Ketamine: “lost in translation?”

Last month I shared a BMJ Editorial on Ketamine by Dr Sameer Jauhar and Dr Paul Morrison. Since then there have been a number of published BMJ responses and replies. These are all shared below [in date order]:

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28 September 2019
Varun K Jaitly, Consultant Anaesthetist with an interest in Chronic Pain, Wrightington Wigan and Leigh NHS Foundation Trust, Department of Anaesthesia, Royal Albert Edward Infirmary, Wigan Lane, Wigan.

As someone who has been prescribing low dose sublingual/oral ketamine for chronic pain since 2000, I welcome the recent increased interest in this drug [1] [2]. I have published on this experience [3], and whilst numbers are small, my long term observations appear to show that at low doses there does not appear to be any easily observable harm stemming from the use of ketamine. Reassuringly, in recent years, when there have been interruptions in Ketamine supply, patients have not reported an abstinence syndrome. I also welcome the calls for a multiagency register to track use (including off-label use) of esketamine and ketamine and wish to draw attention to a prototype proof of concept runtime version of an Access based registry (and accompanying notes and instructions), which is copylefted and could be used as the basis of such a register [4] [5] [6].

[1] https://blogs.bmj.com/bmj/2019/07/26/rupert-mcshane-a-drug-not-a-miracle…
[2] Jauhar Sameer, Morrison Paul. Esketamine for treatment resistant depression BMJ 2019; 366 :l5572
[3] Jaitly Sublingual Ketamine in chronic pain : Service evaluation by examining over 200 patient years of data
Journal of Observational Pain Medicine – Volume 1, Number 2 (2013) ISSN 2047-0800 (open access) https://issuu.com/munglani/docs/joopm_vol1_ed2_2013
[4] Background notes : https://drive.google.com/file/d/1Vz914BSG1d5rUPS-Pw3oSIzKK0BqGMMO/view?u…
[5] Brief instruction set: https://drive.google.com/file/d/0By9yu1O6Wr-hU2xEaXhXTVVBUXJnTzhWRW1xNjd…
[6] Runtime Version of Access database: https://drive.google.com/file/d/1Vva9o0b_TpiF40KNdjGlo8ktbu6r-I-N/view?u…

Competing interests: Over the years I have attended meetings and had lunches/dinners sponsored by a range of pharmaceutical firms and equipment manufacturers.I have also lectured on and written about the use of Ketamine in chronic pain.

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3 October 2019
Peter C Gøtzsche, Michael P Hengartner, James Davies, John Read, Anne Guy, Sami Timimi and Peter Kinderman, all from the Council for Evidence-based Psychiatry

Esketamine for depression? No thanks, please
Sameer Jauhar’s and Paul Morrison’s praise of esketamine (1) is not deserved. Common sense tells us that a drug cannot possibly have a dramatic effect on depression within the first day of treatment unless something is terribly wrong.

Ketamine seems to work mainly through stimulation of opioid receptors. In a cross-over trial of 12 very severely depressed patients (Hamilton score of 27.4), a colossal “effect” was observed the first day post-infusion of ketamine + placebo, a reduction of 22.3, which corresponds to an effect size of 7.0 (2). With ketamine + naltrexone (an opioid antagonist), the reduction was only 5.6, and the difference to the other condition was 16.7, or an effect size of 2.5. As prolonged opioid use can cause depression (3), long-term use of esketamine might increase the risk of chronic depression.

In comparison, meta-analyses of depression pills have shown effect sizes of only 0.2 to 0.3, and not after one day, but after weeks (4,5).

Jauhar and Morrison mention dissociation as a harm of esketamine. Dissociative drugs are hallucinogens, which produce feelings of detachment from the environment and self. No wonder they write that ketamine was initially used in psychiatry as a drug model of psychosis!

Jauhar and Morrison write that the effects of ketamine and esketamine fit with “modern theory that depression emerges from an impoverished neural network rather than serotonin deficiency.” It is not clear what they mean by this, and newness does not make a theory any more reliable than the discarded hypothesis about a chemical imbalance causing depression. Further, there is no scientific support for long term use, yet such use is now common in US private clinics following FDA approval.

We are convinced it could be demonstrated that alcohol, morphine, cocaine, ecstasy and MDMA also exert an “effect” on depression within the first day, but that does not make these substances acceptable. They may have acute euphoric effects, but frequent and long-term use often results in dysphoric mood states.

Jauhar and Morrison write that ketamine is widely used as a street drug, but that the risk of esketamine being so used seems low, given its high cost. We do not agree. Ketamine ranks highly on the list of commonly abused substances (2), and the price of a narcotic cannot prevent widespread abuse.

The dream of a quick fix for depression must stop.

