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

Kessler, David S.; MacNeill, Stephanie J.; Tallon, Deborah; Lewis, Glyn; Peters, Tim J.; Hollingworth, William; Round, Jeff; Burns, Alison; Chew-Graham, Carolyn A.; Anderson, Ian M.; Shepherd, Tom; Campbell, John; Dickens, Chris M.; Carter, Mary; Jenkinson, Caroline; Macleod, Una; Gibson, Helen; Davies, Simon; Wiles, Nicola J.


David S. Kessler

Stephanie J. MacNeill

Deborah Tallon

Glyn Lewis

Tim J. Peters

William Hollingworth

Jeff Round

Alison Burns

Carolyn A. Chew-Graham

Ian M. Anderson

Tom Shepherd

John Campbell

Chris M. Dickens

Mary Carter

Caroline Jenkinson

Helen Gibson

Simon Davies

Nicola J. Wiles


Objective: To investigate the effectiveness of combining mirtazapine with Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) or Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants for patients in primary care who had not responded to an antidepressant.
Design: A two parallel-group multi-centre, placebo controlled, randomised trial comparing the addition of mirtazapine to placebo for patients who had been adherent to an SSRI or SNRI for at least 6 weeks and were still depressed. Participants were stratified by centre and minimised by baseline Beck Depression Inventory score [BDI-II], gender and current psychological therapy. Participants, their General Practitioners (GPs), and the research team were blind to the allocation. Primary analyses compared the two groups as allocated without imputing missing data Setting: 106 general practices in 4 centres in the UK; Bristol, Exeter, Hull and North Staffordshire.
Participants: Between August 2013 and October 2015, we recruited 480 participants aged over 17 years, 69.1% of whom were female. Participants scored >13 using the BDI-II and fulfilled International Classification of Diseases [ICD]-10 criteria for depression. Exclusion criteria included bipolar disorder, psychosis and major alcohol/substance abuse. 431 (89.8%) were included in the (primary) 12-week follow-up.
Intervention: 241 participants were randomised to mirtazapine and 239 to placebo, both given in addition to their usual SSRI/SNRI medication. They were followed up at 12, 24 and 52 weeks.
Main outcome measures: Depressive symptoms at 12 weeks post-randomisation, measured using the BDI-II score as a continuous variable. Secondary outcomes include measures of anxiety, quality of life and adverse effects at 12, 24 and 52 weeks.
Results: BDI-II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline BDI-II and minimisation/stratification variables, although the confidence interval included the null (mean (SD) BDI-II 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=0.087)). Adverse effects were more frequent in the mirtazapine group and associated with stopping the trial medication.
Conclusion: This study did not find evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI antidepressant over placebo in a treatment resistant group of primary care patients with depression. This remains an area of important unmet need where there is limited evidence of effective treatment options.


Kessler, D. S., MacNeill, S. J., Tallon, D., Lewis, G., Peters, T. J., Hollingworth, W., …Wiles, N. J. (2018). Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: Phase III randomised placebo controlled trial (MIR). BMJ, 363, Article k4218.

Journal Article Type Article
Acceptance Date Sep 28, 2018
Online Publication Date Oct 31, 2018
Publication Date Oct 31, 2018
Deposit Date Dec 5, 2018
Publicly Available Date Dec 6, 2018
Journal BMJ
Print ISSN 0959-8138
Electronic ISSN 1756-1833
Publisher BMJ Publishing Group
Peer Reviewed Peer Reviewed
Volume 363
Article Number k4218
Keywords General Medicine
Public URL
Publisher URL


Article (424 Kb)

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This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) 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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