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Varenicline and Depression:
a Literature Review
Dr Eugene YH Yeung; Dr Beverly L Bachi; Dr Shann Long;
Dr Jessica SH Lee; Mr Yueyang Chao
August 2015
Doctors Academy Publications
Varenicline is the most effective smoking cessation monotherapy medication. Pre-marketing trials excluded participants with psychiatric disorders. This literature review investigated the effects of varenicline among patients with depression

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WJMER, Volume 9, Issue 1, 2015
Doctors Academy

Clinical Review
World Journal of Medical Education and Research:
DAUIN 20150075
An Official Publication of the Education and Research Division of Doctors Academy
Varenicline and Depression: a Literature
Review

Dr Eugene YH Yeung; Dr Beverly L Bachi; Dr Shann Long; Dr Jessica SH Lee;
Mr Yueyang Chao
Institution
Abstract
College of Medical and Dental Introduction: Varenicline is the most effective smoking cessation monotherapy medication. Sciences, University of Pre-marketing trials excluded participants with psychiatric disorders. This literature review Birmingham, B15 2TT investigated the effects of varenicline among patients with depression. Method: On 30th December 2013, a literature search was performed using PubMed with the following search terms: 1) varenicline and 2) depression. From the 75 retrieved documents, 13 WJMER, Vol 9: Issue 1,
articles are used in this review. Results: Seven case reports show exacerbation of 2015
psychiatric symptoms in patients with depression taking varenicline. One case report shows that varenicline improves the affective symptoms of a smoker who developed depression and suicidal tendencies during previous cessation attempts. Two observational studies (n = 217 and 9) show worsening of psychiatric symptoms in patients with depression taking varenicline, and one study (n = 110) shows improvement. There are two clinical trials on patients with depression taking varenicline. One trial (n = 1117) shows worsening of psychiatric symptoms, whereas the other one (n = 525) shows improvement of smoking abstinence and no worsening of psychiatric symptoms. Discussion: The findings suggest that varenicline could worsen psychiatric symptoms in patients with depression. Clinicians should err on the side of caution and closely monitor patients with a history of depression taking varenicline.
Key Words
Varenicline, Depression, Psychiatry, Smoking Cessation, Adverse Effect

Corresponding Author:
Mr Eugene YHY, E-mail: [email protected]
warning regarding these adverse events.9 Doctors It is believed that depression is a predictor of are advised to closely monitor patients with a smoking initiation.1 Smoking prevalence among history of psychiatric il ness on varenicline for any patients with depression is about 1.5 times higher changes in mood or behaviour such as suicidal than that of people without depression.2 Only 37% thoughts or acts. of the depressed smokers are able to abstain from smoking for one week, compared to 56% of the non Varenicline acts as a partial agonist at the a4b2 -depressed smokers.3 It has been suggested that nicotinic acetylcholine receptor that binds more patients trying to stop smoking who have histories tightly to the receptor than nicotine itself.10 This of severe depression should be serially monitored mechanism prevents nicotine stimulation in the and given prophylactic antidepressant therapy.4 mesolimbic dopamine system, which is associated with nicotine addiction.8 At the same time, Varenicline is currently the most effective smoking varenicline, to a lesser degree, stimulates dopamine cessation monotherapy medication on the market5, activity, and thus decreases craving and withdrawal with a 12-week abstinence rate of 43.9% (versus symptoms of nicotine. Similarly, bupropion is a 29.8% and 17.6% in the bupropion and placebo dopaminergic and noradrenergic agent which has groups, respectively) and a six-month abstinence official indications for both the treatment of rate of 29.7% (versus 20.2% and 13.2% in the depression and smoking cessation.8 Nevertheless, bupropion and placebo groups, respectively).6,7 the FDA Adverse Event Reporting System (AERS) However, in the pre-marketing clinical trials of database from 1998 through September 2010 varenicline, patients with psychiatric disorders (such reported a total of 2925 cases of suicidal/self- as schizophrenia, bipolar disorder and major injurious behaviour or depression due to depressive disorders) were excluded.8 Numerous varenicline.11 The number of cases was significantly post-marketing reports of serious psychiatric larger than the number among bupropion and symptoms led to the manufacturer adding a boxed nicotine replacement users (229 and 95, WJMER, Volume 9, Issue 1, 2015
Doctors Academy
World Journal of Medical Education and Research:
Clinical Review
An Official Publication of the Education and Research Division of Doctors Academy
DAUIN 20150075
respectively).11 The depressive symptoms are English (n = 2), and articles that do not discuss the hypothesized to be due to varenicline activating the effects of varenicline on patients with history of nicotine acetylcholine receptors and their subtypes, depression or depressive symptoms (n = 43). From such as ganglionic (α3β4) receptors.12 the retrieved documents, 13 articles are used in this literature review (Figure 1).