1 Jauhar S, Morrison P. Esketamine for treatment resistant depression. We should cautiously welcome this new therapeutic option. BMJ 2019;366:l5572.
2 Williams NR, Heifets BD, Blasey B, et al. Opioid receptor antagonism attenuates antidepressant effects of ketamine. Am J Psychiatry 2018;175(12):1205–15.
3 Mazereeuw G, Sullivan MD, Juurlink DN. Depression in chronic pain: might opioids be responsible? Pain 2018;159(11):2142-5.
4 Jakobsen JC, Katakam KK, Schou A, et al. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC Psychiatry 2017;17:58.
5 Munkholm K, Paludan-Müller AS, Boesen K. Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis. BMJ Open 2019;9(6):e024886.

Competing interests: No competing interests

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6 October 2019
Sameer Jauhar, Senior Research Fellow, Consultant Psychiatrist and Paul Morrison, King’s College, London, South London and Maudsley NHS Foundation Trust, IoPPPN, King’s College, Denmark Hill Campus

Lost in translation(al neuroscience)?
We thank Gøtzsche et al for their comments regarding our Editorial [1], though do need to correct a number of erroneous assertions, that appear related to ideology as opposed to basic principles of clinical medicine, neuroscience and pharmacology.

Gøtzsche et al’s argument loses internal consistency as early as the second paragraph. They write that a drug cannot have a rapid, “dramatic” effect on depression (according to “common sense”) yet contradict themselves by citing data which, in their own words, shows that ketamine has a rapid, “colossal” antidepressant effect.

They state that “ketamine seems to work mainly through stimulation of opioid receptors”, citing a study where naltrexone was added to ketamine and attenuated its antidepressant effects [2]. Ketamine is an acknowledged non-competitive NMDA receptor antagonist [3]. Whilst the naltrexone blocking study is interesting, all it indicates is that ketamine may have downstream effects on this system. The extrapolation that ketamine can cause depression because opiates may cause chronic depression is illogical – the pharmacology of both compounds is fundamentally different.

Having appeared to cede on the question of efficacy, Gøtzsche et al pour cold water on the ketamine effect itself, arguing that it is not genuine anti-depression per se, but acute euphoria which is being measured. They pursue an odd strategy, apparently naïve to basic molecular pharmacology, by lumping ketamine, alcohol, morphine, cocaine, ecstasy and MDMA (sic) together in a common class of acute euphoriants. Having done so, they speculate that the whole class, ketamine included, masquerade as antidepressants during acute euphoria, but reveal themselves over the longer-term as harmful, addictive, dysphoric drugs. This is the basis of their appeal that the development of ketamine as a “quick fix for depression must stop”.

When research evidence is taken into account, Gøtzsche et al’s argument falls apart at the behavioural, clinical as well as the molecular level. For example, Berman and co-workers showed that after a 40-minute infusion, the antidepressant effects of ketamine actually increased over the course of the next 3 days [4]. In another study, Murrough and colleagues gave a series of 40-minute infusions and were able to extend the antidepressant effect of ketamine to 2½ weeks beyond the final infusion [5]. The trials cited in our Editorial also show continued separation from placebo, over the course of the acute trials. These findings refute Gøtzsche et al’s claim that the behavioural pharmacology of ketamine follows an acute-euphoria/chronic-dysphoria structure, rather than being genuinely antidepressant. Murrough’s group went on to conduct a randomised trial which compared the putative antidepressant effects of ketamine with midazolam infusions, the latter serving as an active placebo. (Incidentally, midazolam comfortably fulfils the membership criteria for Gøtzsche et al’s acute-euphoric/chronic-dysphoric class.) The main finding, in a sample of 73 treatment resistant patients, was that ketamine markedly outperformed midazolam as an antidepressant [6]. Depression scores as rated by the MADRS at 24-hours post-infusion were 8 points lower in the ketamine group. Clinically, it is difficult to understand how Gøtzsche et al suggest alcohol could have similar acute effects to those seen in ketamine trials – clinicians are well aware that acute alcohol use is a risk factor for suicide in people with mood disorders [7], whilst ketamine has been shown to reduce suicidality [8].

Clearly Gøtzsche et al’s conception of a general class of addictive acute-euphoric/chronic-dysphoric drugs, in which all psychoactive molecules can be tarred with the same brush is too simplistic.

We are slightly surprised that Gøtzsche et al disagree with our suggestion that esketamine is less likely to be abused, on account of its cost compared to ketamine. They state, “the price of a narcotic cannot prevent widespread abuse.” There is no citation given, and evidence from the US opiate crisis suggests a relationship between cheaper heroin, availability and heroin-related overdoses, ie market dynamics do affect use of “narcotics” [9].

