May 24, 2023

expert reaction to trial looking at ketamine versus ECT for nonpsychotic treatment-resistant major depression

Results from a trial looking at ketamine versus ECT for nonpsychotic treatment-resistant major depression have been published in the NEJM.

Professor Subodh Dave, Dean of the Royal College of Psychiatrists, said:

“ECT is a NICE-approved, evidence-based treatment option for those with severe mental illness that hasn’t responded to other treatments. We know that it can be lifesaving and, in most cases, improves patient outcomes. When ECT is being considered as a treatment choice, it is important that the patient is fully informed of its associated risks.

“It is important that we continue to explore the potential for new treatments, and we note the findings of this research with interest. There are early signs that ketamine may make a positive contribution to the treatment of people with severe mental illness that hasn’t responded to other treatments, but more research is needed, particularly around the maximum safe dose and frequency and longer term effects. 

“As ketamine is not currently licenced, we would also like to see a registry put in place for patients receiving this treatment, allowing for data collection across large numbers of patients.”

Prof Rupert McShane, Consultant Psychiatrist, Oxford Health NHS Foundation Trust; and Associate Professor of Psychiatry, University of Oxford, said:

“Ketamine is at least as good as ECT and causes less memory loss: this trial in people whose depression was bad enough to need ECT is unequivocal.  The results of this high quality, pragmatic study are remarkably similar to those of a previous Swedish study¹ of inpatients.

“A limitation of the study is that all participants knew whether they were having ECT or ketamine which means that their expectations could have influenced the results.  However, these expectations match what would have happened outside a clinical trial setting: blinding is not feasible in such studies.

“What does this mean for practice?  We badly need better treatments to help the most seriously ill people with depression.  The infrastructure needed to provide ECT is very similar to the infrastructure needed for IV ketamine.  The UK already has a network of 90 ECT clinics which treats about 2000 people a year.  These studies should now encourage Trusts and commissioners to work to develop their ECT clinics so that they can provide both of these options.

“We must not, however, be tempted to think that this is a panacea: depression is a disorder that returns.  Conventional antidepressants are taken regularly to prevent relapse.  Knowing when to stop maintenance treatment – whether with ECT or ketamine – is difficult and requires more research.  ECT will continue to be needed.  For example, the elderly, who were not well represented in this study, do better with ECT than ketamine; and this study did not treat patients with the most severe depression associated with delusions and hallucinations.

“As long as we keep in mind that managing maintenance treatment is a specialist business, and we develop a national data system to track ketamine use, we will be able to avoid the potential harm of ketamine abuse.”

1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9154276/

Prof George Kirov, Clinical Professor, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, said:

“The authors have conducted the largest comparison of ECT vs. Ketamine to date.  The results show that Ketamine infusions produced better outcomes, in contrast to previous trials.

“There is something odd about the results.  The remission rate in the ECT arm of the study was only 21.8% (on MADRS), by far the lowest remission rate reported for ECT that I know of.  One should expect at least 40% remission in ECT patients, while rates above 50% have been shown in most reports, and far higher for those with psychotic depression.  In comparison, Ketamine produced 37% remission rates, very similar to the previous reports.  The authors chose the less conservative criterion of “response”, i.e. 50% improvement on mood rating scales, as their primary outcome, which delivers better outcomes but is not the outcome usually used in ECT research where remission is the treatment aim.

“The explanation should be found in the type of patients included in the study.  There were no psychotic patients (ECT is most effective in psychotic depression), they were mostly outpatients (while ECT patients, in the UK at least, are mostly in-patients), they had capacity and were much younger (at least compared to the average ECT patient treated in the UK; older patients have higher remission rates with ECT).  There were very few patients with a melancholic type of depression, while just over half were rated as having “anxiety features”).  Patients were treated with right unilateral ultrabrief ECT, which might not be the most effective delivery method.

“It is clear that the population treated in this study is not representative of the typical population of ECT patients and perhaps not surprisingly, these patients did not do very well with ECT.  The remission rates on Ketamine were very similar to those in previous studies.  This looks like a population that is more likely to be referred for Ketamine therapy (non-psychotic and younger people).

