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Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR)

BMJ 2018; 363 doi: (Published 31 October 2018) Cite this as: BMJ 2018;363:k4218
  1. David S Kessler, reader1,
  2. Stephanie J MacNeill, lecturer2,
  3. Deborah Tallon, researcher1,
  4. Glyn Lewis, professor3,
  5. Tim J Peters, professor1,
  6. William Hollingworth, professor1,
  7. Jeff Round, senior lecturer1,
  8. Alison Burns, researcher1,
  9. Carolyn A Chew-Graham, professor4,
  10. Ian M Anderson, professor5,
  11. Tom Shepherd, researcher4,
  12. John Campbell, professor6,
  13. Chris M Dickens, professor6,
  14. Mary Carter, researcher6,
  15. Caroline Jenkinson, researcher6,
  16. Una Macleod, professor7,
  17. Helen Gibson, researcher7,
  18. Simon Davies, professor8,
  19. Nicola J Wiles, professor1
  1. 1Population Health Sciences, Bristol Medical School, Bristol BS8 2BN, UK
  2. 2Bristol Randomised Trials Collaboration, Population Health Sciences, Bristol Medical School, Bristol, UK
  3. 3Division of Psychiatry, University College London, London, UK
  4. 4Primary Care and Health Sciences, Keele University, Keele, UK
  5. 5Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK
  6. 6Exeter Medical School, University of Exeter, Exeter, UK
  7. 7Hull York Medical School, Hull, UK
  8. 8Centre for Addiction and Mental Health, Toronto, Canada
  1. Correspondence to: D S Kessler david.kessler{at}
  • Accepted 28 September 2018


Objective To investigate the effectiveness of combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants for treatment resistant depression in primary care.

Design Two parallel group multicentre phase III randomised placebo controlled trial.

Setting 106 general practices in four UK sites; Bristol, Exeter, Hull, and Keele/North Staffs, August 2013 to October 2015.

Participants 480 adults aged 18 or more years who scored 14 or more on the Beck depression inventory, second revision, fulfilled ICD-10 (international classification of diseases, 10th revision) criteria for depression, and had used an SSRI or SNRI for at least six weeks but were still depressed. 241 were randomised to mirtazapine and 239 to placebo, both given in addition to usual SSRI or SNRI treatment. Participants were stratified by centre and minimised by baseline Beck depression inventory score, sex, and current psychological therapy. They were followed up at 12, 24, and 52 weeks. 431 (89.8%) were included in the (primary) 12 week follow-up.

Main outcome measures Depressive symptoms at 12 weeks after randomisation, measured using the Beck depression inventory II score as a continuous variable. Secondary outcomes included measures of anxiety, quality of life, and adverse effects at 12, 24, and 52 weeks.

Results Beck depression inventory II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline scores and minimisation or stratification variables, although the confidence interval included the null (mean (SD) scores at 12 weeks: 18.0 (12.3) in the mirtazapine group, 19.7 (12.4) in the placebo group; adjusted difference between means −1.83 (95% confidence interval −3.92 to 0.27); P=0.09). Adverse effects were more common in the mirtazapine group and were associated with the participants stopping the trial drug.

Conclusion This study did not find evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI over placebo in a treatment resistant group of primary care patients with depression. This remains an area of important unmet need where evidence of effective treatment options is limited.

Trial registration Current Controlled Trials ISRCTN06653773.


  • Contributors: DSK, GL, SD, NJW, TJP, WH, IMA, JC, CMD, CAC-G, and UM were responsible for the original proposal and securing funding for the trial. DT joined them in drafting the original protocol. DSK as chief investigator had overall responsibility for the management of the study and the Bristol site. JC and CMD had responsibility for the Exeter site, UM for the Hull site, and CAC-G for the Keele/North Staffs site. All authors contributed to the refinement of the protocol. DT and AB had overall responsibility for the data collection and were supported by CJ, MC, TS, and HG. SJM, TJP, and NJW wrote the statistical analysis plan. SJM did the main analyses with input from TJP, NJW, and DSK. DSK wrote the initial draft of the report. He is the guarantor. All authors contributed to and approved the final report. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This research was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project 11/129/76) and supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS, or Department of Health. The funding source had no role in study design, data collection, data analysis, interpretation of data, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; DSK, JR, GL, NJW, and TJP report grants from NIHR HTA during the conduct of the study; and IMA reports personal fees from Lundbeck-Otsuka, Takeda, and Lundbeck outside the submitted work; there were no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This study was approved by the South East Wales research ethics committee C (ref 12/WA/0350). Participants gave informed consent to take part in the study.

  • Data sharing: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be available beginning three months and ending five years after article publication to researchers who provide a methodologically sound proposal. The study protocol and statistical analysis plan will also be available. To gain access, data requestors will need to sign a data access agreement. Proposals should be directed to david.kessler{at}

  • Transparency: The lead author affirms that the manuscript is an honest, accurate and transparent account of the study and that no important aspects of the study have been omitted.

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