It is the case that Gøtzsche and co-critics have been well-publicised in expressing organised antipathy towards the range of physical treatments in psychiatry, including monoamine based anti-depressants, anti-psychotics and ECT [10,11]; their criticism of ketamine is by no means unique. Indeed, they go much further by arguing that psychiatric syndromes such as major depression don’t actually exist. Instead they appear to conceptualise a more pervasive “distress” which arises from Western-style economics and early abuse. Gøtzsche and co-critics appear to regard neuroscience as largely irrelevant for understanding psychological distress, and typically espouse socio-political explanations and interventions [12,13].

Certainly, the views of Gøtzsche and co-critics are useful in making psychiatry question itself. That said, the downsides of ketamine as a treatment for depression have already been factored in, as we made clear in our Editorial. Gøtzsche et al provide nothing new in terms of downside – the potential for misuse/addiction is well recognised, and the challenge, as in any other area of medicine is to mitigate against downside. In contrast to the views of Gøtzsche et al. it is clear that many patients with hitherto stubbornly resistant depression have benefitted from treatment with ketamine, when all other approaches have failed. To deny those patients an effective therapy, and to “stop” the further refinement of glutamate based anti-depressants seems very unfair, particularly as the objections to ketamine appear to stem from an ideological framework that doesn’t appear to be acquainted with (and/or acknowledge) the science of pharmacology at a behavioural, clinical or molecular level.

References:
1 Jauhar S, Morrison P. Esketamine for treatment resistant depression. BMJ 2019;366:l5572. doi:10.1136/bmj.l5572
2 Williams NR, Heifets BD, Blasey C, et al. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am J Psychiatry 2018;175:1205–15. doi:10.1176/appi.ajp.2018.18020138
3 Hirota K, Lambert DG. Ketamine: its mechanism (s) of action and unusual clinical uses. British journal of anaesthesia 1996;77:441–444.
4 Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47:351–4. doi:10.1016/s0006-3223(99)00230-9
5 Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 2013;74:250–6. doi:10.1016/j.biopsych.2012.06.022
6 Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013;170:1134–42. doi:10.1176/appi.ajp.2013.13030392
7 Sher L, Oquendo MA, Richardson-Vejlgaard R, et al. Effect of acute alcohol use on the lethality of suicide attempts in patients with mood disorders. J Psychiatr Res 2009;43:901–5. doi:10.1016/j.jpsychires.2009.01.005
8 Wilkinson ST, Ballard ED, Bloch MH, et al. The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis. Am J Psychiatry 2018;175:150–8. doi:10.1176/appi.ajp.2017.17040472
9 Unick G, Rosenblum D, Mars S, et al. The relationship between US heroin market dynamics and heroin-related overdose, 1992-2008. Addiction 2014;109:1889–98. doi:10.1111/add.12664
10 Gøtzsche PC. Deadly psychiatry and organised denial. Art People 2015.
11 Read J, Cunliffe S, Jauhar S, et al. Should we stop using electroconvulsive therapy? BMJ 2019;364:k5233. doi:10.1136/bmj.k5233
12 Davies J. Cracked: Why Psychiatry is Doing More Harm Than Good
13 Read J, Mosher LR, Bentall RP Models of Madness: Psychological, Social and Biological Approaches to Schizophrenia (The International Society for Psychological and Social Approaches to Psychosis Book Series)

Competing interests: SJ is co-investigator on a research study in psychosis, funded by Alkermes. King’s College, London, has received fees from Lundbeck for lectures SJ has given on psychosis.

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8 October 2019
Zekria Ibrahimi, psychiatric patient, West London Mental Health Trust, Wellcome Library

Esketamine- related to a drug of abuse- may be producing a new psychic state rather than a ‘cure’
Joanna Moncrieff’s theory is that psychiatric drugs- anti-depressants or anti-psychotics- are not producing any cure for a putative chemical imbalance in the brain, but rather are themselves creating an altered mental state, if not a dopamine-driven ‘high’, then a flattened emotional response that some agitated patients may actually prefer. The weekly or monthly depixol or risperidone depot in the out-patients’ clinic, given by a nurse, seems to provide the patient with an impression of being looked after, in a scientific setting. The old insulin shock treatment was intrinsically not therapeutic, but it gave the appearance of an advanced procedure to ‘reassure’ the patient. In psychiatry, one could say that placebo is king.

The fact that esketamine is related to a drug of abuse (ketamine) would seem to confirm Moncrieff’s ‘drug-centred model’. There is a fashion nowadays for using street drugs such as Ketamine and LSD in a framework of psychiatric care. Of course, a drug like LSD was employed in psychiatric research long ago (2).

Cynically, one might refer to the cost of Esketamine and the expense of monitoring it (as with bloods for clozapine and agranulycytosis). Is Esketamine another example of Big Pharma leaping onto a fashionable psychiatric bandwagon- that of ‘cool’ street drugs in the guise of possible therapies?