“In this respect the study delivers an important message: patients who are younger, non-psychotic, with capacity and possibly those with anxiety features, (including those with suicidal ideation) could be considered for Ketamine therapy first, rather than ECT, while ECT should be reserved for the more severely ill, psychotic, elderly, or catatonic patients.”

Prof James Stone, Professor of Psychiatry, Brighton and Sussex Medical School; and Honorary Consultant Psychiatrist, Sussex Partnership NHS Foundation Trust, said:

“This is a well-designed multi-centre study comparing intravenous ketamine with ECT for treatment-resistant major depression.  The study found that intravenous ketamine was as effective as ECT in the treatment of severe depression.  It is of great interest because ECT is often the only option for patients with such severe depression that they put their life at risk through inability to eat or drink.  ECT is known to be an effective treatment in these circumstances, but carries a risk of potentially irreversible memory loss, as well as the risks associated with anaesthetic use.  Intravenous ketamine could be a safer alternative to ECT with a lower risk of side effects.  At present, intravenous ketamine has not been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK for the treatment of depression and is only used for this purpose on a limited basis in specialist centres.  Because of this, it is unlikely that intravenous ketamine will be offered as an alternative to ECT by many Mental Health Trusts in the UK.  The study does highlight that there is a problem with maintenance of response with both ECT and ketamine, and further work on maintaining the antidepressant effects – either through psychotherapy or other medications – is required.”

Dr Michael Bloomfield, UKRI Principal Clinical Research Fellow, Translational Psychiatry Research Group Head, and Consultant Psychiatrist, UCL, said:

“Severe depression can be a potentially disabling and life-threatening condition.  Whilst there are effective treatments for depression including medicines and psychotherapies (talking therapies), some patients with severe depression remain unwell despite having tried other treatments.  Electroconvulsive therapy (ECT) is an effective and potentially life-saving treatment for people with severe depression.  However, just as is the case with any other medical treatment, not everyone responds to treatment with ECT and ECT is not without potential side-effects.  Recent research has found that the anaesthetic medicine ketamine, when used in safe medical settings, is also an effective alternative treatment to ECT for people with severe depression.

“This well conducted study compared ketamine treatment to ECT and found that ketamine was not inferior to ECT.  Whilst further research is needed comparing these two treatments, this new study adds to the evidence that ketamine treatment should be considered as an additional treatment to be considered in patients with severe depression.  It is important to emphasise that people experiencing severe depression should not use recreational ketamine to try to self-medicate.  This is because of the need to have psychiatrists monitor response to treatment and risk of suicide, and also because the dose and purity of street ketamine can never be guaranteed in the same way that medical grade ketamine is.

“Although this study is a step forward in depression research, some patients continued to have severe symptoms despite treatment with ketamine or ECT.  It is therefore essential that we continue to develop new treatment approaches for depression and understand which treatments works best for whom.”

‘Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression’ by A. Anand et al. was published in the NEJM at 23:45 UK time on Wednesday 24 May 2023.

DOI: 10.1056/NEJMoa2302399

Declared interests

Professor Subodh Dave: “No conflicts to declare.”

Prof Rupert McShane: “I am in the immediate past Chair of the Royal College of Psychiatrists ECT and related treatments committee.  I have run an ECT clinic for the last 23 years.  I have also run a ketamine clinic for the last 14 years which has treated over 300 patients  Ketamine treatment service – Oxford Health NHS Foundation Trust.  I represented the RCPsych in their appeal against NICE’s rejection of esketamine nasal spray for treatment resistant depression appeal-decision (nice.org.uk).  I run an academic conference about ketamine Ketamine & Related Compounds International Journal Club & Conference (ketamineconference.org).”

Prof George Kirov: “I am ECT Lead in Cardiff&Vale Health Board and have been a member of the UK Committee for ECT and Related Treatments.”

Prof James Stone has worked with Janssen on trials of esketamine.  He founded the ketamine clinic at the Maudsley Hospital and has set up a pilot scheme for the use of ketamine in patients with depression in Sussex Partnership NHS Trust.  His statement reflects his own opinion and not that of Sussex Partnership NHS Foundation Trust or Brighton and Sussex Medical School.

For all other experts, no reply to our request for DOIs was received.