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

Edward Shorter’s comments


         Sam Gershon’s comment is so bang-on that it scarcely requires comment.  A couple of thoughts:

         Ketamine was patented in 1963 and has been around for donkey’s years.   Carlos Zarate’s study in 2006 at NIMH opened the door anew to discussing it not as an anesthetic but as an antidepressant (Zarate, Singh, Carlson et al. 2006).

         Ketamine has been the object of some very thoughtful investigation.  In 2012 Barney Carroll shared with David Healy the thought that, “Fixed moods and psychomotor retardation in melancholia are just the emotion-circuit counterparts of rigidity and slowness in the motor system.  In each case (Parkinson Disease and mood disturbance) there is increased activity involving glutaminergic neurotransmission, and this hyperactivity can be attenuated by NMDA receipt antagonists such as ketamine… I see nothing mysterious about ketamine in melancholia and the Carlos Zarate studies probably had mixed results because they enrolled both melancholic and non-melancholic depressive subtypes.” [ii] Carroll to Healy and correspondents, Feb 11, 2012

         It is encouraging that this theoretical formulation by Carroll hits the nail more sharply on the head than almost anything else written to date on this subject.

         But ketamine has bounded from the world of thoughtful neuroscience into the clinic.  And here, not all results have been equally encouraging.  It is dismaying that ketamine has reached into the world of “pediatric bipolar disorder,” a virtually non-existent illness by which “severe behavioural and emotional dysregulation” is meant (Dirk Dhossche’s formulation).  One enthusiastic group led by Demitri Papolos reported excellent results with intranasal ketamine in 12 youths with “treatment-refractory" pediatric bipolar disorder (Papolos, Teicher, Faedda et al. 2013).  But ketamine is a deliriant.  Kids love this kind of thing.  What would you expect?  (10 of the 12 patients were boys and “treatment refractory” meant their behaviour didn’t improve on a whole spectrum of antipsychotics and antidepressants, but now on ketamine they’re seeing stars.)

         In the 1980s, similar boys used ketamine (“Special K”) as a street hallucinogen.  It may be that ketamine can cut pediatric suicidality and HAM-D scores, but so do other treatments, especially ECT, with longer lasting therapeutic results.

         Ketamine seems to poop out after about two weeks.  The similarity of the response of depression to amphetamine treatment comes to mind, with the proviso that results with amphetamine are longer lasting (Klein 1980).

         In any event, clinicians in the trenches have long had discouraging experiences with ketamine.  In 2013, John M. (“Mickey”) Nardo commented in his widely read blog, “1 Boring Old Man”: “I knew ketamine as a common reason for people to be brought to the Emergency Department – not something to give them when they get there.”  The current hype must be balanced against a historically quite negative load of opinion.

         Also in 2013, James Murrough’s RCT ascertained that ketamine cut symptoms in “treatment resistant depression" better than the anesthetic midazolam within 24 hours of treatment.  About half the patients relapsed over the next week Murrough, Iosifescu, Chang et al. 2013).

         The field was by now desperate for solid findings.  Did ketamine produce long-term results in real depression or not?  How do we find out?

         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.  If there is a genuine signal then a small Kuhn-style study will find it most efficiently.”[vii] Carroll to correspondents, May 16, 2014

         Such a study was never done.

         And so the drums beat.  In 2017 an APA “consensus statement,” led by Gerald Sanacore (whose conflict of interest statement was almost longer than the document itself) – in a group that included Charles Nemeroff and Alan Schatzberg – said that ketamine warranted “cautious optimism” (Sanacora, Frye, McDonald et al. 2017). 

         This is not to say that ketamine is without its uses.  In 2018 Canadian investigators reported that using ketamine instead of propofol as an anesthetic in ECT produced remission after fewer ECT sessions (Gamble, Bi, Bowen et al. 2018).  This was of considerable interest, but not germane to ketamine as an “antidepressant.”

         It is disturbing that a short-term euphoriant such as ketamine could now be billed as a stupendous new antidepressant with a novel mechanism of action.  In March 2019 the FDA greenlighted Janssen to bring out “esketamine” for “treatment-resistant depression,” meaning patients unresponsive to SSRIs.   Immediately, the drums began beating wildly for esketamine (Spravato) as the first effective AD in ages, it was claimed.  Michael Thase, a long-standing friend of Janssen, had led the three trials, two of which were negative.

         I agree with Sam.  I’m getting cold chills running up my spine.


Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-64.

Papolos DF, Teicher MH, Faedda GL, Murphy P, Mattis S. Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype. J Affect Disord. 2013;147(1-3):431-6.

Klein DF. Diagnosis and Drug Treatment of Psychiatric Disorders: Adults and Children, 2nd ed. Williams & Wilkins, 1980;428-429, 558-559

Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-42.

Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P, Nemeroff CB; American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry, 2017;74:399-405. 

Gamble JJ, Bi H, Bowen R, Weisgerber G, Sanjanwala R, Prasad R, Balbuena L. Ketamine-based anesthesia improves electroconvulsive therapy outcomes: a randomized-controlled study. Can J Anaesth. 2018;65(6):636-646.


October 17, 2019