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NIHR Signal Combining mirtazapine with other antidepressants is not effective for treatment-resistant depression

Published on 15 January 2019

doi: 10.3310/signal-000709

Adding mirtazapine to first-line antidepressants for adults with treatment-resistant depression does not improve symptoms when compared with placebo (dummy pills). People taking mirtazapine are more likely to experience side effects, and stop taking their treatment.

This NIHR-funded trial took place in 106 general practices in England, recruiting 480 adults with mild to severe depression. All participants had been taking selective serotonin reuptake inhibitor (SSRI) or serotonin-noradrenaline reuptake inhibitor (SNRI) antidepressants for at least six weeks but were still depressed.

The findings show that this combination has no benefit if used routinely in primary care for people who haven’t responded to treatment with other antidepressants.

NICE guidance on recognising and managing depression in adults is currently being updated, due for publication in December 2019. This evidence may inform the update.

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Why was this study needed?

Depression affects nearly 1 in 6 people in the UK and is the third most common reason for seeing a GP. Treatment can involve a combination of lifestyle changes, talking therapies and medication. Antidepressants, in particular, selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake inhibitors (SNRIs), are often the first line treatment for moderate to severe depression.

Research has shown that many people do not respond to initial treatment, even when they take an adequate dose for an appropriate length of time. There is no clear evidence about effective combinations of drugs that could be used in these situations. Mirtazapine, an antagonist of the presynaptic α2-autoreceptor, works differently to SSRIs and SNRIs, potentially improving a person’s response if used in addition.

Four previous trials and a systematic review of combination approaches have shown mixed results. This trial aimed to resolve the question about whether this combination approach using mirtazapine could be an effective option.

What did this study do?

This randomised controlled trial recruited 480 adults who had a diagnosis of depression and had been taking an SSRI or SNRI antidepressant for at least six weeks but still had symptoms. They were included if they scored at least 14 on the Beck depression inventory (BDI II); a scale 0 to 63, with high scores (over 29) indicating severe depression and scores below 26 indicating mild depression.

Baseline scores were similar in both groups, about 31, indicating severe depression despite initial treatments. Two hundred and forty-one participants were randomised to the mirtazapine combination group. In addition to continuing their SSRI or SNRI, they then took one 15mg capsule of mirtazapine daily for two weeks, followed by two 15mg capsules for up to 50 weeks. The 239 people in the comparison group were given identical-looking placebo capsules.

Participants, clinicians, assessors and the research team were unaware of who was in which group. Follow-up rates were good, with 90% assessed at 12 weeks.

What did it find?

  • At baseline, both groups had BDI II scores of about 31 indicating moderate-severe depression.
  • After 12 weeks both groups had improved substantially, but there was little difference in severity of depression symptoms between the groups, suggesting that treatment with the SSRI or SNRI continues to have an effect for more than six weeks. The mean BDI II score in the mirtazapine group was 18.0 (mild depression), and in the placebo group was 19.7 (adjusted mean difference -1.83, 95% confidence interval -3.92 to 0.27). The difference in BDI II scores between the groups was smaller at 24 and 52 weeks.
  • Adverse events were more common in the mirtazapine group with 50% of people reporting side effects, compared with 30% in the placebo group.
  • People in the mirtazapine group were more likely to stop taking their trial drug. Of the 121 people taking mirtazapine who reported side effects, 46 stopped taking it. In the placebo group, 71 people reported adverse events, and 9 of them stopped.

What does current guidance say on this issue?

NICE’s 2009 guideline on the recognition and management of depression in adults has a section on combining and augmenting medications if someone hasn’t responded well to initial treatment. It says that if a person with depression is informed about, and prepared to tolerate, the increased side-effect burden, then mirtazapine can be considered in combination with another antidepressant. This should only normally be started in primary care after consultation with a consultant psychiatrist.

This guideline is currently being updated, due for publication in December 2019.

What are the implications?

This trial did not show any benefit in taking mirtazapine in combination with SSRI or SNRI antidepressants for people who had shown resistance to initial treatment. 

It suggests that if people are given more time on antidepressants (in a research setting), severe depression can improve with or without additional pharmacological treatment. Only about 13% were having psychological therapy in either group at the start of the trial.

This information will inform the discussion between clinicians and patients and suggests this combination of drugs has more side effects and negligible benefit for this hard to treat group of people.

Citation and Funding

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.

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 11/129/76) and supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol.

Bibliography

Henssler J, Bschor T and Baethge C. Combining antidepressants in acute treatment of depression: a meta-analysis of 38 studies including 4511 patients. Can J Psychiatry. 2016;61(1):29-43.

Kessler D, Burns A, Tallon D et al. Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression: the MIR RCT. Health Technol Assess. 2018;22(63).

NHS website. Clinical depression. London: Department of Health and Social Care; 2016.

NICE. Depression. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2015.

NICE. Depression in adults: recognition and management. CG90. London: National Institute for Health and Care Excellence; 2009.

Why was this study needed?

Depression affects nearly 1 in 6 people in the UK and is the third most common reason for seeing a GP. Treatment can involve a combination of lifestyle changes, talking therapies and medication. Antidepressants, in particular, selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake inhibitors (SNRIs), are often the first line treatment for moderate to severe depression.

