Adding mirtazapine to SSRIs or SNRIs... does it work?

Adding mirtazapine to SSRIs or SNRIs... does it work?
What is the point of evidence? Sometimes it can help to leap medicine forward. Just think of all those strokes and heart attacks we save now with evidence-based interventions. But, just as usefully, sometimes it can help to put the brakes on, to give us time to pause and reflect on interventions that have become widespread in practice ahead of an evidence base. The use of vaginal MESH is a classic recent example of this, but in the field of therapeutics what about using mirtazapine in combination with SSRIs for ‘treatment resistant depression’?

So, imagine you have been treating Sue for depression. She has not responded despite talking therapy and two different SSRIs at maximum dose. What next? Should we try adding in mirtazapine?

Now I have to admit I never been a big fan of mirtazapine. It has always struck me as a bit of a ‘sledge hammer’ drug. People often seem to be over sedated on it, weight gain is common and people complain of feeling sluggish. That said I have some patients, like you, who do brilliantly on it, it is a useful choice in agitated depression with severe insomnia and despite my misgivings it came out well in this year’s big Lancet comparative meta-analysis as monotherapy in acute major depression, with a higher response rate and lower drop-out rate than many other antidepressants.

But I have been concerned to see how rapidly it has become used in recent years in addition to SSRIs or SNRIs as augmentation therapy in treatment resistant cases. This has become common practice in no time and without an evidence base to support it. There is a pharmacological rationale for combining it, in that it has a different mode of action to SSRI or SNRI with the potential for an additive and possible synergistic action (I once heard a psychiatrist describe the combination as ‘rocket fuel’). 

However, does it actually work in practice? 

Previous studies have shown mixed results, so a recent high quality RCT is welcome BMJ2018;363;k4218. This excellent study was based in primary care and looked at 500 patients like Sue, with major depression that had not responded despite 6 weeks of an SSRI or SNRI. They were then randomised in a blinded RCT to adding in mirtazapine 30mg or placebo. At 12 weeks there was no clinically significant benefit for adding mirtazapine compared to placebo, and yet an increased chance of adverse effects.

So, time to pause and reflect before reaching for the prescription tab and adding mirtazapine. The evidence informs us it doesn’t work and increases adverse effects. But where does that leave us with poor Sue? How can evidence usefully inform what we should do next to help her?

These are the sort of topics covered in out Hot Topics GP Update course. For more information about our Australian Hot Topics GP Update 2019 dates, click here.

This blog was originally published via the NB Medical Hot Topics Blog, on 13th December 2018.


Dr Genevieve Yates

Genevieve is an educator, a GP and a writer in the Northern Rivers region of NSW.