15 June 2020

We were dismayed to see that you recently published a piece calling patients taking esketamine ‘unwitting guinea pigs participating in another pharmaceutical experiment’.^{Reference Horowitz and Moncrieff1} (Lack of) style aside, the arguments advanced by Horowitz and Moncrieff to support their inflammatory statement do not hold up.

First, the clinical trial programme to establish efficacy and safety of the esketamine nasal spray in treatment-resistant depression (TRD), a substantial group of those with depression,^{Reference Bartova, Dold, Kautzky, Fabbri, Spies and Serretti2} was developed in agreement with health regulatory agencies, including the Food and Drug Administration and Committee for Medicinal Products for Human Use. After careful consideration, the health regulatory authorities approved the application of three short-term and two long-term studies. Do Horowitz and Moncrieff claim superior insight to the bodies that hold pharma to account?

Second, the authors observe that esketamine can be abused. This is true, as for many essential medications, just not material: the administration of esketamine nasal spray was and will be done under close supervision in a healthcare setting, and none of the patients in the development programme demonstrated a pattern of abuse. Furthermore, the dosage schedule becomes less frequent as treatment progresses, so the amount of drug administered falls, which is clearly not in keeping with addiction. They also imply that, for reasons of safety, ketamine is no longer used as an anaesthetic; this is completely false. Indeed, it is the converse of the truth. Ketamine is listed by the World Health Organization as an essential medicine because of its safety profile compared with other anaesthetics.^{Reference Taylor, Nutt, Curran, Fortson and Henderson3}

Third, with regard to suicide, the results presented in their Table 1 are misleading, since all three suicides were within the open-label study phase, e.g. a phase where there was no placebo control. To tabulate these suicides against placebo is invalid. Suicidality is a main component of TRD.^{Reference Bartova, Dold, Kautzky, Fabbri, Spies and Serretti2} The completed suicide rate in the esketamine development programme is 0.17 per 100 patient years, less than the completed suicide rate of 0.47 per 100 patient years in a recent meta-analysis of 15 000 patients with TRD.^{Reference Bergfeld, Mantione, Figee, Schuurman, Lok and Denys4}

Fourth, the long-term efficacy and safety of TRD are better than the authors insinuate. Safety studies^{Reference Wajs, Aluisio, Holder, Daly, Lane and Lim5} as well as practical experience^{Reference Kasper, Cubała, Fagiolini, Ramos-Quiroga, Souery and Young6} indicate that most treatment-emergent side-effects occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Cognitive performance generally either improved or remained stable post baseline. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 h post dose. There was no case of interstitial cystitis or respiratory depression.^{Reference Kasper, Cubała, Fagiolini, Ramos-Quiroga, Souery and Young6}

Esketamine nasal spray is a treatment for TRD which has a novel mechanism of action and offers an additional therapeutic option for patients who have already failed several lines of treatment. Your instructions require authors of ‘analysis’ papers to provide ‘an unbiased approach in evaluating the relevant evidence’. Patients, their therapists and the research teams who have worked on esketamine across the world deserve them to be observed better than this.