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Ketamine, Cum Grano Salis

Ketamine, Cum Grano Salis

The findings reported in Arline Kaplan’s article on ketamine (New Claims and Findings for Ketamine in Severe Depression ), are certainly exciting, particularly for those of us who have attended the considerable suffering of many patients with treatment-resistant depression (TRD). TRD has been defined in various ways, but recent opinion has considered TRD as depression that has responded inadequately to at least 2 trials with antidepressants from different pharmacological classes, with adequate dosage, duration, and adherence to treatment.1 TRD may occur in as many as 60% of depressed patients,2 and effective remedies are hard to come by. If the early and encouraging ketamine findings are borne out in large, randomized, double-blind, controlled studies, this will represent a significant advance in our treatment options for MDD.3

And yet, there are several reasons for taking the ketamine findings with a substantial grain of salt. First, there is history. Those of us who have been treating mood disorders for the past 30 or more years have seen many “amazing new remedies” fizzle out, once tested in carefully controlled trials. This is not to diminish the importance or integrity of the keta-mine research thus far. It is only to say that the number of ketamine-treated patients is still small; the duration of study, quite short; and the durability of ketamine’s apparent benefits, limited to a few weeks. Notably, to my knowledge, there have been no controlled studies comparing ketamine (via infusion or other modality) with an active control (ie, a drug that produces some al-teration in consciousness beyond the placebo effect of saline). It is encouraging, however, that such an active-control study is under way at New York State Psychiatric Institute, in which depressed participants are randomly assigned to receive a single intravenous dose of either ketamine or midazolam (a short-acting benzodiazepine with pronounced amnestic effects).4

I also wonder whether the informed consent process for ketamine treatment has included a discussion of alternative treatments known to be effective for TRD; for example, electroconvulsive therapy (ECT). Yes, I’m well aware that ECT carries its own risks (including cognitive side effects) and that there are many administrative and psychological barriers to its availability. Nevertheless, ECT is “acknowledged as the most effective acute treatment for severe mood and psychotic disorders.”5 Surely, a patient with severe, treatment-resistant MDD should be apprised of ECT as an alternative to a ketamine trial, if consent is to be fully “informed.” And, in my view, other agents with well-documented efficacy in TRD—such as adjunctive lithium or triiodothyronine (T3)6—should also be included in the informed consent process, assuming the patient has not already tried these agents.

Finally—though this may surprise some who consider “treatment” in psychiatry to include only somatic therapies—there are also good rea-sons to consider psychotherapy in some nonmelancholic, nonpsychotic cases of TRD.7-9 Although studies are quite limited and methodologically flawed, one recent review concluded that “primary care providers should consider psychotherapy when treating patients with treatment-resistant depression.”8

All that said, I well understand that some TRD patients are acutely suicidal and may not benefit quickly from “established” treatments that require weeks or months for full effect. In such cases, and after a thorough informed consent process (which is more than signing a “form”), a ketamine trial may indeed be worth considering.



1. Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52:46-54.

2. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649-659.

3. Pies R. Are antidepressants effective in the acute and long-term treatment of depression? Sic et non. Innov Clin Neurosci. 2012;9:31-40.

4. Kellner CH, Greenberg RM, Murrough JW, et al. ECT in treatment-resistant depression. Am J Psychiatry. 2012;169:1238-1244.

5. McIntyre RS, Müller A, Mancini DA, Silver ES. What to do if an initial antidepressant fails? Can Fam Physician. 2003;49:449-457.

6. Brown WA.Treatment response in melancholia. Acta Psychiatr Scand Suppl. 2007;(433):125-129.

7. Trivedi RB, Nieuwsma JA, Williams JW Jr. Examination of the utility of psychotherapy for patients with treatment resistant depression: a systematic review. J Gen Intern Med. 2011;26:643-650.

8. Wiles N, Thomas L, Abel A, et al. Cognitive behavioural therapy as an adjunct to pharmacotherapy for primary care based patients with treatment resistant depression: results of the CoBalT randomised controlled trial. Lancet. 2012 Dec 6; [Epub ahead of print]. doi:10.1016/S0140-6736(12)61552-9.

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