Samuel Gershon: Ketamine, the "new" breakthrough in the trestment of depression


Ken Gillman’s comment on Samuel Gershon’s reply to David Janowsky’s and Edward Shorter’s comments


        I have updated my website commentary, “Brief history of tranylcypromine,” which Professor Shorter helped me with several years ago. It is no longer brief but reading the latest contributions about ketamine illustrates that the two stories have some interesting parallels, especially regarding the sporadically ambivalent attitude of the FDA to randomised controlled trial data, as opposed to other investigational approaches.

        As Professor Shorter reminds us, “…in 2014 Carroll laid out a pathway for investigation: ‘What ketamine needs is a focused investigative trial in patients with unequivocal melancholia — a Roland Kuhn study, if you will — rather than large commercial-style trials in generic major depression.’” And Samuel Gershon added, “Do we have here an important new anti-depressant? And, does the FDA review of the data on which they have given special approval justify the enthusiastic reception of this compound as a really safe and effective therapeutic agent for depression?”

        The investigation of ketamine for the “complex regional pain” syndrome, which has been taking place over roughly the same two-decade period, might contain some lessons.  I note the latest reviews: Duong, Bravo, Todd et al. (2018) show “…35 RCTs of variable quality… further research is required”; and Orhurhu, Orhurhu, Bhatia and Cohen (2019) added “Evidence suggests… short-term analgesic benefit.”

        This serves to demonstrate how correct Barney Carroll was; unfortunately, we have not learned from history and a quality investigation in severe melancholic depression has never been done, either for tranylcypromine or for ketamine. It would be preferable if this were not an RCT, but something like a trial of patients who have relapsed after ECT.  Rapid relapse after ECT is common, of the order of 50%, and it may be that whatever ketamine does is equally transient.



Duong S, Bravo D, Todd KJ, Finlayson RJ, Tran Q. Treatment of complex regional pain syndrome: an updated systematic review and narrative synthesis. Can J Anaesth, 2018; 65(6):658-84.

Orhurhu V, Orhurhu MS, Bhatia A, Cohen SP. Ketamine Infusions for Chronic Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Anesth Analg, 2019; 129(1):241-54.


September 17, 2020