If varenicline exacerbates underlying depressive symptoms, patients with depression may be prone to experience them. The efficacy of varenicline may The first case report on the effects of varenicline on be reduced among these patients, because they may patients with depression was published in June 2008. stop the therapy early due to side effects. There is A man experienced an acute exacerbation of not yet a literature review that discusses the depressive symptoms, which resolved after he association of psychiatric symptoms with the use of stopped his varenicline treatment.13 Since then, varenicline among patients with depression. The there have been six other case reports that current review aims to investigate the efficacy and described exacerbation of psychiatric symptoms in side effects of varenicline among patients with patients with depression taking varenicline.14-19 One case reports suggests the use of bupropion to treat exacerbation of depressive symptoms associated with varenicline.18 In contrast, varenicline has been On 31st December 2013, a literature search was shown to improve the affective symptoms of a performed using PubMed with the fol owing search smoker who developed depression and suicidal terms: 1) varenicline and 2) depression. A total of tendencies during previous cessation attempts.20 Table 1 lists these case reports and case series.
PubMed Search: 30 December 2013 There are three observational studies on patients with depression taking varenicline: 1) an open- labeled study on 110 outpatient smokers with persistent depressive symptoms shows significant improvement in Quick Inventory of Depressive Symptomatology starting from week 2;21 2) A 6-18 P: human subjects with history of depression month questionnaire on 217 varenicline users shows that depressive symptoms at the time of C: placebo or any comparators varenicline initiation (measured by Patient Health O: clinical characteristics, efficacy, adverse effects Questionnaire-2, a screening tool for depression) are associated with suicidal ideation;22 and 3) A 12- week open-labeled study on nine bipolar patients Search results: 75 articles with subsyndromal depression shows that varenicline reduces cigarette use but increases hypomanic symptoms.23 Table 2 lists these
Excluded in the systematic review: 62 articles observational studies. Editorials (n = 1) There are two clinical trials in subjects taking Patient information package (n = 1) varenicline. The first trial shows that varenicline can Pre-clinical studies (n = 7) exacerbate psychiatric symptoms in patients with probable history of major depression,24 whereas a Articles not in English (n = 2) more recent trial shows that varenicline-treated Irrelevant articles (n = 43) participants with depression have higher smoking abstinence rate versus placebo.25 Table 3 lists these
clinical trials. Included in the systematic review: 13 articles Figure 1: The PICO (Participants, Intervention, Comparator,
Discussion
Outcome) statement and study selection flow chart Despite some inconsistencies, the current literature for the literature review review provides insights that can guide clinical 75 documents were retrieved. Two researchers practice. Clinicians should closely monitor reviewed the titles and abstracts of all documents. varenicline users with a history of depression for The documents are included in the current review if any changes in mood or behaviour. Psychiatric side they meet the PICO criteria (Figure 1).
effects that have been reported include anxiety, Documents are excluded if they were editorials (n = paranoia, irritability, restlessness, hallucinations, 1), patient information package (n = 1), pre-clinical hypomania, depressive symptoms, suicidal thoughts studies (n = 7), reviews (n = 8), articles not in or acts. Although a case report suggests the use of WJMER, Volume 9, Issue 1, 2015
Doctors Academy
Clinical Review
World Journal of Medical Education and Research:
DAUIN 20150075
An Official Publication of the Education and Research Division of Doctors Academy
Year Age Gender Varenicline Dose
Short Description of the Case
Country Reference
A patient, with a history of recurrent Day 1-3: 0.5 mg twice major depressive disorder, experienced daily, day 4-7: 0.5 mg an acute exacerbation of depressive twice daily, from day 8: symptoms, which resolved after he 1 mg twice daily stopped his varenicline treatment. Unknown (starting A patient with a history of depression three months prior experienced mood and psychotic to admission and disturbance, which resolved after continuing until the discontinuing varenicline. day of admission) A patient with a history of major Day 1-3: 0.5 mg twice depression and alcohol abuse daily, day 4-7: 0.5 mg experienced severe anxiety, which resolved after discontinuing varenicline. According to the A patient with a history of major depressive disorder, took varenicline 2008 35 Female instructions, to a final twice, and became paranoid each time dose of 1 mg twice after initiation of varenicline. A patient with a history of post- traumatic stress disorder, depression, and alcohol dependence, experienced United visual hallucination after initiation of A patient with a history of depressive symptoms experienced irritability and restlessness when he was on varenicline, and then experienced maniac episodes after discontinuation A patient with a history of depression Unknown in the 1st and anxiety felt more depressed and episode (for two had suicidal thoughts both times after 2010 49 Female weeks); 1 mg twice a she was started on varenicline. The day in the 2nd episode addition of bupropion to varenicline (for three weeks) alleviated her depression and suicidal Table 1A: Case reports that showed varenicline was associated with exacerbation of psychiatric symptoms.
