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

David Janowsky’s comment


         Dr. Samuel Gershon has opened the door to an important discussion of how the anesthetic agent, drug of abuse and now antidepressant, ketamine,  should fit into the treatment of depression.   He touches on the issue of there being a rush of enthusiasm,  the development of an associated media frenzy and  the possibility that there may have been some ignoring of rigor in the rush  to approve an FDA-sanctioned treatment for resistant depression.  This is specifically true for the recent FDA approval of nasal esketamine, although Dr. Gershon does not focus on esketamine specifically.

         A recent study by Popova, Daly E, Trivedi et al. (2019)  serves as the basis for discussion of   many of the issues eluded to  by Dr. Gershon.  In this phase three, double-blind trial, adults with depression and a history of non-response to two or more antidepressants were studied.  Subjects received an oral antidepressant not previously given to the patient and either twice weekly nasal esketamine or nasal placebo for 28 days. The esketamine plus oral antidepressant and the placebo plus oral antidepressant had baseline MADRAS depression rating scales averaging 37.0  and 37.3, respectively, i.e. having moderate to severe  depression, and a score of 15.6 and 20.3, respectively,  at the end of the study.  Remission, defined as a total MADRAS score of 12 or less on test day 28, occurred in 52.5%  of the esketamine plus antidepressant group and 31.0% of the control group.  Sixty-nine and three 10ths  percent of the active esketamine plus antidepressant group  and 52.0% of the control group  showed a 50% or greater decrease in MADRAS scores, defined as a response  (Popova, Daly, Trivedi et al, 2019; Brauser D, 2019). The difference between the two groups favored  the active esketamine plus oral antidepressant group over the oral antidepressant plus placebo, with a difference in improvement noted at two days after the first administration and continuing throughout the 28-day study period.  The authors note that there was an unexpected improvement  in the antidepressant plus placebo group, given that these patients were supposed to have been treatment resistant. Although the oral antidepressant plus esketamine group improved more than the oral antidepressant plus placebo group, the antidepressant plus placebo group showed clinically significant improvement.  Furthermore, if the slopes of improvement of the antidepressant plus  placebo group had continued for another week, the 5-week improvement  for the antidepressant plus  placebo group would have equaled the 4-week improvement of  nasal esketamine plus antidepressant group, assuming a continuing slope of improvement.

         In related work, Daly, Trivedi, Janik et al. (2019), performed a follow-up maintenance study in which esketamine  plus an oral antidepressant  responders and remitters  were divided into  those  continuing on esketamine and an oral antidepressant and those continuing on placebo and an oral antidepressant. These authors report that time to relapse in these treatment resistant depression patients was significantly longer, compared to the placebo-controlled group.

         Dr. Alan Schatzberg (2019), in a companion article to the Popova, Daly, Trivedi et al. (2019) article (3)  offers  a  more  skeptical point of view.  He points out  that there were three treatment trials and only one (described above) actually  reached statistical significance, although all three had similar change scores.  He notes  that only an  initial esketamine  administration may be necessary to cause the augmented  antidepressant effects since most of the change in the active drug  group occurred in the first  two days of the study; after that,  the difference  was maintained.   He points out that esketamine may have mu opioid properties which may have implications for the safety of treatment and associated withdrawal risk symptoms and relapse, with patients placed on placebo after esketamine withdrawal relapsing faster than usually occurs in antidepressant withdrawal studies.  He also  notes that three patients committed suicide in the  esketamine plus antidepressant group,  versus  none in the placebo plus antidepressant group,  and rapid decreases in  esketamine dosage appeared to lead to  more frequent relapse. He also  notes that the observed efficacy of esketamine was only “mild” and he  ultimately urges us to keep observing and to consider the potential pitfalls.

         A fourth article (Huetteman 2019) appeared on the MDedge/Psychiatry website and presented a Kaiser Health News summary  entitled “FDA overlooked  red flags in esketamine testing.”  As part of this article, the author notes that esketamine nasal spray information,   presented to the FDA as part of the approval process, showed  only modest evidence that it worked in only limited trials. The evidence included the observation that three patients committed suicide, as noted above.  The article states  that the FDA was under political pressure to rapidly “green light” drugs that treat life threatening conditions such as depression and thus the drug was approved in spite of some deep misgivings. Furthermore, this “greenlighting”  allowed the drug approval process  to be subject to shortcuts.   The author notes that Jess Fiedorowiz, a member of the  FDA advisory committee  described  the claims of efficacy as  “almost certainly exaggerated” after hearing the evidence; the drug approval process was subject to shortcuts such as the nature of the trials required for approval and the definition of drug resistance. Additionally, the article points out that the advantage over placebo was only 4 points on a 60-point scale and there is some evidence that the patient group was not actually treatment resistant, since treatment with a new antidepressant plus placebo led to a significant decrease in MADRAS score.

         Finally, it should be noted that other than development of  a novel method of administration and a slightly different form of ketamine, the major difference between all prior studies of ketamine and those evaluating esketamine is that the FDA has given approval for nasal esketamine as a treatment for treatment resistant depression, given along with an oral antidepressant agent.  A patent exists for that use and, hence, FDA acceptable  pharmaceutical studies  have occurred.   The bottom line of all this is that it is likely that insurance companies will pay for nasal esketamine as a treatment for at least treatment resistant depression, whereas much less expensive use of off label ketamine, in wide use now and growing, will be unlikely to obtain pharmaceutical industry evaluation, FDA approval or insurance reimbursement since, being in the public domain,  it cannot be patented in its current form.  The alternative of government funding of  studies of ketamine as an orphan drug, leading to FDA approval, at least to date, do not appear to be forthcoming.  Hopefully at some point, such studies will be supported and if ketamine as such is indeed proven to be an antidepressant,  ketamine itself  will be able to evolve from  off label usage to an FDA approved treatment of depression. FDA approval could be for  parental ketamine meeting criteria  as a stand-alone drug/antidepressant or as an adjunctive agent or in combination with more conventional antidepressants.



Brauser D. Experts Go Toe-to-Toe Over Esketamine Depression Study. May 21, 2019.  

Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X, Lane R, Lim P, Duca AR, Hough D, Thase ME, Zajecka J, Winokur A, Divacka I, Fagiolini A, Cubala WJ, Bitter I, Blier P, Shelton RC, Molero P, Manji H, Drevets WC, Singh JB. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment resistant depression, a randomized clinical trial. JAMA Psychiatry. 2019 Jun 5. doi: 10.1001/jamapsychiatry.2019.1189. [Epub ahead of print].

Huetteman E. FDA overlooked red flags in esketamine testing. MDedge/Psychiatry, Kaiser Health News. June 12, 2019.

Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, Mazzucco C, Hough D, Thase ME, Shelton RC, Molero P, Vieta E, Bajbouj M, Manji H, Drevets WC, Singh JB. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry. 2019;176(6):428-38.

Schatzberg A. A Word to the Wise About Intranasal Esketamine. Am J Psychiatry. 2019;176(6):422-4.


December 19, 2019