomized, Double-Blind, Placebo-Controlled Clinical Trials of Varenicline. Drug-Safety 33, 289–301 (2010). https://doi.org/10.2165/11319180-000000000-00000

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