Year Age Gender Varenicline Dose
Short Description of the Case
Country Reference
Varenicline improved the affective Days 1–3: 0.5 mg/day, symptoms and abstinence of a smoker days 4–7: 2 x 0.5 mg/ who developed depression and suicidal tendencies during previous cessation Table 1B: Case reports that suggested varenicline was associated with improvement of psychiatric symptoms.
WJMER, Volume 9, Issue 1, 2015
Doctors Academy
World Journal of Medical Education and Research:
Clinical Review
An Official Publication of the Education and Research Division of Doctors Academy
DAUIN 20150075
Year Subjects
varenicline (0.5 mg daily for three days, 0.5 mg twice daily for Depressive symptoms at the three days, then 1 mg time of varenicline initiation (measured by Patient Health United 2012 varenicline complete 12 weeks). Questionnaire-2) were An opportunity to associated with suicidal take varenicline for an additional 12 weeks if successful during the initial 12-week period. Significant reduction from baseline to end point in the number of cigarettes smoked per day (-2.4), urge to smoke (-45.9), and CO levels (-2.5 ppm). Varenicline dosed per No significant change in open-labeled guidelines in addition depressive symptoms as to self-help booklets Montgomery-Åsberg behavioral counseling Depression Rating Scale. A statistically significant but clinically insignificant increase in hypomanic symptoms was observed. Table 2A: Observational studies that showed varenicline was associated with exacerbation of psychiatric symptoms.
Year Subjects
Varenicline (started at 0.5 mg daily and titrated to 1 mg twice Significant improvement in smokers An eight-week, Quick Inventory of daily) in addition to Depressive Symptomatology States stable doses of the starting in week two patients‘ regular Table 2B: Observational studies that showed varenicline was associated with improvement of psychiatric symptoms.
WJMER, Volume 9, Issue 1, 2015
Doctors Academy
Clinical Review
World Journal of Medical Education and Research:
DAUIN 20150075
An Official Publication of the Education and Research Division of Doctors Academy
Year Subjects
Comparator
Reference
Varenicline side effects and Subjects with probable history of major outcomes were compared between participants with depression were more 2009 varenicline likely to report agitation, States and without probable history of major anger, confusion, depression, and anxiety. Varenicline-treated participants had higher smoking abstinence rate with stably A phase 4, versus placebo at weeks current or parallel, 1:1 Varenicline, 1 mg twice study showed no clinical United 2013 past major allocation, daily, or placebo for 12 significant difference weeks, with 40-week non- depression double-blind, between groups in and no randomizatio treatment fol ow-up. suicidal ideation or behavior, and no overall worsening of depression or anxiety in either Table 3: Clinical trials that showed varenicline was associated with exacerbation of psychiatric symptoms.
bupropion to treat exacerbation of depressive and observational studies show incidence of symptoms associated with varenicline, clinicians psychiatric outcomes associated with varenicline, should be cautious about this information because it they are prone to responder bias. One of the is not based on clinical trials. Health Canada observational studies used the Patient Health recommends that patients should stop treatment Questionnaire-2, which is a screening rather than with varenicline and contact their healthcare diagnostic tool for depression. In addition, the provider immediately if they have, or if their families literature search was limited to English articles and or caregivers observe, psychiatric symptoms or PubMed search accessible in two university behaviours that are not typical for the patient.9 subscriptions, and thus might have omitted some important articles. Although the intention of this review is to investigate both the efficacy and side effects of Conclusion
varenicline among patients with depression, there is Despite some inconsistencies, the findings suggest only one clinical trial that investigates the efficacy of that varenicline could worsen psychiatric symptoms varenicline. The case reports, case series, and in patients with depression. Clinicians should be observational studies in the current study are prone advised to closely monitor patients with a history of to having bias and confounding factors. For example, depression on varenicline, although there are no patients and clinicians may be aware of the clinical trials on how to treat those patients. There association between varenicline and depressive is one clinical trial that demonstrates the efficacy of symptoms from the media that lead to responder varenicline in patients with depression, but clinicians bias. The social histories and other mental il ness of should err on the side of caution and carefully weigh the subjects may be confounding factors that the potential benefits and harms on an individual contribute to their depressive symptoms. Based on the double-blinded, placebo-control ed trial in the current review, at least we know varenicline could References
