OPEN LETTER, COPIED TO ALL CONCERNED WITH THE ECT-KETAMINE STUDY, INCLUDING NATIONAL INSITUTE FOR HEALTH RESEARCH, NATIONAL RESEARCH ETHICS SERVICE, AND PARTICIPATING NHS TRUSTS AND UNIVERSITIES

 

June 19, 2014

 

We are a group of nine mental health experts, including four psychiatrists and affiliates of five Universities. We are writing to you (as a funder, an ethics committee or a NHS Trust) to raise concerns about, and recommend suspension and investigation of, the ‘Ketamine augmentation of ECT to improve outcomes in depression’ study.

{Funder Ref Number: EME-10/90/04 REC Ref: 12/NW/0021 EudraCT Number: 2011-005476-41 ISRCTN Ref: ISRCTN14689382 CTA Ref: 23148/0004/001-0001 Ketamine-ECT Study Protocol – Version 4.2 (03.07.2013)}.

 

When several mental health staff in the Manchester area started to contact some of us, from August 2013, with concerns about this study, we contemplated writing to you all at that stage to immediately pass on those concerns, as they seemed legitimate and significant.

 We decided instead to write to Professor xxxxxxxxxx (and his co-investigators) raising our concerns and asking for further information. Our first correspondence with him was on 29^th October, 2013.

 Professor xxxxxxxxxxx declined, on two separate occasions, to send us key documents, including the Ethics Application and the Funding Application, necessary for us to make an informed decision about what our professional/ethical responsibilities were with regard to whether to raise our concerns with yourselves.

 This necessitated our making a Freedom of Information request, on 19^th November, 2013.

 Having finally received all the information necessary for us to make an informed decision we made a final attempt to resolve the issues without having to involve Ethics Committees, Funders and NHS Trusts.

 There follows a complete copy of the email we sent to Professor xxxxxxxxxxxx and his team, on March 14, 2014.

 

 

Dear xxxxxxxx and colleagues

We are sorry about the long delay in responding since receiving the information we requested via the FOI Act.

There was a large amount of information and we needed to read it very carefully.

Having done so, we have the following four concerns (and one comment).

 

1. EFFECTIVENESS OF ECT

The facts of the matter, although open to interpretation like all bodies of research, are as follows (Read and Bentall, 2010, pp. 335-337):

Of the ten studies that have ever compared ECT to placebo (simulated ECT [SECT]) five have found no difference during the treatment period. Of the other five, four either invalidated their findings by administering ECT to the SECT group or found differences only for subgroups of patients and/or differences perceived only by one group of raters but not by other groups of raters.

More importantly, there has never been a single study that has shown that ECT is superior to SECT at follow up (ranging from 1 to 6 months). None of the eight meta-analyses published have claimed superiority beyond the end of treatment (p. 337)

Furthermore, despite repeated claims by ECT proponents about the ‘life-saving capacity’ of ECT, no study has ever found that ECT prevents suicide more effectively than SECT.

Under these circumstances, your claim that ECT is effective, in the study protocol, the ethics application, the funding application and the Participant Information Sheet [PIS], is incorrect and misleading. Your statements actually go well beyond the claim that it is effective. You repeatedly use phrases like ‘the most effective antidepressant treatment’, ‘a large therapeutic effect against sham treatment’ and even ‘it is widely recognised as the most effective treatment antidepressant treatment’ {italics added}. On p. 8 of the Ethics Application you state ‘ECT is recommended as a possible treatment for this group of patients by NICE because it is the most effective treatment available’. We can find no such statement in the NICE guidelines.

The most concerning location of these misleading claims is the PIS, where you write ‘Electroconvulsive Therapy (ECT) is the most effective treatment for severe depression and it can be life-saving’. We believe these two false statements to potential participants are unethical, because they subvert the participants’ ability to give informed consent.

(Statements such as ‘psychological treatment outcomes are extremely disappointing’ [Study Protocol p. 5] are equally biased and misleading but are not relevant to the content of the PIS)

 

2. SAFETY OF ECT

Here we must commend you for the many statements acknowledging the sometimes long-lasting cognitive dysfunction caused by ECT, which is often denied or minimised by other ECT proponents.

However, your statement in the study protocol (p 1) that ‘otherwise ECT is a very safe and effective treatment’ ignores multiple studies showing that ECT involves a small but significant mortality risk, most frequently via cardiac arrest or stroke (Read & Bentall, 2010, pp. 341-342). We believe that ECT recipients, whether or not they are involved in a study, should be informed of that risk.

 

3. EFFECTIVENESS OF KETAMINE

Your claims of the effectiveness of ketamine in treating depression, which form a significant part of the rationale for your study, seem premature and exaggerated. For example, you claim, in the Study Protocol, that ‘One of the most exciting new findings in the treatment of depression has been the replicated, very rapid antidepressant effect after a single dose of intravenous ketamine alone’. However, a recent review concluded: “Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy…” (Mathew et al., 2012). Another review highlights: ‘… the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks’ (Rot et al., 2013).

There does not appear to have been a single study demonstrating that a single dose of ketamine has any long-term benefit for depressed patients. In fairness, you acknowledge that ‘relapse occurs very rapidly on stopping treatment’ (Study Protocol, p. 2).

We conclude that the statement in the PIS, that ‘… ketamine is believed to work together with the effect of ECT to improve mood’ is, without a qualifier such as ‘in the very short-term’ or ‘temporarily’, misleading to potential participants who are seeking a solution to their depression.

