Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression: the MIR RCT

Background: Depression is usually managed in primary care and antidepressants are often the first-line treatment, but only half of those treated respond to a single antidepressant.

Objectives: To investigate whether combining mirtazapine with Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) or Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants results in better patient outcomes and more efficient NHS care than SNRI or SSRI therapy alone in Treatment Resistant Depression (TRD).

Design: MIR is a two-parallel group, multi-centre, pragmatic, placebo controlled, randomised trial with allocation at the level of the individual.

Setting: Participants were recruited from primary care in Bristol, Exeter, Keele/Manchester and Hull/York.

Participants: Eligible participants were: aged ≥18 years; taking an SSRI/SNRI antidepressant for at least 6 weeks at an adequate dose; scored ≥14 on the Beck Depression Inventory (BDI-II); adherent to medication; met the International Classification of Diseases and Related Health Problems, Tenth edition (ICD-10) criteria for depression.

Interventions: Participants were randomised by computer-generated code to oral mirtazapine or matched placebo, starting at 15mg daily for 2 weeks and increasing to 30mg daily, for up to 12 months in addition to their usual antidepressant. Participants, their General Practitioners, and the research team were blind to the allocation.

Main outcome measures: The primary outcome was depression symptoms at 12 weeks post-randomisation compared to baseline, measured as a continuous variable using the BDI-II. Secondary outcomes (at 12, 24 and 52 weeks) included: response, remission of depression; change in anxiety symptoms; adverse effects; quality of life; adherence to medication; health and social care use, and cost-effectiveness. Outcomes were analysed on an intention to treat basis. A qualitative study explored patients’ views and experiences of managing depression, and GPs’ views on prescribing a second antidepressant.

Results: 480 patients were randomised (mirtazapine and usual care: n=241; placebo and usual care n=239) with 431 patients (89.8%) followed-up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group compared with the placebo group after adjustment for baseline BDI-II and minimisation and stratification variables (difference=-1.83 (95% confidence interval: -3.92 to 0.27. p=0.087)). This was smaller than the minimal clinically important difference and the confidence interval included the null. The difference became smaller at subsequent time points (24 weeks: -0.85 (95% CI: -3.12 to 1.43); 12 months: 0.17 (95% CI: -2.13 to 2.46)). More participants in the mirtazapine group withdrew from the trial medication citing mild adverse effects (46 vs 9).
Conclusions: This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI antidepressant over placebo in primary care patients with TRD. There was no evidence that the addition of mirtazapine was a cost-effective use of NHS resources. GPs and patients were concerned about adding an additional antidepressant.

Limitations

Voluntary unblinding for participants after the primary outcome at 12 weeks made interpretation of longer term outcomes more difficult.

Future work

TRD remains an area of important unmet need with limited evidence of effective treatments. Promising interventions include augmentation with atypical antipsychotics and treatment using transcranial magnetic stimulation.

Trial Registration: EudraCT Number: 2012-000090-23; ISRCTN06653773