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World Journal of Medical Education and Research:
Clinical Review
An Official Publication of the Education and Research Division of Doctors Academy
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2008;193(4):322-326. 15. Pirmoradi P, Roshan S, Nadeem SS. 3. Kinnunen T, Doherty K, Militello FS, Garvey AJ. Neuropsychiatric disturbance after initiation of Depression and smoking cessation: varenicline in a patient with a history of alcohol characteristics of depressed smokers and abuse and major depression. Am J Health Syst effects of nicotine replacement. J Consult Clin Pharm 2008;65(17):1624-1626. Psychol 1996;64(4):791-798. 16. Lyon GJ. Possible varenicline-induced paranoia 4. Els C, Kunyk D, Sidhu H. Smoking cessation and and irritability in a patient with major neuropsychiatric adverse events: are family depressive disorder, borderline personality physicians caught between a rock and a hard disorder, and methamphetamine abuse in place? Can Fam Physician 2011;57(6):647-9, remission. J Clin Psychopharmacol 2008;28 5. Fiore M. Treating tobacco use and dependence: 17. Raidoo BM, Kutscher EC. Visual hallucinations 2008 update: Clinical practice guideline. : associated with varenicline: a case report. J Med DIANE Publishing; 2008. Case Rep 2009;3:7560-1947-3-7560. 6. Gonzales D, Rennard SI, Nides M, Oncken C, 18. Karam-Hage M, Shah KR, Cinciripini PM. Azoulay S, Bil ing CB, et al. Varenicline, an Addition of bupropion SR to varenicline alpha4beta2 nicotinic acetylcholine receptor alleviated depression and suicidal ideation: a partial agonist, vs sustained-release bupropion case report. Prim Care Companion J Clin and placebo for smoking cessation: a randomized control ed trial. JAMA 2006;296 PCC.09l00800blu. 19. Hussain S, Kayne E, Guwanardane N, Petrides 7. Jorenby DE, Hays JT, Rigotti NA, Azoulay S, G. Varenicline induced mania in a 51 year old Watsky EJ, Wil iams KE, et al. Efficacy of patient without history of bipolar il ness. Prog varenicline, an alpha4beta2 nicotinic Neuropsychopharmacol Biol Psychiatry 2011;35 acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for 20. Grosshans M, Mutschler J, Hermann D, Mann smoking cessation: a randomized control ed K, Diehl A. Reduced affective symptoms during trial. JAMA 2006;296(1):56-63. tobacco dependence treatment with 8. Compendium of Pharmaceuticals and varenicline. Addiction 2009;104(5):859-861. Specialties. Champix product monograph. 2011 21. Philip NS, Carpenter LL, Tyrka AR, Whiteley LB, Price LH. Varenicline augmentation in 9. Health Canada. Champix (varenicline tartrate) - depressed smokers: an 8-week, open-label Changes to the Canadian Product Monograph - study. J Clin Psychiatry 2009;70(7):1026-1031. For Health Professionals.[online]. 2013 [cited 22. Cowan CM, Wink JS, DeZee KJ. Use of the 2014 Feb 3]. Available from: Patient Health Questionnaire-2 to predict suicidal ideations in patients taking varenicline. Am J Addict 2012;21(4):356-362. 10. Le Fol B, George TP. Treatment of tobacco 23. Frye MA, Ebbert JO, Prince CA, Lineberry TW, dependence: integrating recent progress into Geske JR, Patten CA. A feasibility study of practice. CMAJ 2007;177(11):1373-1380. varenicline for smoking cessation in bipolar 11. Moore TJ, Furberg CD, Glenmullen J, patients with subsyndromal depression. J Clin Maltsberger JT, Singh S. Suicidal behavior and Psychopharmacol 2013;33(6):821-823. depression in smoking cessation treatments. 24. McClure JB, Swan GE, Jack L, Catz SL, PLoS One 2011;6(11):e27016. Zbikowski SM, McAfee TA, et al. Mood, side- 12. Mineur YS, Picciotto MR. Nicotine receptors effects and smoking outcomes among persons and depression: revisiting and revising the with and without probable lifetime depression cholinergic hypothesis. Trends Pharmacol Sci taking varenicline. J Gen Intern Med 2009;24 2010;31(12):580-586. 13. Popkin MK. Exacerbation of recurrent 25. Anthenel i RM, Morris C, Ramey TS, Dubrava depression as a result of treatment with SJ, Tsilkos K, Russ C, et al. Effects of varenicline varenicline. Am J Psychiatry 2008;165(6):774. on smoking cessation in adults with stably 14. Pumariega AJ, Nelson R, Rotenberg L. treated current or past major depression: a Varenicline-induced mixed mood and psychotic randomized trial. Ann Intern Med 2013;159 episode in a patient with a past history of depression. CNS Spectr 2008;13(6):511-514. WJMER, Volume 9, Issue 1, 2015
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