References:
(1) The Myth of the Chemical Cure. A Critique of Psychiatric Drug Treatment. Joanna Moncrieff. Palgrave Macmillan. 2008
(2) Acid. A New Secret History of LSD. David Black. Vision Paperbacks. 2001

Competing interests: No competing interests

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11 October 2019
Peter C Gøtzsche, Michael P Hengartner, James Davies, John Read, Anne Guy, Sami Timimi and Peter Kinderman, all from the Council for Evidence-based Psychiatry

In their reply, “Lost in translation (al neuroscience)?,” Sameer Jauhar and Paul Morrison use straw men, such as alleging, incorrectly, that we believe morphine, alcohol and MDMA constitute one drug class (1). They also falsely state that we are driven by ideology; that, oddly, we argue that depression doesn’t exist; and that we have expressed “organised antipathy” towards various psychiatric treatments including antipsychotics and ECT. Some of us have explained, based on randomised trials and observational studies, why antipsychotics and ECT seem to do more harm than good (2,3). The general public agrees with us (4). This is not ideology or antipathy but simple fact.

Jauhar and Morrison cite a study where seven patients randomised to intravenous ketamine or saline were followed up for 72 hours (5). Another study they cite was a mess (6). It involved 24 patients who got up to 6 intravenous infusions of ketamine administered open-label three times a week over a 12-day period. Only participants meeting response criteria were monitored for relapse. At the same time, some participants took part in a placebo-controlled study of venlafaxine. Seventeen of the 24 patients responded to ketamine with a rapid decline in depressive symptoms. However, 13 of the 17 responding patients relapsed a median of 18 days after the last infusion. We do not know which other treatments the 4 patients who did not relapse had received. A third study they cite compared depressive symptoms only 24 hours after treatment with esketamine or midazolam infusions (7).

In a 2018 study they did not cite, where 68 patients were randomised to intranasal esketamine or placebo, there was no difference between the two groups by day 25 in either depression scores or suicidal risk (8). The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.

Based on the references Jauhar and Morrison provide it seems that they think results after a few days or a couple of weeks are sufficient evidence and that results beyond this should be ignored. However, short-term results cannot provide a rational basis for treatment recommendations for depression. As we do not know whether esketamine is more likely to benefit than to harm those with resistant depression, this drug should not be used in clinical practice but only as an experimental drug in randomised trials of adequate length, with long-term follow up, and with patient relevant outcomes. It is not enough to simply render the patients acutely euphoric with a hallucinogenic substance.

1 Jauhar S, Morrison P. Lost in translation(al neuroscience)? BMJ 2019 Oct 6. https://www.bmj.com/content/366/bmj.l5572/rapid-responses.
2 Gøtzsche PC. Deadly psychiatry and organised denial. Copenhagen: People’s Press; 2015.
3 Read J, Bentall R. The effectiveness of electroconvulsive therapy: a literature review. Epidemiol Psichiatr Soc 2010;19:333-47.
4 Jorm AF, Korten AE, Jacomb PA, et al. ”Mental health literacy”: a survey of the public’s ability to recognise mental disorders and their beliefs about the effectiveness of treatment. Med J Aus 1997;166:182-6.
5 Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47:351–4.
6 Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 2013;74:250–6.
7 Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013;170:1134–42.
8 Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry 2018;175:620-30.

Competing interests: No competing interests

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11 October 2019

Sameer Jauhar, Senior Research Fellow, Consultant Psychiatrist and Paul Morrison, King’s College, London, South London and Maudsley NHS Foundation Trust, IoPPPN, King’s College, Denmark Hill Campus

Response to Moncrieff & Horowitz: Evidence Based Medicine or A Brave New World?

Sameer Jauhar, Senior Research Fellow, Consultant Psychiatrist and Paul Morrison, King’s College, London, South London and Maudsley NHS Foundation Trust, IoPPPN, King’s College, Denmark Hill Campus

At high risk of bias?

Gøtzsche et al state, “Some of us have explained, based on randomised trials and observational studies, why antipsychotics and ECT seem to do more harm than good (2,3). The general public agrees with us (4). This is not ideology or antipathy but simple fact.”

They cite Gøtzsche’s book [1] and a narrative review by Read and Bentall [2]. It should be noted that the latter review contradicts the findings of a Lancet meta-analysis by the UK ECT Review Group (with the same corpus of studies available) [3]. On examining the studies included by Read and Bentall, the reason for this is inclusion of old, poorly controlled studies which did not test primary outcomes specified in the review. Studies included had numbers as low as 4 and 12, and were reported as non-significant (with no inferential statistics), without reporting sample size.)

