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

TY - JOUR

T1 - Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression

T2 - the MIR RCT

AU - Kessler, David

AU - Burns, Alison

AU - Tallon, Debbie

AU - Lewis, Glyn

AU - MacNeill, Stephanie

AU - Round, Jeff

AU - Hollingworth, William

AU - Chew-Graham, Carolyn

AU - Anderson, Ian

AU - Campbell, John

AU - Dickens, Chris

AU - Macleod, Una

AU - Gilbody, Simon

AU - Davies, Simon

AU - Peters, Tim J

AU - Wiles, Nicola

N1 - © Queen’s Printer and Controller of HMSO 2018.This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2018/11/2

Y1 - 2018/11/2

N2 - 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 or not 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: The MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomised trial with allocation at the level of the individual.SETTING: Participants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele.PARTICIPANTS: Eligible participants were aged ≥ 18 years; were taking a SSRI or a SNRI antidepressant for at least 6 weeks at an adequate dose; scored ≥ 14 points on the Beck Depression Inventory-II (BDI-II); were adherent to medication; and met the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, criteria for depression.INTERVENTIONS: Participants were randomised using a computer-generated code to either oral mirtazapine or a matched placebo, starting at a dose of 15 mg daily for 2 weeks and increasing to 30 mg daily for up to 12 months, in addition to their usual antidepressant. Participants, their general practitioners (GPs) and the research team were blind to the allocation.MAIN OUTCOME MEASURES: The primary outcome was depression symptoms at 12 weeks post randomisation compared with 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 events (AEs), 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: There were 480 patients randomised to the trial (mirtazapine and usual care, n = 241; placebo and usual care, n = 239), of whom 431 patients (89.8%) were followed up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group than the placebo group after adjustment for baseline BDI-II score and minimisation and stratification variables [difference -1.83 points, 95% confidence interval (CI) -3.92 to 0.27 points; p = 0.087]. This was smaller than the minimum clinically important difference and the CI included the null. The difference became smaller at subsequent time points (24 weeks: -0.85 points, 95% CI -3.12 to 1.43 points; 12 months: 0.17 points, 95% CI -2.13 to 2.46 points). More participants in the mirtazapine group withdrew from the trial medication, citing mild AEs (46 vs. 9 participants).CONCLUSIONS: This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to a SSRI or a 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: Treatment-resistant depression 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: Current Controlled Trials ISRCTN06653773; EudraCT number 2012-000090-23.FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 63. See the NIHR Journals Library website for further project information.

AB - 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 or not 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: The MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomised trial with allocation at the level of the individual.SETTING: Participants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele.PARTICIPANTS: Eligible participants were aged ≥ 18 years; were taking a SSRI or a SNRI antidepressant for at least 6 weeks at an adequate dose; scored ≥ 14 points on the Beck Depression Inventory-II (BDI-II); were adherent to medication; and met the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, criteria for depression.INTERVENTIONS: Participants were randomised using a computer-generated code to either oral mirtazapine or a matched placebo, starting at a dose of 15 mg daily for 2 weeks and increasing to 30 mg daily for up to 12 months, in addition to their usual antidepressant. Participants, their general practitioners (GPs) and the research team were blind to the allocation.MAIN OUTCOME MEASURES: The primary outcome was depression symptoms at 12 weeks post randomisation compared with 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 events (AEs), 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: There were 480 patients randomised to the trial (mirtazapine and usual care, n = 241; placebo and usual care, n = 239), of whom 431 patients (89.8%) were followed up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group than the placebo group after adjustment for baseline BDI-II score and minimisation and stratification variables [difference -1.83 points, 95% confidence interval (CI) -3.92 to 0.27 points; p = 0.087]. This was smaller than the minimum clinically important difference and the CI included the null. The difference became smaller at subsequent time points (24 weeks: -0.85 points, 95% CI -3.12 to 1.43 points; 12 months: 0.17 points, 95% CI -2.13 to 2.46 points). More participants in the mirtazapine group withdrew from the trial medication, citing mild AEs (46 vs. 9 participants).CONCLUSIONS: This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to a SSRI or a 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: Treatment-resistant depression 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: Current Controlled Trials ISRCTN06653773; EudraCT number 2012-000090-23.FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 63. See the NIHR Journals Library website for further project information.

KW - Adult

KW - Aged

KW - Antidepressive Agents/administration & dosage

KW - Cost-Benefit Analysis

KW - Depressive Disorder, Treatment-Resistant/drug therapy

KW - Drug Therapy, Combination

KW - Female

KW - Health Expenditures/statistics & numerical data

KW - Health Resources/economics

KW - Humans

KW - Male

KW - Medication Adherence/statistics & numerical data

KW - Mental Health

KW - Middle Aged

KW - Mirtazapine/administration & dosage

KW - Quality of Life

KW - Quality-Adjusted Life Years

KW - Serotonin Uptake Inhibitors/administration & dosage

KW - Serotonin and Noradrenaline Reuptake Inhibitors/administration & dosage

KW - Severity of Illness Index

KW - Social Work/economics

KW - Time Factors

U2 - 10.3310/hta22630

DO - 10.3310/hta22630

M3 - Article

C2 - 30468145

SN - 1366-5278

VL - 22

SP - 1

EP - 136

JO - Health technology assessment

JF - Health technology assessment

IS - 63

ER -