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About 30% of people receiving treatment for depression will not respond to at least 2 consecutive treatments and are generally considered to be “treatment-resistant”.

Professor Steven Marwaha, Institute for Mental Health, University of Birmingham responds to a recent NICE guideline consultation which does not recommend Esketamine for patients with TRD. He argues that the recommendation could have a serious impact for those suffering with the condition.

The National Institute for Health and Care Excellence (NICE) have recently released their consultation document outlining that the medication Esketamine is not recommended for treating treatment-resistant depression.

Their recommendation is Esketamine with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) is not recommended, within its marketing authorisation, for treating treatment-resistant depression that has not responded to at least 2 different antidepressants in the current moderate to severe depressive episode in adults.”

This may be of concern to a significant number of people in the UK. Depression, if it is strictly defined, impacts on about 2.9% of the population in the previous week, according to the Adult Psychiatric Morbidity Survey 2014 (report available from NHS Digital). About 30% of people receiving treatment for depression will not respond to at least 2 consecutive treatments and are generally considered to be “treatment-resistant”. That represents a very large number of people in the UK that this new treatment Esketamine could be considered for, and so this NICE consultation recommendation matters. This is especially the case given there is not a large amount of evidence to guide treatment in this area, and the suffering that this condition causes.

Self harm

Esketamine is used via a nasal spray device by the patient under the direct supervision of a healthcare professional. There seems to be evidence from 2 randomised controlled trials that suggest the medication is effective. The NICE document says: “The committee understood that the TRANSFORM-2 and SUSTAIN-1 results showed an improvement in response, remission and relapse rates for Esketamine plus oral antidepressant compared with placebo plus oral antidepressant.”

So why have they chosen not to recommend it? I would encourage people to read the consultation document and respond, but what is most striking and perhaps most interesting, is the discussion that was had and how this decision is made.

The committee accepted that “Treatment-resistant depression has a negative effect on people, their families and carers” and that “There is an unmet need for effective treatment options”. In my clinical and research view these two points cannot be overstated enough, and there will be few stakeholders that disagree.

The document states: “The committee heard from other clinical experts who noted that electroconvulsive therapy (ECT) should also be a comparator because the processes involved in administering Esketamine are similar to those for ECT”. The committee seem to be equating ECT and having intranasal Esketamine and this doesn’t seem right. The two interventions are entirely different treatments. Whilst effective, a large number of people will not be willing to have ECT because of stigma or concern about it. Also, resources needed for ECT, involve significant medical (including anaesthetist) and nursing time, stringent governance procedures including second opinions and safeguards. It doesn’t seem correct to be equating the two treatments in forming a judgement. The committee also felt that the treatment should have been compared to psychotherapy. The amount of evidence for psychotherapy in the acute treatment of TRD is low. Also, very frequently people simply cannot use it because of the thinking problems such as poor concentration and memory that TRD causes.

The NICE document states: “The evidence for Esketamine is limited in its generalisability to the NHS”. Their basis for saying this seems to be that NHS patients with TRD were not part of the trials that have shown the medication to be effective. Are we to think that people with TRD being treated in the NHS are fundamentally different to elsewhere in the world? The committee provide no evidence for this. They were also concerned that people with acute suicidal risk or with other conditions as well as depression (co-morbidity) had been excluded from the studies. Whilst important, this is common to trials of interventions in mental health, including those for psychological therapies. It would be interesting to know whether these criteria have been applied to assessing other treatments.


One aspect that appears to have been instrumental to the committee’s decision was the costs of the medication and the health economics modelling. Whilst we would all like more competitively priced medications (it is public money after all), the way the committee understood mental health and treatments was of interest. The committee felt “It is not appropriate to include an effect of Esketamine on mortality”. Their basis for this seems to have been that they didn’t accept treatment of TRD could reduce suicide risk. In doing so the committee appear to be refuting evidence indicating that a] TRD is associated with suicidal thinking and suicide; and b] that treating TRD will reduce the risk of completed suicide (or at least risk), a basic tenet of mental health care.

On costs, what was particularly striking, was the statement: The NHS commissioning expert advised that Esketamine would require a significant investment to become part of NHS clinical practice. The committee heard that adopting Esketamine would result in displacement of other mental health treatments because of its cost.” Should we assume that new mental health treatments cannot be sanctioned because they might displace other mental health treatments or need new investment? How does this fit with the continuous announcements of more money towards mental health treatment. The underlying assumption here is that if new treatments for TRD are available we cannot benefit from them, because they will need investment. This should be of concern to all.

Finally, there was no Psychiatrist on the NICE committee (at least from what can be seen on the minutes) and it is difficult to understand why. There seemed to be a representative of a very wide range of other healthcare professionals, but just not Psychiatrists. To my mind this shows. Whilst it may turn out to be NICE policy, that a specialist in the field is not allowed in the committee for fear that they may advocate for a treatment, this will sit as odd to many people in the field, including myself and the wider community.

There is an odd disconnect reading this appraisal document and the experiences and needs of people with TRD and clinicians working towards improving the mental health of this population, week in week out, up and down the country. People with TRD, their carers, and clinicians desperately need new and effective treatments for this condition and we should respond to this consultation document in whatever way we can. 

Other views can be found here

Conflicts of interest:

The views expressed here are not those of the University of Birmingham or Birmingham and Solihull Mental Health Trust. The author has received funding to attend educational events from Sunovion, Lundbeck and Janssen.