Robert M. Anthenelli, MD; Chad Morris, PhD; Tanya S. Ramey, MD, PhD; Sarah J. Dubrava, MS; Kostas Tsilkos, MD; Cristina Russ, MD; Carla Yunis, MD, MPH
Disclaimer: The views expressed in this article by Dr. Anthenelli are his own and do not necessarily represent those of the Department of Veterans Affairs or the University of California.
Acknowledgment: The authors thank all of the investigators involved in this study.
Financial Support: This study was funded by Pfizer. Dr. Anthenelli's writing of this manuscript was funded, in part, by a Department of Veterans Affairs Merit Review award (NEUA-003-08S) and by a National Institute on Alcohol Abuse and Alcoholism grant (AA019720). Dr. Morris was supported, in part, by grants from the University of California, San Francisco, Smoking Cessation Leadership Center, and Colorado Department of Public Health and Environment. Drs. Ramey, Tsilkos, Russ, and Yunis and Ms. Dubrava are employees of Pfizer. Editorial support was provided by Abegale Templar, PhD, of Engage Scientific and funded by Pfizer.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-0777.
Reproducible Research Statement: Study protocol: Sections available at www.clinicaltrials.gov/ct2/show/NCT01078298. Statistical code and data set: Not available.
Requests for Single Reprints: Robert M. Anthenelli, MD, Mental Health Care Line (116), VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Anthenelli: Office of Mental Health (116), VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161.
Dr. Morris: Behavioral Health and Wellness Program, University of Colorado, Anschutz Medical Campus, Department of Psychiatry, Campus Box F478, 1784 Racine Street, Building 401, Aurora, Colorado 80045.
Dr. Ramey: Pfizer Global Research and Development, Neuroscience Research Unit, 700 Main Street, 3rd Floor, Office 314, Cambridge, MA 02139.
Ms. Dubrava: Pfizer, Primary Care Business Unit, 445 Eastern Point Road, MS 8260-2224, Groton, CT 06340.
Drs. Tsilkos, Russ, and Yunis: Pfizer, Primary Care Business Unit, 235 East 42nd Street, New York, NY 10017.
Author Contributions: Conception and design: R.M. Anthenelli, T.S. Ramey, S.J. Dubrava, K. Tsilkos, C. Russ, C. Yunis.
Analysis and interpretation of the data: R.M. Anthenelli, C. Morris, T.S. Ramey, S.J. Dubrava, K. Tsilkos, C. Russ, C. Yunis.
Drafting of the article: R.M. Anthenelli, C. Morris, T.S. Ramey, K. Tsilkos, C. Russ, C. Yunis.
Critical revision of the article for important intellectual content: R.M. Anthenelli, C. Morris, T.S. Ramey, K. Tsilkos, C. Yunis.
Final approval of the article: R.M. Anthenelli, C. Morris, T.S. Ramey, S.J. Dubrava, K. Tsilkos, C. Russ, C. Yunis.
Provision of study materials or patients: R.M. Anthenelli, C. Morris.
Statistical expertise: S.J. Dubrava.
Administrative, technical, or logistic support: K. Tsilkos, C. Yunis.
Collection and assembly of data: R.M. Anthenelli, T.S. Ramey, S.J. Dubrava, C. Yunis.
Depression is overrepresented in smokers.
To evaluate smoking abstinence and changes in mood and anxiety levels in smokers with depression treated with varenicline versus placebo.
Phase 4, multicenter, parallel, 1:1 allocation, double-blind, randomization trial. Randomization, stratified by antidepressant use and depression score at baseline, was blocked in sizes of 4. (ClinicalTrials.gov: NCT01078298)
38 centers in 8 countries.
525 adult smokers with stably treated current or past major depression and no recent cardiovascular events.
Varenicline, 1 mg twice daily, or placebo for 12 weeks, with 40-week nontreatment follow-up.
Primary outcome was carbon monoxide–confirmed continuous abstinence rate (CAR) for weeks 9 to 12. Other outcomes included CARs assessed during nontreatment follow-up and ratings of mood, anxiety, and suicidal ideation or behavior.
