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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

Mirtazapine added to SSRIs or SNRIs for resistant depression: EBM and the Declaration of Helsinki.

The publication of the trial adding mirtazapine to SSRIs or SNRIs for resistant depression (MIR) deserves comment.(1)

First, could Kessler and colleagues provide data about psychological interventions, before prescribing SSRIs or SNRIs as well as after their failure? Indeed, most episodes of depression that persist are often successfully treated with specific psychosocial interventions, notably cognitive behavioural therapy (CBT) or behavioural activation as a first line. These treatments, robustly evidence-based in the real-life setting and over the long term,(2,3) are often preferred by patients(4) and known to improve self-esteem, agency, and social functioning.(5)

Second, were patients informed about NICE recommendations for “inadequate response to initial interventions”? Eg. ( “For people with moderate or severe depression, provide a combination of antidepressant medication and a high-intensity psychological intervention.”(6) The use of a placebo when a recommended treatment is available is a breach of the Helsinki declaration, even more considering the duration of this trial (52 weeks).

Third, why were some patients prescribed SNRIs although NICE recommends “SSRI in a generic form …” ( More specifically why were prescriptions of escitalopram and duloxetine allowed in the protocol? There is no evidence that escitalopram or citalopram are superior in terms of efficacy compared to other antidepressants. In contrast, robust documentation has existed since 2001 linking them to serious cardiovascular adverse effects (QT prolongation and deadly torsades de pointes).Similarly, duloxetine has no efficacy advantage versus other antidepressants but has the potential for life-threatening liver injury and severe skin reactions, including Stevens–Johnson syndrome.(7)

Last, could ref 8 be a duplicate publication?

1 Kessler DS, MacNeill SJ, Tallon D et al; Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR). BMJ 2018;363:k4218.

2 Wiles NJ, Thomas L, Turner N, Garfield K, Kounali D, Campbell J et al Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial. Lancet Psychiatry 2016;3:137-44.

3 Richards DA, Ekers D, McMillan D et al. Cost and Outcome of Behavioural Activation versus Cognitive Behavioural Therapy for Depression (COBRA): a randomised, controlled, non-inferiority trial. Lancet 2016;388:871-80.

4 McHugh RK, Whitton SW,Peckham AD, Welge JA, Otto MW. Patient preference for psychological vs pharmacologic treatment of psychiatric disorders: a meta-analytic review. J Clin Psychiatry 2013;7:595-602.

5 Kolovos S, Kleiboer A, Cuijpers P. Effect of psychotherapy for depression on quality of life: meta-analysis. Br J Psychiatry 2016;209:460-468.

6 NICE. Depression in adults: recognition and management. Clinical guideline [CG90] Published date: October 2009 Last updated: April 2018. Available at Accessed 6 Dec 2018

7 Prescrire. Towards better patient care: drugs to avoid in 2017. Rev Prescrire 2017; 37:137-148 Accessed Accessed 6 Dec 2018

8 Kessler D, Burns A, Tallon D. Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression: the MIR RCT. Health Technol Assess 2018;2:1-136.

Competing interests: No competing interests

06 December 2018
alain braillon
senior consultant
university hospital