The study cited to show the public agree that psychiatric treatments do not work is from 1997, though Gøtzsche et al neglect to mention the same sample of people rated vitamins and special diets as more helpful than antidepressants and antipsychotics. We do not share this opinion, and neither did the study authors, who concluded that public mental health literacy should be improved as a result of their findings [4]. Empirical analysis suggests psychiatric treatments are as beneficial as those seen in general medicine [5].

We do not understand Gøtzsche et al’s analysis of the studies we cited, including the one comparing ketamine to midazolam, showing a difference at 24 hours, and the point they wish to make. We cited these studies to illustrate that ketamine did not follow the acute euphoric/chronic dysphoric effects claimed by Gøtzsche et al.

In citing Canuso et al [6] as evidence of no improvement with esketamine at day 25 Gøtzsche. et al neglect to mention that symptom (MADRS) change at this time point was not a primary efficacy measure (change at 4 hours was, and was significant). The study had a sample size of 68, and would not have been powered to show a change: findings were described by the authors as preliminary.
We do not understand the conclusions drawn by Gøtzsche et al that the references we gave are only relevant for two weeks. We simply cited the trials submitted to the FDA, that were of four weeks’ duration (as well as the maintenance trial), and reported those results.

The concluding sentence, where Gøtzsche et al state “It is not enough to simply render the patients acutely euphoric with a hallucinogenic substance” ignores any of the neuroscience or behavioural pharmacology we gave, and is simply factually inaccurate.

In summary Gøtzsche et al, in responding to ourselves, cite literature that is non evidence-based (their book, a narrative review with methodological failings, a 1997 survey of public opinion with dubious conclusions), selectively cite secondary outcomes from a preliminary trial, and make sweeping statements about the behavioural pharmacology of ketamine that are simply inaccurate. This is in addition to their prior response that had a number of factual errors that we pointed out.

Whilst we admire their persistence, and share their view in regard to caution and safety, we suggest interested readers acquaint themselves with the literature cited by Gøtzsche et al before drawing their own conclusions. In our opinion, there is little foundation to the arguments made, with high risk of bias.

It does seem we disagree with Gøtzsche et al on fundamental principles of evidence-based medicine, and therefore protracted discussion with Gøtzsche et al will probably not be fruitful.

References
1 Gøtzsche PC. Deadly psychiatry and organised denial. Art People 2015.
2 Read J, Bentall R. The effectiveness of electroconvulsive therapy: a literature review. Epidemiol Psichiatr Soc 2010;19:333–47.
3 UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 2003;361:799–808. doi:10.1016/S0140-6736(03)12705-5
4 Jorm AF, Korten AE, Jacomb PA, et al. ‘Mental health literacy’: a survey of the public’s ability to recognise mental disorders and their beliefs about the effectiveness of treatment. Med J Aust 1997;166:182–6.
5 Leucht S, Hierl S, Kissling W, et al. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. The British Journal of Psychiatry 2012;200:97–106.
6 Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry 2018;175:620–30. doi:10.1176/appi.ajp.2018.17060720

Competing interests: SJ is co-investigator on a research study in psychosis, funded by Alkermes. King’s College, London, has received fees from Lundbeck for lectures SJ has given on psychosis.

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21 October 2019

Sameer Jauhar, Senior Research Fellow, Consultant Psychiatrist and Paul Morrison, King’s College, London, South London and Maudsley NHS Foundation Trust, IoPPPN, King’s College, Denmark Hill Campus

Dazed and confused? In reply to the response by Horowitz and Moncrieff

We thank Horowitz & Moncrieff for their continued response to our Editorial. We address their concerns, as below.

They state we utilise a “bait and switch” by providing evidence on ketamine, as we do not state this was IV as opposed to nasal ketamine.
They seem to have ignored the original Editorial, where we stated, “Esketamine, an isomer of ketamine, can be given intranasally because it has a higher affinity for the N-methyl-D-aspartate (NMDA) receptor than ketamine.” There are no RCTs of nasal ketamine. We are surprised that anyone could construe this as misleading.

They state the “meta-analysis” we cite covered IV ketamine and not nasal esketamine, and assume (again) we are misleading. We stated this was a meta-analysis of ketamine. As above, we do not understand why this is of concern to Horowitz and Moncrieff.

Horowitz and Moncrieff appear to be further confused as to the difference between ketamine and esketamine when they state we cite “another study that examined intravenous ketamine and not nasal esketamine.” This is another mistake on their part. We correctly stated this was a study of esketamine, and the title of the reference they cite contains, “esketamine”- it was an IV esketamine trial [1].

Horowitz and Moncrieff state we “cite studies that last only a few days as evidence of efficacy.” Whilst some studies we cite did have short duration, the esketamine studies submitted to the FDA, covered in our Editorial and our response to Horowitz and Moncrieff lasted longer than a few days, the acute trials lasting 4 weeks.

