April 12, 2023

expert reaction to systematic review and meta-analysis comparing ECT and ketamine for major depressive episodes

A systematic review published in JAMA Psychiatry looks at the use of ketamine vs electroconvulsive therapy (ECT) for major depressive episodes.

Prof Andrew McIntosh, Professor of Psychiatry, University of Edinburgh and a member of the MQ Mental Health Research Science Council, said:

“Manon and colleagues considered whether Ketamine or ECT was more effective for the treatment of a ‘Major Depressive Episode’ in a newly published systematic review and meta-analysis of randomised controlled trials (RCTs) published today.

“ECT has long been used to treat people with severe or treatment resistant forms of depression, and the evidence from RCTs suggest that it is significantly more effective than placebo and more rapid and efficacious than antidepressants. Clinical trials have also found that the anaesthetic agent Ketamine is effective in more severe and treatment resistant forms of depression when given intravenously, but without the need to electrically induce a seizure. Whether ECT or ketamine is the best treatment for severe and treatment resistant forms of depression is not known. This new systematic review attempts to answer this important question in a systematic review and meta-analysis of RCTs of people with Major Depressive Episodes. The included RCTs typically enrolled people with depression managed in hospital or being referred for ECT. The findings of this review will be more relevant to people with severe and treatment resistant forms of depression.

“Menon and colleagues systematic reviewed published RCTs directly comparing Ketamine with ECT for ‘Major Depressive Episodes’. The 5 studies (of 278 depressed patients) included in the review had many methodological limitations and were judged by Menon and colleagues to be at high risk of bias. Across all studies, it was not possible to be sure whether ECT or ketamine was the more effective treatment, although the participants treated with ECT tended to do better than those treated with ketamine. Because of the high risk of bias, the authors then conducted a second analysis involving only two higher-quality RCTs. In this analysis, ECT outperformed ketamine in the treatment of depressive symptoms, and was associated with a 27% relative improvement in ‘response’ and a 43% improvement in remission.   

“These findings suggest that, in individuals with a major depressive episode that has been treated in hospital or considered for ECT, ECT may be more effective than ketamine. These conclusions should, however, not be accepted without a degree of scepticism. First, the meta-analysis findings were non-significant in the main (planned) analysis and all studies had significant methodological limitations. Some of these limitations (eg lack of blinding) were understandable: how does one perform blinding when one treatment (ECT) requires a general anaesthetic. Nevertheless, other difficulties (including the methods of randomisation) could be addressed in future studies. The number of participants included in this review was also relatively small. Just 211 patients were considered when only the two methodologically stronger trials were assessed.

“While the authors claim that the advantage of ECT over ketamine is small, the effect sizes in the main paper, and the supplement, suggest that the treatment differences are potentially clinically meaningful. For example, 85/113 patients treated with ECT responded (75.2%) compared to 68/116 on ketamine (58.6%). The frequency of headache, muscle pains and dissociation side effects also differed significantly between treatments, although other important side effects (e.g. cognition) did not. These results suggest that meaningful differences in efficacy and side effects may be found by future larger well-designed RCTs.

“The findings from this systematic review and meta-analysis are not robust enough to prompt changes in clinical practice. This is primarily due to the methodological limitations of the studies included in the review and their small sample sizes. There is certainly insufficient evidence to ‘swap’ ECT for intravenous ketamine in people with severe or treatment resistant depression based on this review, but there is remaining uncertainty about their true relative benefits.” 

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

“The study is conducted well. But there is one problem: most of the evidence is coming from one huge trial conducted in Sweden. I am familiar with its results, as I have seen the senior author present it. The other studies add small numbers of patients and the authors even present a sensitivity analysis after removing studies of poor quality, thus leaving only 2 studies and exposing even further the dependence of the results on one single study. The small studies should not be blamed for their size, as this is very difficult research to perform. On the other hand, the trends were in the same direction.

“I still think this is important research. It establishes the superiority of ECT against an active comparator (ketamine) which is very popular now and accepted to be quite effective.” 

Prof Allan Young, Director, Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, said:

“Major depressive episodes often do not respond to conventional antidepressants or psychotherapy.  Ketamine has been shown to help some treatment resistant depressed patients as has ECT.  Clearly the relative benefits of these two treatments need to be understood better but this review of the existing literature suggests that ECT may benefit some more than ketamine.  There is evidence that ketamine with ECT may add little extra benefit (https://pubmed.ncbi.nlm.nih.gov/28359862/) but much more work needs to be done to fully understand how these treatments fit best into the treatment pathway for major depressive episodes.  However, based on this evidence, ECT clearly still merits a place in the treatment pathway.”

Dr Rupert McShane, Associate Professor, Department Psychiatry, University of Oxford, said:

“ECT and ketamine are both potent treatments for depression.  This meta-analysis shows that they are, broadly speaking, equally as good as each other with perhaps a slight advantage for ECT.  Whether or not there is a difference depends on exactly how you define it and how you cut the data.  Despite the slight advantage for ECT in this analysis, the authors support using ketamine before ECT, especially in patients who are worried about the cognitive risks of ECT.   This seems sensible.  The trial by Ekstrand and colleagues from Lund, the largest and longest study, found that older patients did better with ECT, younger patients did better with ketamine and that 7% of patients receiving ECT complained of memory problems a year later.  The large ELEKT trial from the US is expected to report later this year and when that happens it may be safer to draw conclusions about comparative efficacy.”

Prof David Nutt, The Edmond J Safra Chair and Head of the Centre for Neuropsychopharmacology, Division of Brain Sciences, Dept of Medicine, Imperial College London, said:

“This is a fair analysis of the current evidence we have on ECT and ketamine in treating major depressive episodes. The authors conclusions are supported by the analysis. It would be ideal if all NHS trusts could offer both options to give patients some choice in their treatment options.”

‘Ketamine vs Electroconvulsive Therapy for Major Depressive Episode, A Systematic Review and Meta-analysis’ by name of first author et al. was published in JAMA Psychiatry at 16:00 UK time on Wednesday 12^th April.

DOI: 10.1001/jamapsychiatry.2023.0562

Declared interests

Prof George Kirov: “I have no interest to declare, but I run the ECT service in Cardiff.”

Prof Allan Young: “Employed by King’s College London; Honorary Consultant SLaM (NHS UK)

Deputy Editor, BJPsych Open

Editor of the Journal of Psychopharmacology

Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage

Consultant to Johnson & Johnson

Consultant to Livanova

Received honoraria for attending advisory boards and presenting talks at meetings organised by LivaNova.  Principal Investigator in the Restore-Life VNS registry study funded by LivaNova.

Principal Investigator on ESKETINTRD3004: “An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.”

Principal Investigator on “The Effects of Psilocybin on Cognitive Function in Healthy Participants”

Principal Investigator on “The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)”

UK Chief Investigator for Novartis MDD study MIJ821A12201

Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK)

No shareholdings in pharmaceutical companies.”

Dr Rupert McShane: “Former Chair, ECT and Related Treatments Committee, Royal College of Psychiatrists; I run a ketamine clinic and an ECT service.”

Prof David Nutt: “I act part time as chief research officer for Awaknlifesciences a company that offers ketamine treatment in the private sector.”

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