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.
TRIAL REGISTRATION: Current Controlled Trials ISRCTN06653773.
I hadn't been, nor had I even heard of, adding mirtazapine to patients with depression who are unresponsive to SSRIs, but apparently it has been adopted by some. So good to know for those folk.
Disappointing but important to know that the augmentation strategy of adding mirtazapine to SSRIs or SNRIs did not add benefit.
Augmentation is often recommended. This will help reduce medication burden in patients who are already suffering.
An excellent very pragmatic study that can offer clear guidance on what not to use as an augmenting strategy in an area with many possibilities and unclear evidence.
This is a negative study, but it is hugely helpful to know what does not work. In this case, adding mirtazapine when an SSRI/SNRI is not effective, is also not effective.
Solid conclusions that are relevant for primary care clinicians: the addition of mirtizipine to an SSRI/SSNI has very modest clinical benefit and comes with a substantial risk for (serious) adverse events.
A serious limitation not noted in the paper is that no information is provided on the doses of SSRIs and SNRIs, other than they were adequate. In my experience, primary care providers often do not maximize dosage before concluding treatment resistance. In addition, this study used a single dose (30 mg) of mirtazapine. Many patients require more (45-60 mg) for a response.
Very important study of a high-priority research question. Adding mirtazapine is a widely espoused therapeutic option. This study, that is by far the largest TNK, shows no good evidence of benefit.
As a psychiatrist, I am interested in finding effective augmentation strategies for the sizable number of patients who fail to adequately respond to antidepressant monotherapy. This study refutes the relatively widespread belief that mirtazapine augmentation of SSRI/SNRI antidepressants is effective. While the outcome is disappointing, the study reinforces the need for continued research to identify effective augmentation strategies.