We are confused by the conclusions drawn by Horowitz and Moncrieff from the maintenance study of esketamine that was submitted to the FDA [2]. They state, “it is probable that in this study ‘relapse’ was confounded by withdrawal effects, which were not considered”.
They seem to have not read the paper fully, or ignored sections that are not in keeping with their views. In the trial the authors did measure withdrawal, and state, “No evidence of a distinct withdrawal syndrome was observed during the 2 weeks after cessation of esketamine nasal spray as assessed by the 20- item Physician Withdrawal Checklist.”[2] There is no mention or critique of this measure.

When citing other literature they seem similarly confused. The review they cite as evidence for withdrawal symptoms occurring with ketamine [3] quotes data from a study of people who were abusing ketamine regularly and had contact with various health and government organisations, just over 50% developing withdrawal symptoms. This is a wholly different population from those entering and partaking in the esketamine trial. Therefore the relevance to the trial is unclear.

Further confusion is apparent in their interpretation of safety data from the trial. They state, “at least 20% of patients assigned to esketamine experience significant side effects, including a stroke, seizures, disorientation, hypothermia and suicidal ideation, all in the esketamine treatment group.” This is a very different interpretation of the safety data to that provided in the paper. The paper states, “Most AEs were mild to moderate, observed after dosing, and generally resolved in the same day.”, and was paraphrased in the Editorial.

The authors of the trial state 6 serious adverse events were reported for esketamine plus antidepressant in the induction phase, and no serious adverse events reported for optimization or maintenance phases. 7 people experienced 1 or more AEs during the maintenance phase and had to leave the study, 4/152 (2.6%) in the esketamine plus AD group, 3/145 (2.1%) in the placebo plus AD group.

Finally, Horowitz and Moncrieff traverse the issue of what constitutes a clinically significant difference using the MADRS and state that the difference between esketamine and placebo is not clinically relevant, when we suggested it was. They cite Stefan Leucht et al’s paper, where change in MADRS with mirtazapine was measured using MADRS and Clinical Global Impression severity and improvement scales, in people with MDD [4]. This gave approximations for MADRS change corresponding to more global clinician-rated change. However, this has little relevance for the trials we describe, as we describe difference between esketamine and placebo, in treatment-resistant depression, as opposed to change in one group in MDD. The authors of one of the trials [5] addressed this, conducting analyses of CGI-S scores, citing a study comparing active drug to comparator in MDD, deriving a relationship between MADRS change and clinical relevance [6], suggesting change seen between esketamine and placebo was clinically relevant. Furthermore, accepting for dichotomising of data, responder rates were higher in the esketamine groups when results were pooled from both adult trials, as stated in our Editorial [7].

In summary, Horowitz and Moncrieff appear to compound erroneous assertions made in their earlier response by mis-citing, selectively citing and misunderstanding the literature, as it pertains to efficacy, safety and clinical interpretation of trials.

Whilst this may provide a soundbite for those who disapprove of pharmacological treatments in psychiatry, we suggest interested readers go through the original literature and make up their own minds.

In our opinion, though possibly well-meaning in terms of patient safety, scrutiny of the actual data and our responses reveals a very different picture to the narrative given by Horowitz and Moncrieff (that we believe to be overtly gloomy, in keeping with their prior response). We feel we have a different interpretation of what constitutes evidence-based medicine, and would suggest further discussion with them will add little.

We reiterate our prior message of cautious optimism for glutamate-based treatments such as esketamine for treatment-resistant depression, with scrupulous monitoring, and longer-term studies and effectiveness data.

References
1 Singh JB, Fedgchin M, Daly E, et al. Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study. Biol Psychiatry 2016;80:424–31. doi:10.1016/j.biopsych.2015.10.018
2 Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry Published Online First: 5 June 2019. doi:10.1001/jamapsychiatry.2019.1189
3 Li J-H, Vicknasingam B, Cheung Y-W, et al. To use or not to use: an update on licit and illicit ketamine use. Subst Abuse Rehabil 2011;2:11–20. doi:10.2147/SAR.S15458
4 Leucht S, Fennema H, Engel RR, et al. What does the MADRS mean? Equipercentile linking with the CGI using a company database of mirtazapine studies. J Affect Disord 2017;210:287–93. doi:10.1016/j.jad.2016.12.041
5 Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. AJP 2019;176:428–38. doi:10.1176/appi.ajp.2019.19020172
6 Montgomery SA, Möller H-J. Is the significant superiority of escitalopram compared with other antidepressants clinically relevant? Int Clin Psychopharmacol 2009;24:111–8. doi:10.1097/YIC.0b013e32832a8eb2
7 Jauhar S, Morrison P. Esketamine for treatment resistant depression. BMJ 2019;366:l5572. doi:10.1136/bmj.l5572

Competing interests: SJ is co-investigator on a research study in psychosis, funded by Alkermes. King’s College, London, has received fees from Lundbeck for lectures SJ has given on psychosis.