68.4% versus 66.5% of the varenicline and placebo groups, respectively, completed the study. Varenicline-treated participants had higher CARs versus placebo at weeks 9 to 12 (35.9% vs. 15.6%; odds ratio [OR], 3.35 [95% CI, 2.16 to 5.21]; P < 0.001), 9 to 24 (25.0% vs. 12.3%; OR, 2.53 [CI, 1.56 to 4.10]; P < 0.001), and 9 to 52 (20.3% vs. 10.4%; OR, 2.36 [CI, 1.40 to 3.98]; P = 0.001). There were no clinically relevant differences between groups in suicidal ideation or behavior and no overall worsening of depression or anxiety in either group. The most frequent adverse event was nausea (varenicline, 27.0%; placebo, 10.4%). Two varenicline-group participants died during the nontreatment phase.
Some data were missing, and power to detect differences between groups was low in rare events. Smokers with untreated depression, with co-occurring psychiatric conditions, or receiving mood stabilizers and antipsychotics were not included.
Varenicline increased smoking cessation in smokers with stably treated current or past depression without exacerbating depression or anxiety.
Although varenicline increases quit rates in smokers, some question its efficacy and safety in patients with psychiatric disorders.
In this trial, 525 smokers with stably treated current or past major depression and no recent cardiovascular disease were randomly assigned to varenicline, 1 mg twice daily, or placebo for 12 weeks. More participants treated with varenicline than those receiving placebo stopped smoking. Varenicline caused nausea but did not worsen depression or anxiety.
About one third of the participants did not complete the study.
Varenicline can increase smoking cessation rates in some smokers with stable depression without exacerbating depression or anxiety.
Study flow diagram.
* Participants could discontinue treatment but remain in the study. Treatment phase was weeks 1 through 12.
† Discontinuations from study due to reasons classified by the investigators as “no longer willing to participate” were withdrawal of consent for unknown reasons (n = 28), lack of motivation to quit smoking (n = 12), lack of clinical response (n = 9), new job or schedule change (n = 7), moved out of area (n = 3), nonadherence to the study protocol (n = 3), transportation issues (n = 1), and incarceration (n = 1).
‡ Discontinuations from study classified by the investigators as “protocol violations” were nonadherence to study visits (n = 5), bupropion use (n = 3), nonadherence to study medication (n = 2), and illicit drug use (n = 2).
§ Discontinuations from study due to reasons classified by the investigators as “other” were new job or schedule change (n = 24), moved out of area (n = 24), nonadherence to study (n = 3), lack of motivation to quit smoking (n = 2), transportation issues (n = 2), and suspicion of alcohol use (n = 1).
Table 1. Patient Characteristics at Baseline
Continuous abstinence rates defined as percentage of abstinent participants, from week 9 to each clinic visit through week 52.
Data shown are observed data. Vertical bars show 95% CIs. Odds ratios shown are for CARs during weeks 9 to 12 (primary end point), 9 to 24, and 9 to 52 (secondary end points) and were calculated under the assumption that those who discontinued the study and were lost to follow-up were smokers for the rest of the study. CAR = continuous abstinence rates; OR = odds ratio.
MADRS total scores mean change from baseline.
Vertical bars show 95% CIs. MADRS = Montgomery–Åsberg Depression Rating Scale. Top. Mean change from baseline overall. Bottom. Mean change from baseline by responder status; 95% CIs for quitters only.
HAM-A total scores mean change from baseline.
Vertical bars show 95% CIs. HAM-A = Hamilton Rating Scale for Anxiety.
Table 2. Solicited and Volunteered Treatment-Emergent AEs
Table 3. Participants With Positive Responses on the C-SSRS
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Author Insight Video - Robert M. Anthenelli, MD
Anthenelli RM, Morris C, Ramey TS, Dubrava SJ, Tsilkos K, Russ C, et al. Effects of Varenicline on Smoking Cessation in Adults With Stably Treated Current or Past Major Depression: A Randomized Trial. Ann Intern Med. 2013;159:390-400. doi: 10.7326/0003-4819-159-6-201309170-00005
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Published: Ann Intern Med. 2013;159(6):390-400.
Cardiology, Coronary Risk Factors, Smoking, Tobacco, Alcohol, and Other Substance Abuse.
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