15 June 2020

We read the Analysis^{Reference Horowitz and Moncrieff1} regarding the evidence base for esketamine in treatment-resistant depression (TRD). We have concerns about selective reporting, misinterpretation and factual errors.

First, the authors state that ‘stopping regular use causes a withdrawal syndrome’. The review states that withdrawal symptoms occurred in 12 of 30 people taking ketamine at high frequency,^{Reference Morgan and Curran2} some up to 9 g (considerably higher than that in treatment trials). No information on numbers, severity or time course is given in the primary paper. The other review cited as evidence of withdrawal syndrome gives 50% prevalence in regular ketamine users. With less than 50% of both samples of ketamine misusers developing withdrawal, and no criteria set, causal inference is unclear. Considering withdrawal to be a confounder for relapse in the maintenance trial, they cite the Food and Drug Administration (FDA), questioning the validity of the withdrawal checklist, which shares items with the Montgomery–Åsberg Depression Rating Scale (MADRS). They neglect that this report states: ‘Acute esketamine withdrawal is likely not a factor, as dosing is infrequent during the maintenance phase’. The trial authors’ statement ‘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’ appears fairly self-explanatory.

Second, the authors state that ketamine probably exerts rapid effects by causing a ‘high’ and disregard evidence suggesting that this is maintained, stating that no randomised controlled trial evidence exists, citing a 2017 Royal College of Psychiatrists (RCPsych) report. This ignores the acute esketamine trial submitted to the FDA, covered in this Analysis piece, published subsequent to that RCPsych report, where a difference was seen at day 2 and maintained at day 28. Several studies of ketamine have shown an extended effect, albeit weeks rather than months – but certainly outwith the ‘high’.

Third, in questioning the clinical significance of MADRS change (the primary endpoint in esketamine trials), they cite analysis of mirtazapine trials in depression, linking Clinical Global Impressions to MADRS. Extrapolating within-group findings from depression to group placebo data has been highlighted as a mistake,^{Reference Furukawa3} and extrapolating this to TRD is difficult to understand.

Fourth, the authors mention the FDA raising concerns over one site in the maintenance trial, with re-analysis by one researcher excluding this site showing no effect of esketamine on relapse. They neglect that this author conducted his own analysis, using an incorrect statistical technique, with numerical errors – re-analysis using the prespecified test showed a difference.^{Reference Singh, Daly, Mathews, Fedgchin, Popova and Hough4}

Fifth, regarding safety, the authors selectively report events (e.g. Table 1/1861) giving prevalence of bladder problems but do not mention that most side-effects were transient and minor (stated in the original papers and the FDA report the authors themselves cite).⁵

In summary, it is difficult, with the selective citing and factual error, to see how one can come to any balanced conclusions from this Analysis piece.