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22 October 2019

Peter C Gøtzsche, Michael P Hengartner, James Davies, John Read, Anne Guy, Sami Timimi and Peter Kinderman, all from the Council for Evidence-based Psychiatry

Re: Esketamine for treatment resistant depression

In their latest reply, Jauhar and Morrisson seem to continue to rely on misrepresentation, distortion and obfuscation, all exaggerating the safety and efficacy of esketamine. Rather than continue to point out their latest errors we focus instead on the fact that they do not mention, let alone rebut, the crux of our response.

In their initial response they highlighted three references, from which the longest response to ketamine was reported just 18 days after treatment. We cited one very recent study of esketamine that they did not include, in which there was no difference from placebo on depression or suicide risk by day 25, but in which esketamine participants experienced nausea, dizziness, dissociation, unpleasant taste, and headache.

On this crucial evidence-based question, we have demonstrated, mainly using the references Jauhar and Morrisson cite in support of esketamine, why the available evidence finds that it is more likely to harm than benefit patients with resistant depression. Thus, the only reasonable and ethical evidence-based conclusion is that this drug should not be used in clinical practice but only as an experimental drug in randomised trials of adequate length, with long-term follow up, and with patient relevant outcomes assessing both harms and benefits.

It is regretful that Jauhar and Morrison seem to have chosen to pull out of this debate without addressing our substantive points.

Competing interests: No competing interests

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23 October 2019

Mark A Horowitz, Clinical Research Fellow and Trainee Psychiatrist, and Joanna Moncrieff, University College London and North East London NHS Foundation Trust, Department of Psychiatry, University College London

A concluding summary of the efficacy and safety of esketamine from the data presented by Janssen to the FDA

We thank Jauhar and Morrison for their effort to re-engage with the substantive topic. Unfortunately, they still do not address the fundamental lack of evidence of esketamine’s efficacy and its long-term safety.

There is no debate over the addictive nature of ketamine, and its S- (more active) enantiomer, esketamine. Ketamine is known to produce tolerance [1] and repeated use is associated with a recognised withdrawal syndrome [2,3]. Craving and drug-seeking behaviour are commonly encountered in its use as a recreational drug. Contrary to Jauhar and Morrison’s assertion, and as evidenced in other drugs of abuse, when a drug can cause tolerance, dependence and withdrawal, it does not matter what population it is administered to – its dependence-inducing properties are characteristics of its pharmacology, and addiction will always be a risk.

Public Health England (PHE) has just published a review of drug classes causing dependence and withdrawal, including opioids, benzodiazepines, z-drugs, gabapentinoids, and antidepressants, concluding that one in four Britons are on these drugs, a widespread issue of concern [4]. When each of these classes of drug were introduced into clinical practice they were said to have ‘safe profiles’, and were approved for use based on short-term studies in the absence of comprehensive long-term safety studies. Recognition of the damage these drugs have done to many patients caught in a cycle of dependence and withdrawal effects has taken decades.

The PHE report comments on these “recurring patterns”: “New medicines are seen as an important part of the solution to a condition, resulting in widespread use. Their dependence or withdrawal potential are either unknown at this point, due to a lack of research, or perhaps downplayed. As evidence of harm from dependence or withdrawal emerges, efforts are made to curtail prescribing. The repetition of this pattern is striking.”[4].

But dependence is not the only concern. Long-term use of ketamine can be associated with irreversible damage to the urinary tract, which can lead to renal failure, and cognitive dysfunction, a portion of which may be irreversible [3].

We summarise the four efficacy trials submitted by Janssen to the FDA, to ensure that there is no selective citing: there were three 4-week trials, and one discontinuation study. Two 4-week trials demonstrated no difference in MADRS scores between placebo and esketamine in depressed patients [5,6]. The third showed a difference of 4.0 points between esketamine and placebo at 4 weeks on the MADRS scale, favouring esketamine [7]. For reference, placebo alone reduced MADRS scores by 17.0 points. Therefore, ketamine had an effect one quarter that of the placebo effect, even though the trial would inevitably not have been double-blind. We leave it to the reader to decide whether this difference in a 60-point scale, present in only one of three trials, suggests any real clinical value.

The discontinuation trial followed sixteen weeks of esketamine treatment [8]. Such trials are problematic because of adverse effects associated with stopping a drug that has been used repeatedly. Physiological withdrawal symptoms can be mistaken for relapse, and the process of withdrawal may also precipitate or bring forward a relapse that may not otherwise have occurred. Discontinuation trials are not normally accepted as evidence of efficacy by the FDA but in this case the FDA made an exception because of the ‘breakthrough’ nature of esketamine [9] .