 

4. SAFETY OF KETAMINE

Ketamine is a ‘street drug’ which, while undoubtedly producing a ‘high’ (seen as an ‘antidepressant’ effect by some psychiatrists), has multiple significant adverse effects. In light of these effects the ACMD recommended, in 2013, that the government reclassify ketamine to become a Class B drug. On 12 February 2014 the Home Office announced they would follow this advice.

We note that the PIS acknowledges that among ‘the most common side effects’ are ‘hallucinations, vivid dreams, nightmares…’ etc. (p. 3). We also note, however, that you are accurately inform potential participants that you are using a lower dose than used when ketamine is used as an anaesthetic. Nevertheless your claim in the PIS that you ‘expect very few side effects’ is not really an evidence-based expectation. Earlier in the PIS (p. 2) you argue that ‘by the time you wake up from the ECT treatment the effect of ketamine will have mostly or completely worn off’. As you know, the immediate post ECT period almost invariably involves a high level of confusion and disorientation and anything that potentially exacerbates, even minimally, confusion and distress during that period should be avoided, and certainly not minimised to potential participants. Furthermore, your argument that the effects may have worn off by the time consciousness is regained, is irrelevant to vivid dreams and nightmares.

 

Mathew, S., et al. (2012). Ketamine for treatment-resistant unipolar depression. CNS Drugs, 26, 189–204.

Read, J. & Bentall, R. (2010). The effectiveness of electroconvulsive therapy: a literature review. Epidemiology and Psychiatric Sciences, 19, 333-347.

Rot, M., et al. (2012). Ketamine for depression: where do we go from here? Biological Psychiatry, 72, 537–547.

 

RECRUITMENT

From the data provided to us we calculate that in some locations there has been an increase in the number of people receiving ECT since the study commenced (most notably an 80% increase in the Manchester site). However, other sites have seen reductions and overall there is not an increase. So the increases in some locations, although quite large in some instances, may well be accounted for by random variation.

 

On the basis of the points raised above we request that you:

1. Amend the PIS from ‘Electroconvulsive Therapy (ECT) is the most effective treatment for severe depression and it can be life-saving’ to ‘Electroconvulsive Therapy (ECT) has been found to temporarily improve mood for some depressed people’.

 

2. Add to the PIS ‘ECT has a small increased risk of death, usually from heart failure or stroke’

 

3. Add a qualifier such as ‘in the very short-term’ or ‘temporarily’ to the PIS statement that ‘… ketamine is believed to work together with the effect of ECT to improve mood’.

 

4. Delete from the PIS ‘We therefore expect very few side effects using ketamine in this study and previous experience is that side effects don’t seem to be troublesome when it is used in this way’.

 

We will be contacting you in six months to ask for an update on the number of patients referred for ECT at the different sites.

As researchers ourselves we realise that these requests may cause additional work and, perhaps, irritation. Please be assured that our concerns are not raised – as suggested in the minutes of your Trial Management Group meeting (5.11.13) – because we are ‘hostile’ or ‘against the use of ECT’ (although the latter may apply to some of the signatories) but because we are genuinely concerned – as we assume you all are – about the wellbeing and safety of potential participants to your study, and about the importance of informed consent in all research. We would expect others to raise similar concerns about our own studies if we had inadvertently missed or minimized risks.

 

Please acknowledge receipt of this email and let us know whether you think a month is a reasonable time frame to consider and respond to our requests.

 

 

Professor xxxxxxxxxxxxx has subsequently agreed to only partially address only one of our four requests.

Specifically he has, rather than change the PIS from ‘Electroconvulsive Therapy (ECT) is the most effective treatment for severe depression and it can be life-saving’ to ‘Electroconvulsive Therapy (ECT) has been found to temporarily improve mood for some depressed people’,  changed it to ‘Electroconvulsive Therapy (ECT) has been found to be the most effective short-term treatment for severe depression in clinical trials’  This is definitely less misleading but remains potentially misleading nevertheless as it implies, to vulnerable potential participants, that ECT is the most effective treatment, which is certainly debatable.

He has declined our three other requests to change what we believe to be misleading statements about the safety of ECT and about the safety and efficacy of ketamine.

We feel we have now exhausted our efforts to encourage Professor xxxxxxxxx and his team to stop making what we believe to be misleading statements to potential participants.

Having carefully considered the issues over many months now, it is our shared opinion that this study may be unethical because it appears to be making inaccurate statements about the risks and benefits to people who are depressed, some of them severely/suicidally depressed (if the usual criteria for ECT are being applied) and who may therefore feel desperate enough to accept any treatment that is offered to them.

 

We ask, therefore, that you suspend ethics approval, funding and Trust support/permission for this trial while you investigate whether our concerns are warranted.

We have, of course, informed Dr xxxxxxxxxxxx and his co-researchers that we are writing to you. We have also made it clear to them that although we have concerns about the study as a whole we would be satisified if they made the changes to the PIS that we have requested.

We realise that you will need time to consider our concerns and recommendation. In due course please respond to (or request further information from) Professor John Read (readj@liv.ac.uk) who will pass on your response to the group as a whole. Thank you for taking the time to consider this complex set of issues.

 

Professors John Read and Richard Bentall  Clinical Psychology, University of Liverpool

 

Dr Pat Bracken  Consultant Psychiatrist -West Cork Mental Health Service

 

Dr Adam Danquah Clinical Psychologist Pennine Care NHS Foundation Trust

 

Jacqui Dillon Chair, Hearing Voices Network – UK

 

Dr Suman Fernando  Consultant Psychiatrist (retired) – London Metropolitan University

 

Dr David Harper  Clinical Psychologist, University of East London

 

Dr Philip Thomas  Psychiatrist, University of Bradford

 

Dr Sami Timimi  Consultant Psychiatrist – Lincolnshire Partnership Foundation NHS Trust & Lincoln University