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Antidepressant use and risk of cardiovascular outcomes in people aged 20 to 64: cohort study using primary care database

BMJ 2016; 352 doi: (Published 22 March 2016) Cite this as: BMJ 2016;352:i1350
  1. Carol Coupland, professor of medical statistics in primary care1,
  2. Trevor Hill, research statistician1,
  3. Richard Morriss, professor of psychiatry and community mental health2,
  4. Michael Moore, professor in primary care research3,
  5. Antony Arthur, professor in nursing science4,
  6. Julia Hippisley-Cox, professor of clinical epidemiology and general practice1
  1. 1Division of Primary Care, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK
  2. 2Institute of Mental Health, Nottingham NG8 1BB, UK
  3. 3University of Southampton Medical School, Primary Care and Population Sciences, Aldermoor Health Centre, Southampton SO16 5ST, UK
  4. 4School of Health Sciences, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich NR4 7TJ, UK
  1. Correspondence to: C Coupland carol.coupland{at}
  • Accepted 20 February 2016


Objective To assess associations between different antidepressant treatments and rates of three cardiovascular outcomes (myocardial infarction, stroke or transient ischaemic attack, and arrhythmia) in people with depression.

Design Cohort study.

Setting UK general practices contributing to the QResearch primary care database.

Participants 238 963 patients aged 20 to 64 years with a first diagnosis of depression between 1 January 2000 and 31 July 2011.

Exposures Antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, duration of use, and commonly prescribed individual antidepressant drugs.

Main outcome measures First diagnoses of myocardial infarction, stroke or transient ischaemic attack, and arrhythmia during five years’ follow-up. Cox proportional hazards models were used to estimate hazard ratios, adjusting for potential confounding variables.

Results During five years of follow-up, 772 patients had a myocardial infarction, 1106 had a stroke or transient ischaemic attack, and 1452 were diagnosed as having arrhythmia. No significant associations were found between antidepressant class and myocardial infarction over five years’ follow-up. In the first year of follow-up, patients treated with selective serotonin reuptake inhibitors had a significantly reduced risk of myocardial infarction (adjusted hazard ratio 0.58, 95% confidence interval 0.42 to 0.79) compared with no use of antidepressants; among individual drugs, fluoxetine was associated with a significantly reduced risk (0.44, 0.27 to 0.72) and lofepramine with a significantly increased risk (3.07, 1.50 to 6.26). No significant associations were found between antidepressant class or individual drugs and risk of stroke or transient ischaemic attack. Antidepressant class was not significantly associated with arrhythmia over five years’ follow-up, although the risk was significantly increased during the first 28 days of treatment with tricyclic and related antidepressants (adjusted hazard ratio 1.99, 1.27 to 3.13). Fluoxetine was associated with a significantly reduced risk of arrhythmia (0.74, 0.59 to 0.92) over five years, but citalopram was not significantly associated with risk of arrhythmia even at high doses (1.11, 0.72 to 1.71 for doses ≥40 mg/day).

Conclusions This study found no evidence that selective serotonin reuptake inhibitors are associated with an increased risk of arrhythmia or stroke/transient ischaemic attack in people diagnosed as having depression between the ages of 20 to 64 or that citalopram is associated with a significantly increased risk of arrhythmia. It found some indication of a reduced risk of myocardial infarction with selective serotonin reuptake inhibitors, particularly fluoxetine, and of an increased risk with lofepramine.


  • We acknowledge the contribution of practices that contribute to the QResearch, as well as Egton Medical Information Systems (EMIS) and the University of Nottingham for expertise in establishing, developing, and supporting the database. We acknowledge the Office of National Statistics for providing mortality data.

  • Contributors: CC, JH-C, RM, AA, and MM contributed to the overall conception and design of the study. CC wrote the first draft of this manuscript. JH-C did the data extraction. TH and CC did the statistical analyses. All authors contributed to interpretation of results and drafting of this manuscript. All authors read and approved the final manuscript. CC is the guarantor.

  • Funding: The project was funded by the National Institute for Health Research (NIHR) School for Primary Care Research (project number 81). The funding body did not play a role in the study design, the writing of the manuscript, or the decision to submit the manuscript for publication. This paper presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. RM’s contribution to the study has been funded through the NIHR Collaboration for Leadership in Applied Health Research and Care East Midlands (CLAHRC EM).

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: financial support from NIHR for the submitted work; JH-C is director of QResearch, which is a not for profit venture between the University of Nottingham and EMIS (commercial supplier of GP clinical systems); no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The project has been independently peer reviewed and accepted by the QResearch Scientific board and has been approved in accordance with the agreed procedure with the Trent Research Ethics Committee (reference number: MREC/03/4/021).

  • Transparency declaration: The lead author (the manuscript’s guarantor) affirms that this 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.

  • Data sharing: The patient level data from the QResearch are specifically licensed according to its governance framework. See for further details.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See:

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