20 June 2020

Horowitz and Moncrieff evaluated the use of esketamine in the management of treatment-resistant depression, following its approval by the USA, UK, and EU.^{Reference Horowitz and Moncrief1} The authors addressed the five trials evaluated by the Food and Drug Administration (FDA) and concluded that the evidence was scant and that safety concerns have not been addressed sufficiently.

The TRANSFORM-2 efficacy trial was among these studies and was described as ‘pivotal’ by the FDA.² The trial demonstrated that the use of esketamine nasal spray alongside a newly initiated antidepressant resulted in a decrease of 19.8 points on the MADRS after 28 days. By comparison, there was a reduction of 15.8 points in the control group.^{2,Reference Popova, Daly, Trivedi, Cooper, Lane and Lim3} Leucht et al interpreted the clinical relevance of MADRS responses and defined a clinical change of ‘very much improved’ as a MADRS reduction of 27–28 points, ‘much improved’ as a reduction of 16–17 points and ‘minimally improved’ as a reduction of 7–9 points.^{Reference Leucht, Fennema, Engel, Kaspers-Janssen, Lepping and Szegedi4} Horowitz and Moncrief therefore concluded that the 4.0 point difference observed between the treatment and control groups in the TRANSFORM-2 trial corresponded to a ‘less than minimal’ clinical improvement.

Leucht et al, however, did not analyse the clinical relevance of the difference in MADRS scores between treatment and placebo groups but rather looked at the absolute change of MADRS scores in ‘both placebo and drug treated patients’ from a variety of open-label, comparator-controlled or placebo-controlled studies. Therefore, the absolute reduction of 19.8 points in the TRANSFORM-2 treatment group would confer a clinical benefit between ‘much improved’ and ‘very much improved’.

I urge Horowitz and Moncrieff to reconsider the results from the TRANSFORM-2 trial and reflect on their views on esketamine's efficacy.