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Editorials

Esketamine for treatment resistant depression

BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l5572 (Published 23 September 2019) Cite this as: BMJ 2019;366:l5572

Opinion

A drug not a miracle—why we need a new system for monitoring ketamine

Response to Jauhar and Morrison: First do no harm: the case of esketamine

If there is an ideology we espouse it is the principle of ‘first do no harm’, fundamental to the practice of medicine, and we do not believe that this stance is “gloomy” or “bleak” but a responsible approach to the licensing of new medications. This approach is especially pertinent in the context of growing awareness of the dependence and withdrawal issues associated with commonly prescribed psychotropic medications [1], issues that have arisen as a consequence of not performing adequate long-term studies in these medications before licensing.

Setting aside their polemical ad hominem attacks, Jauhar and Morrison continue to present the evidence for the efficacy of ketamine in a much more favourable light than is warranted by the mixed findings in the studies they cite. They perform a ‘bait and switch’ in citing data related to intravenous ketamine rather than nasal ketamine, cite studies that last only a few days as evidence of efficacy and cite a study which used a discontinuation design to suggest relapse prevention properties, a design almost certain to confound withdrawal symptoms for relapse.

The “meta-analysis of nine high quality studies” is, in fact, a study of intravenous ketamine and not the nasal esketamine that is currently the subject of discussion [2]. Even these studies of intravenous ketamine only measure depressive symptoms for seven days [2] following treatment, hardly useful in determining the long-term effect of this drug or its derivatives.

The “numerous” studies that show esketamine outperforms placebo includes another study that examined intravenous ketamine and not nasal esketamine, conducted by the manufacturer of the drug, only measuring outcomes for two days [3], and a negative study that showed that nasal esketamine was slightly better than placebo at 24 hours, but not by day 25 [4].

The third study cited was conducted by the manufacturer of esketamine in 67 patients, showing a modest effect of esketamine at 8 and 15 days following treatment, with at most 12 patients in each esketamine dosing arm [5]. Evidence of sustained change in this study was derived from groups of at most 9 (6 in placebo treatment group), after a second round of randomisation [5]. The fourth study showed a 4 point advantage on the MADRS when adding esketamine to antidepressant alone at 28 days, a size of improvement unlikely to have clinical relevance (see below), especially considering the increased incidence of dissociation, nausea, vertigo, dysgeusia and dizziness in the esketamine treatment group [6].

The final study they cite is a discontinuation study of ketamine [7]. Patients who had achieved remission on esketamine were randomised to continue or abruptly discontinue their medication. As withdrawal effects are already recognised for ketamine [8], it is probable that in this study ‘relapse’ was confounded by withdrawal effects, which were not considered, making it difficult to justify the claim that this study demonstrates that esketamine prevents relapse. There may also have been a nocebo effect, whereby people who attributed any improvement to esketamine, with its noticeable subjective effects, would have also noted its absence. Strikingly, 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 [7].

The last study they cite showed a negative finding for esketamine at 28 days in MADRS score [9], and common incidence (>20%) of adverse events of nausea, dissociation, dizziness, vertigo and headache.

None of the studies involved a pharmacologically active placebo. A bittering agent was added to the intra-nasal placebo to mimic the bitterness of ketamine, but this would not control for the breaking of the blind that would have occurred due to the psychoactive effects of ketamine.

Furthermore the 3.84 point difference in the MADRS score derived from a selected subset of these studies is unlikely to be clinically significant, despite Jauhar and Morrison’s claims to the contrary [10]. The scale has a maximum score of 60 points, and a change of 7-9 points is required to correspond to a rating of ‘minimal improvement’ on the Clinical Global Impressions Improvement scale (CGI-I) with ‘much improved’ corresponding to a 17-19 point reduction in MADRS scores [11].

Overall, it appears that the effects of esketamine on depression scores are likely to be modest, may not persist for more than a few days, while at the same time it is a drug associated with evidence of abuse and withdrawal, and a significant side effect burden. Therefore, it would be prudent to conduct longer term studies on its efficacy and safety, including excluding significant issues with dependence and withdrawal following long-term use, before rushing headlong into the approval of a dissociative anaesthetic agent for general use.

References
1 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...
2 Han Y, Chen J, Zou D, et al. Efficacy of ketamine in the rapid treatment of major depressive disorder: A meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatr Dis Treat 2016;12:2859–67. doi:10.2147/NDT.S117146
3 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
4 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
5 Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry 2018;75:139–48. doi:10.1001/jamapsychiatry.2017.3739
6 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
7 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
8 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
9 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
10 Jauhar S, Morrison P. Esketamine for treatment resistant depression. BMJ 2019;5572:l5572. doi:10.1136/bmj.l5572
11 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

Competing interests: No competing interests

12 October 2019
Mark A Horowitz
Clinical Research Fellow and Trainee Psychiatrist
Joanna Moncrieff
University College London and North East London NHS Foundation Trust
Department of Psychiatry, University College London