Research has shown that many people do not respond to initial treatment, even when they take an adequate dose for an appropriate length of time. There is no clear evidence about effective combinations of drugs that could be used in these situations. Mirtazapine, an antagonist of the presynaptic α2-autoreceptor, works differently to SSRIs and SNRIs, potentially improving a person’s response if used in addition.

Four previous trials and a systematic review of combination approaches have shown mixed results. This trial aimed to resolve the question about whether this combination approach using mirtazapine could be an effective option.

What did this study do?

This randomised controlled trial recruited 480 adults who had a diagnosis of depression and had been taking an SSRI or SNRI antidepressant for at least six weeks but still had symptoms. They were included if they scored at least 14 on the Beck depression inventory (BDI II); a scale 0 to 63, with high scores (over 29) indicating severe depression and scores below 26 indicating mild depression.

Baseline scores were similar in both groups, about 31, indicating severe depression despite initial treatments. Two hundred and forty-one participants were randomised to the mirtazapine combination group. In addition to continuing their SSRI or SNRI, they then took one 15mg capsule of mirtazapine daily for two weeks, followed by two 15mg capsules for up to 50 weeks. The 239 people in the comparison group were given identical-looking placebo capsules.

Participants, clinicians, assessors and the research team were unaware of who was in which group. Follow-up rates were good, with 90% assessed at 12 weeks.

What did it find?

  • At baseline, both groups had BDI II scores of about 31 indicating moderate-severe depression.
  • After 12 weeks both groups had improved substantially, but there was little difference in severity of depression symptoms between the groups, suggesting that treatment with the SSRI or SNRI continues to have an effect for more than six weeks. The mean BDI II score in the mirtazapine group was 18.0 (mild depression), and in the placebo group was 19.7 (adjusted mean difference -1.83, 95% confidence interval -3.92 to 0.27). The difference in BDI II scores between the groups was smaller at 24 and 52 weeks.
  • Adverse events were more common in the mirtazapine group with 50% of people reporting side effects, compared with 30% in the placebo group.
  • People in the mirtazapine group were more likely to stop taking their trial drug. Of the 121 people taking mirtazapine who reported side effects, 46 stopped taking it. In the placebo group, 71 people reported adverse events, and 9 of them stopped.

What does current guidance say on this issue?

NICE’s 2009 guideline on the recognition and management of depression in adults has a section on combining and augmenting medications if someone hasn’t responded well to initial treatment. It says that if a person with depression is informed about, and prepared to tolerate, the increased side-effect burden, then mirtazapine can be considered in combination with another antidepressant. This should only normally be started in primary care after consultation with a consultant psychiatrist.

This guideline is currently being updated, due for publication in December 2019.

What are the implications?

This trial did not show any benefit in taking mirtazapine in combination with SSRI or SNRI antidepressants for people who had shown resistance to initial treatment. 

It suggests that if people are given more time on antidepressants (in a research setting), severe depression can improve with or without additional pharmacological treatment. Only about 13% were having psychological therapy in either group at the start of the trial.

This information will inform the discussion between clinicians and patients and suggests this combination of drugs has more side effects and negligible benefit for this hard to treat group of people.

Citation and Funding

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.

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 11/129/76) and supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol.

Bibliography

Henssler J, Bschor T and Baethge C. Combining antidepressants in acute treatment of depression: a meta-analysis of 38 studies including 4511 patients. Can J Psychiatry. 2016;61(1):29-43.

Kessler D, Burns A, Tallon D et al. Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression: the MIR RCT. Health Technol Assess. 2018;22(63).

NHS website. Clinical depression. London: Department of Health and Social Care; 2016.

NICE. Depression. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2015.

NICE. Depression in adults: recognition and management. CG90. London: National Institute for Health and Care Excellence; 2009.

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

Published on 31 October 2018

D Kessler, S MacNeill, D Tallon, G Lewis, T Peters, W Hollingworth, J Round, A Burns, C Chew-Graham, I Anderson, T Shepherd, J Campbell, C Dickens, M Carter, C Jenkinson, U Macleod, H Gibson, S Davies, N Wiles

Health Technology Assessment , 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

The Beck Depression Inventory, second revision (BDI II), is a multiple choice self-report questionnaire, designed to measure the severity of depression symptoms. The published inventory includes 21 questions, asking people to rate how they have been feeling over the past two weeks.

Each question is scored from 0-3, giving a maximum total of 63. Scoring 0-13 indicates minimal depression, 14-19 mild depression, 20-28 moderate depression, and anything over 29 indicating severe depression. This study used a modification where mild was defined as less than 26, moderate 26-34, or severe over 35.

A difference or improvement of three or four points in BDI II score between treatment and placebo groups is seen as clinically important.

Expert commentary

Many patients will fail to adequately respond to the first antidepressant and trials of other antidepressants are common. Combination of antidepressants, particularly involving the addition of mirtazapine to other agents, is a frequently used strategy and has some support from previous research by Henssler et al., although there is an acknowledged dearth of large well-designed studies.

This study is an interesting addition to the literature and did not find benefit for the addition of mirtazapine to other antidepressants in a sample of depressed patients likely typical of UK family practice.

It suggests that other treatment strategies might be better prioritised.

Allan Young, Professor of Psychiatry, King’s College London

The commentator declares no conflicting interests