We thank Jauhar and Morrison for drawing attention to the investigators’ attempt to measure withdrawal effects. They employed the Physician Withdrawal Checklist (PWC-20), a checklist developed for benzodiazepine withdrawal [10]. The results are not reported, but it is simply stated that ‘no evidence of a distinct withdrawal syndrome was observed during the 2 weeks after cessation of esketamine’ [8].

Given that the PWC-20 includes the symptoms ‘insomnia’, ‘anxiety-nervousness’, ‘dysphoric mood-depression’, ‘difficulty concentrating, remembering’, ‘fatigue’, ‘lack of appetite’, which are identical, or overlap, strongly with 70% of the items on the MADRS one wonders how the authors distinguished relapse from withdrawal.

Indeed, ketamine withdrawal is most commonly associated with fatigue, poor appetite, drowsiness, anxiety, and dysphoria in other studies [2]. Most relapses in the discontinuation study occurred in the first few weeks after esketamine was abruptly stopped, a time period when withdrawal effects are likely to be most relevant, further suggesting confounding by withdrawal.

Furthermore, and especially alarming, there were six deaths, including three suicides, that occurred in the patients assigned to esketamine, and none in those assigned to placebo, in the Phase 2 and 3 studies conducted by Janssen [11]. One death was a motorcycle accident 26 hours after esketamine administration. Two others involved an MI and cardiac failure days after esketamine use, which is known to cause blood pressure spikes (one in a patient with pre-existing risk factors) [11]. Three suicides occurred 4, 12 and 20 days after the last dose of esketamine [9]. Although Janssen sought to explain these deaths as due to ‘the severity of the patients’ underlying illness’ two of the patients had no previous suicidal ideas at baseline or during the study (data was not available for the third patient) [11]. These suicides were dismissed as not drug-related by Janssen, “given the small number of cases … and the lack of consistent pattern among these cases”. However, others have argued that these cases fit with a pattern of a severe withdrawal reaction, and are significant enough in number to constitute a worrying signal [9].

It appears that history is repeating: a known drug of abuse, associated with significant harm, with scant evidence of efficacy, is being submitted for licensing, without adequate long-term safety studies. ‘Scrupulous monitoring’ has not been previously adequate in preventing the rise in prescribed drug dependence.

We hope that the MHRA will ask for further safety and efficacy studies performed in the long-term before this drug is licensed for use in the UK, a point that Jauhar and Morrison seem to be in agreement with us on. No one will thank the MHRA if they introduce another drug that leads to long-term medical complications and significant problems with dependence and withdrawal, just because it has a ‘novel’ mode of action.

References

1 Gerb SA, Cook JE, Gochenauer AE, et al. Ketamine Tolerance in Sprague-Dawley Rats after Chronic Administration of Ketamine, Morphine, or Cocaine. Comp Med 2019;69:29–34. doi:10.30802/AALAS-CM-18-000053

2 Chen WY, Huang MC, Lin SK. Gender differences in subjective discontinuation symptoms associated with ketamine use. Subst Abus Treat Prev Policy 2014;9:1–7. doi:10.1186/1747-597X-9-39

3 Li J-H, Kasinather V, Cheung, et al. To use or not to use: an update on licit and illicit ketamine use. Subst Abuse Rehabil 2011;:11. doi:10.2147/sar.s15458

4 Public Health England. Dependence and withdrawal associated with some prescribed medicines. An evidence review. Published Online First: 2019.https://www.gov.uk/government/publications/prescribed-medicines-review-r…

5 Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: Results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry 2018;175:620–30. doi:10.1176/appi.ajp.2018.17060720

6 Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol 2019;40:1–30. doi:10.1093/ijnp/pyz039

7 Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: A randomized double-blind active-controlled study. Am J Psychiatry 2019;176:428–38. doi:10.1176/appi.ajp.2019.19020172

8 Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients with Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry 2019;08560:893–903. doi:10.1001/jamapsychiatry.2019.1189

9 Schatzberg AF. A word to the wise about intranasal esketamine. Am J Psychiatry 2019;176:422–4. doi:10.1176/appi.ajp.2019.19040423

10 Rickels K, Garcia-Espana F, Mandos LA, et al. Physician withdrawal checklist (PWC-20). J Clin Psychopharmacol 2008;28:447–51. doi:10.1097/JCP.0b013e31817efbac

11 Janssen. Efficacy, safety, and risk-benefit profile of New Drug Application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen Pharmaceuticals, Inc., for the treatment of treatment-resistant depression. 2019;:1–135.

Competing interests: No competing interests