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Smoking cessation treatment and risk of depression, suicide, and self harm in the Clinical Practice Research Datalink: prospective cohort study

BMJ 2013; 347 doi: (Published 11 October 2013) Cite this as: BMJ 2013;347:f5704
  1. Kyla H Thomas, National Institute for Health Research doctoral fellow1,
  2. Richard M Martin, professor of clinical epidemiology12,
  3. Neil M Davies, postdoctoral research associate2,
  4. Chris Metcalfe, reader in medical statistics1,
  5. Frank Windmeijer, professor of econometrics3,
  6. David Gunnell, professor of epidemiology1
  1. 1School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK
  2. 2MRC Integrative Epidemiology Unit (IEU), University of Bristol, UK
  3. 3Department of Economics, Centre for Market and Public Organisation (CMPO), University of Bristol, UK
  1. Correspondence to: K H Thomas kyla.thomas{at}
  • Accepted 28 August 2013


Objective To compare the risk of suicide, self harm, and depression in patients prescribed varenicline or bupropion with those prescribed nicotine replacement therapy.

Design Prospective cohort study within the Clinical Practice Research Datalink.

Setting 349 general practices in England.

Participants 119 546 men and women aged 18 years and over who used a smoking cessation product between 1 September 2006 and 31 October 2011. There were 81 545 users of nicotine replacement products (68.2% of all users of smoking cessation medicines), 6741 bupropion (5.6%), and 31 260 varenicline (26.2%) users.

Main outcome measures Outcomes were treated depression and fatal and non-fatal self harm within three months of the first smoking cessation prescription, determined from linkage with mortality data from the Office for National Statistics (for suicide) and Hospital Episode Statistics data (for hospital admissions relating to non-fatal self harm). Hazard ratios or risk differences were estimated using Cox multivariable regression models, propensity score matching, and instrumental variable analysis using physicians’ prescribing preferences as an instrument. Sensitivity analyses were performed for outcomes at six and nine months.

Results We detected 92 cases of fatal and non-fatal self harm (326.5 events per 100 000 person years) and 1094 primary care records of treated depression (6963.3 per 100 000 person years). Cox regression analyses showed no evidence that patients prescribed varenicline had higher risks of fatal or non-fatal self harm (hazard ratio 0.88, 95% confidence interval 0.52 to 1.49) or treated depression (0.75, 0.65 to 0.87) compared with those prescribed nicotine replacement therapy. There was no evidence that patients prescribed bupropion had a higher risk of fatal or non-fatal self harm (0.83, 0.30 to 2.31) or of treated depression (0.63, 0.46 to 0.87) compared with patients prescribed nicotine replacement therapy. Similar findings were obtained using propensity score methods and instrumental variable analyses.

Conclusions There is no evidence of an increased risk of suicidal behaviour in patients prescribed varenicline or bupropion compared with those prescribed nicotine replacement therapy. These findings should be reassuring for users and prescribers of smoking cessation medicines.


  • We thank Matt Hickman, John Macleod, and Rosie Cornish of the University of Bristol and Martin Frisher of Keele University, for providing support with Read code lists for drug misuse and past psychiatric illness; Edmond Ng of the CPRD for his support with this project. This study is partly based on data from the CPRD obtained under license from the UK MHRA. However, the interpretation and conclusions contained in this study are those of the authors alone. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.

  • Contributors: All authors contributed to the conception and design or the analysis and interpretation of the data. DG, RMM, FW, and CM developed the study protocol. KHT and NMD were responsible for data extraction and analysis. KHT created the Read code lists which were checked by RMM and DG. KHT wrote the paper with contributions from all authors. FW and NMD provided additional support with the instrumental variable analyses, and CM provided support with the propensity score analysis. KT and DG are the study guarantors.

  • Funding: The study was supported by a grant from the MHRA (grant no SDS 33437); the agency approved the study design during the funding process but aside from this the authors carried out the study and publication independently without further involvement of the funder. DG is a senior investigator at the National Institute for Health Research. NMD was the recipient of a four year studentship with the Medical Research Council Centre for causal analysis in translational epidemiology (G0600705) and is currently funded by the Integrative Epidemiology Unit, which is supported by the Medical Research Council and the University of Bristol. FW and NMD are funded by the European Research Council grant DEVHEALTH (269874). KHT is funded by a doctoral fellowship award from the National Institute for Health Research.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: support from the MHRA and the National Institute for Health Research for the submitted work; RMM is a member of the MHRA’s Independent Scientific Advisory Committee for CPRD research and receives expenses and a small fee for meeting attendance and preparation for meetings; DG is a member of the MHRA’s Pharmacovigilance Expert Advisory Group and receives travel expenses and a small fee for meeting attendance and preparation for meetings; no other relationships or activities have been declared that could appear to have influenced the submitted work.

  • Ethical approval: The MHRA’s independent scientific advisory committee reviewed the study protocol for scientific quality. The CPRD group has obtained ethics approval from a multicentre research ethics committee for all purely observational research using CPRD data—that is, studies that do not include patient involvement and are anonymised.

  • Data sharing: No additional data available. Read code and drug code lists for psychiatric illness, psychotic illness, self harm, major chronic diseases, hypnotics, antipsychotics, antidepressants, and drug and alcohol misuse are available on request from the authors.

  • The lead author (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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