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expert reaction to draft NICE guidance on Esketamine nasal spray for treatment resistant depression

NICE have issued their draft guidance on Esketamine nasal spray for treatment resistant depression.


Dr Paul Keedwell, Consultant Psychiatrist, Cardiff University, said:

“A substantial number of individuals suffering from major depression fail to respond to two or more conventional antidepressants. Existing approaches to treatment resistance, including medication combinations, talking therapy, or ECT, often fail, or are unacceptable. New approaches are required to reduce the costs to society of protracted suffering, disability and chronic health care needs.

“The NICE refusal to recommend intranasal esketamine for the management of treatment resistant depression (TRD) will thus disappoint many sufferers in the UK who have failed to respond to existing treatments.

“The committee’s objection to its use in TRD appears to be largely based on cost rather than lack of effectiveness.

“Esketamine is an isomer of ketamine made by Johnson and Johnson. The drug is expensive, and it could be argued that ordinary ketamine, which has been prescribed for decades in various forms as an analgesic, is just as effective in treating depression. However, clinical trials are required to demonstrate the safety and effectiveness of any drug for a new indication, and such trials are also expensive. The costs of any new treatment tend to reduce over time.

“While it is an expensive treatment, the additional costs incurred with any promising new medication must be compared to the financial burden of persisting depression. Furthermore, the costs of acute treatment with the drug are unlikely to exceed those of ECT, a commonly used treatment in this group of patients. Ketamine could replace ECT for TRD going forward.

“While the committee was advised that the set up costs for ketamine clinics would be high, this is not necessarily the case. In Oxford, for example, ketamine has been prescribed for patients within existing ECT facilities, and this is likely to be the model of care, at least initially. Moreover, the intranasal preparation is easier to administer then ECT, and is relatively safe.

“Meanwhile, the guidance downplays the therapeutic potential of esketamine in this difficult to treat population. Although ketamine (or its isomer) is not a panacea, for those who respond, they improve dramatically quickly (in hours, compared with weeks or months), and it seems that they are more likely to go in to complete remission. Partial responders tend to remain quite disabled.

“Another consideration is the emerging evidence that ketamine rapidly quells suicidal thoughts – an effect that could not only reduce levels of self-harm but could also reduce dependence on costly emergency services and crisis admissions to hospital. Although esketamine has not been evaluated in this regard, more information is needed.

“The benefits of ketamine and esketamine do not usually persist beyond days. Repeat doses are therefore required to sustain benefit. However, it seems that, provided doses are given no more than the recommended twice per week, tolerance does not develop. Research at Oxford over the past 10 years has not revealed any evidence of drug-seeking or dose escalation during long term treatment. 

“In someone who’s life is transformed by this drug, the big ethical question is when do you stop it, if ever? Concerns raised by the committee about the potential harms of halting its prescribing need to countered by the observation that many individuals are “dependent” on drugs to keep them well – consider bipolar patients, diabetics, asthmatics and epilepsy sufferers. There is no evidence thus far of a ketamine withdrawal syndrome, only evidence of relapse of depression.

“These guidelines are preliminary. It is hoped that if and when more evidence emerges of the efficacy and cost effectiveness of esketamine the NHS might add this extra weapon to its armoury for managing TRD. For the time being it will be restricted to research centres only.”


Prof David Curtis, Retired Consultant Psychiatrist and Honorary Professor at UCL and QMUL, said:

“This new guidance from NICE seems very sensible. Many psychiatrists have been concerned at the lack of evidence that esketamine is really a helpful treatment for depression. There are also unanswered questions about the extent to which it might cause unwanted effects and how it could be safely used in practice. On this occasion NICE is quite correct to wait for additional information, including the results from further research, rather than allowing esketamine to be used in routine clinical practice.”


Dr Sameer Jauhar, Honorary Consultant Psychiatrist and Research Fellow, Institute of Psychiatry Psychology & Neuroscience, King’s College London (IoPPN), said:

“NICE have recommended that nasal esketamine plus another antidepressant (SSRI or SNRI) is not used for the treatment of moderate to severe depression in people with treatment-resistant depression. It is important to note that treatment-resistant depression here is defined as lack of response to two or more antidepressants.

“Their reasoning is that there is lack of evidence. Specifically, they state there is a lack of comparison to other drug treatments, used in combination with conventional antidepressants and electroconvulsive therapy (ECT). They also state that the available evidence did not include psychological therapies. They bring up the lack of longer-term studies examining maintenance treatment. Probably of most relevance they bring up the significant costs associated with esketamine.

“What is one to make of this?

“The efficacy data for esketamine is actually quite reasonable, certainly compared to other treatments that NICE has evaluated. NICE are entirely correct regarding the lack of evidence comparing esketamine to adjunctive treatments, such as lithium or ECT- though pharmacologically the mode of action of esketamine is completely different, and the evidence for esketamine appears better than that for adjunctive drug treatments.

“Furthermore, there will be a number of people with treatment-resistant depression who will not wish to have ECT, and who may have significant side-effects to other adjunctive drugs, such as lithium.

“In terms of psychotherapy, there are very few trials showing effectiveness or lack of effectiveness in this patient group (who have not had response to two or more antidepressants) -and the existing evidence is generally of low quality. There is only one RCT I am aware of examining CBT, and one of long-term psychodynamic psychotherapy.

“The field- and patients- badly need high quality psychotherapy trials in this population of people, though if one keeps to the evidence, it is hard to understand NICE’s reasoning here.

“The crux of the matter-to my mind- are the latter points regarding continued use, benefit over the longer term, and associated economic costs.

“The modelling NICE uses has to be transparent- and it is, and this seems to be the most relevant argument for not sanctioning the use of esketamine here.

“In summary, the decision-making here appears based on longer-term use and demonstrable cost benefit.

“There will be similar compounds, with novel modes of action, becoming available over the coming years, and this patient group badly needs access to effective treatments, which will – in time- be evaluated by NICE.”


* NICE draft guidance on ‘Esketamine for treating treatment-resistant depression’ was published at 00.01 UK time on Tuesday 28th January. 


Declared interests

Dr Paul Keedwell:  “No declarations of interest.”

Prof David Curtis: “I have no conflicts of interest”

Dr Sameer Jauhar: “I did an editorial for esketamine for the BMJ. No Johnson and Johnson funding. I am also co-investigator on a research study in psychosis, funded by Alkermes. King’s College, London, has received fees from Lundbeck for lectures I have given on psychosis.”

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