Psychiatric Times. Vol. 30 No. 1

Ketamine, Cum Grano Salis

By Ronald Pies, MD | January 17, 2013

The findings reported in Arline Kaplan’s article on ketamine(Drug information 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(Drug information on 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(Drug information on 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.

by John Gehm | January 19, 2013 11:33 AM EST

Sir,
As someone who has recently participated in a ketamine trial at NIH for TRD/Bipolar Depression I take great exception to your comments. They are not based on facts but on stereotypes and represent what those of us who have struggled with this disase for years must begin educating the professional medical community about. Your comment about measuring ketamine against an active control is a valid point. However, that does not diminish the validity of the profound effects of the treatment. Yes, perhaps, as always, "more studies are needed". BUT in the meantime, this treatment could be saving lives right now, today. The effectiveness of ketamine is dramatic. Based on my experience, ketamine is far superior to ECT, psychotherapy, or any other drug currently available. Having experienced my depression of some fifty years draining away in a matter of hours, I can speak to the issue that the effects 'do not last."Feeling my anxiety, guilt, hopelessness, negative self-worth, self-blame, self-consciousness, feelings of worthleness and lack of ambition drain away like the dirty water in a bathtub circling the drain within 2 hours of the ketamine infusion, is a life-altering experience. The power of understanding that there is a healthy, whole person standing there after all one once believed was a part of the self has drained away cannot be overestimated. Yes, the direct, immediate effect of ketamine does fade over a period of 1 to 2 weeks but the original experience remains and is something that one can build on going forward. It profoundly alters one's sense of self and self-efficacy. (And yes, there are the psychomimetic effects but dare I suggest that they might also contribute to the effectiveness of the treatment? However, that is a discussion for another day.) We have known since 2004 that ketamine reduces suicidal ideation and has the potential to save lives right now, right here. How many more people have to succumb to this illness before the medical community will begin to understand that ketamine research is not an either or proposition. We can begin to use it to save lives while we continue to understand how and works and for whom it works best. We don't have to wait for a drug to be developed without the "unfortunate side effects" (unfortunate for who?) and we don't have to wait until all possible candidates have exhausted all potential other remedies. Trust me, we have. Ketamine is safe, effective, inexpensive, and can be used right now. Many, many clinical trials have been ended early due to compassionate concerns. Reviewing the dozens of studies dating back to 2000, ketamine for the treatment of MDD/TRD and, in my case, bipolar depression, certainly qualifies for this.

by Ronald Pies | January 19, 2013 8:41 PM EST

Dear Mr. Gehm:

I very much appreciate your writing about your positive experience with ketamine. I think you make a valid point: we should not wait for further studies (however necessary they may be) before using ketamine in appropriately-selected patients who have been fully informed of the risks and benefits of ketamine, as well as other potential remedies for treatment-resistant depression, such as ECT. Indeed, my concluding point was:

"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."

However, it is too early to conclude--on the basis of a few reports--that "...ketamine is far superior to ECT, psychotherapy, or any other drug currently available." That may turn out to be the case, but the gold-standard research on this question must still be done before we over-sell this potentially valuable treatment.

Respectfully,
Ron Pies MT

by David Feifel | January 25, 2013 2:45 PM EST

An Open Reply to Dr. Pies' Comments by Dr. Feifel

Dr. Pies makes some valid points in regard to the article by Arline Kaplan, but also some unfounded and mildly insulting assumptions. He states, "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... (which is more than signing a "form"). His assumption is that because I discussed the UCSD consent form, this document constitutes the totality of the informed consent we provide to prospective ketamine patients at UCSD.

Almost all our ketamine patients are self- or physician-referred and I cannot recall a single one who was not aware of the ECT option. Before any patient receives ketamine treatments tor TRD at UCSD they undergo a consultation during which past treatments are reviewed and the relevant options are presented to them, including additional pharmacological or psychotherapy approaches that they may not have received, TMS, ECT as well as ketamine. Most patients in my experience strongly want to avoid ECT treatment and I typically find myself needing to disabuse many of these patients of common misperceptions about the risks of ECT. I do this because we have a TRD program, not a ketamine program and I want these patients to recognize the potential benefit of ECT, especially if ketamine or any another option they may chose to receive fails. I agree with Dr Pies that ECT has the strongest body of efficacy evidence for TRD. Having said that however, I do feel that there is a powerful rationale for a trial of ketamine before ECT, given ketamine's relative non-invasive nature and rapid outcome compared to an ECT series. If I were a TRD patient, I would probably want to undergo a ketamine infusion and find out in a single day whether or not I was a responder to it, rather than commit to series of approximately 12 ECT treatments in order to find out if I was a ECT responder.

With regards to Dr Pies, caution about Ketamine's efficacy, "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." I too have been treating mood disorders and conducting clinical and basic research on treatment for psychiatric disorders for decades, so I generally share Dr. Pies' conservative stance on purported breakthrough treatments. I would note, however, that for every new treatment that was reported to be amazing in the clinic and fizzled out when tested in controlled trials, I have seen another that appeared amazing in carefully controlled trials and fizzle out once it reached the clinic. So I have a healthy skepticism toward anecdotal clinical reports as well as positive results from controlled trials. I think the critical thing that separates me and Dr.Pies is that only one of us has seen the effects of ketamine treatments on TRD patients, including ones that have failed ECT. That experience has left me convinced that ketamine is truly a remarkable, unprecedented antidepressant. I have treated TRD patients with medications, ECT and TMS, among other things, but I have not seen the results I am seeing with ketamine. However, I also recognize that ketamine does have a potential fatal flaw which is the transient nature of the efficacy from each treatment. If it turns out that we cannot find a practical way to maintain the prodigious acute benefits in patients over long-periods, than ketamine too, despite its remarkable acute efficacy, may fizzle as a treatment. That, in my opinion, is the challenge before us.

David Feifel, MD, PhD

by Ronald Pies | January 25, 2013 10:04 PM EST

Dr. Pies responds to Dr. Feifel:

I appreciate Dr. Feifel's taking the time to comment on my cautionary note, and I am sorry if he drew the unwarranted inference that I was criticizing him, his UCSD colleagues, or the informed consent process at UCSD. I deliberately avoided naming specific researchers in my piece, precisely to avoid any such personalized criticism. My comments on the informed consent process were intended as general remarks,
pertaining to any treatment-resistant depression (TRD) programs that offer the ketamine option. I am also very encouraged and reassured to hear that, in the UCSD program, patients

"...undergo a consultation during which past treatments are reviewed and the relevant
options are presented to them, including additional pharmacological or psychotherapy
approaches that they may not have received, TMS, ECT as well as ketamine."

This is indeed genuine informed consent, and Dr. Feifel and his colleagues are to be commended for their thoroughness. That said, it has been my experience, and that of many forensic psychiatrists, that "informed consent"in many clinical settingsconsists mainly in the patient's signing a boilerplate consent form--not a genuine and ongoing process, subject to periodic reassessment and revisiting, based on the patient's response to treatment. It was this concern I was addressing--not any aspect of the UCSD or other program's consent procedures. [see, e.g. Goldfarb E et al, Enhancing informed consent best practices: gaining patient, family and provider perspectives using reverse simulation. J Med Ethics. 2012 Sep;38(9):546-51]

I have great respect for the research Dr. Feifel and other investigators are conducting on ketamine and other agents that appear to work via the NMDA receptor; this is certainly a welcome break with the usual SSRI/SNRI lock-step that, in my view, has limited progress in the treatment of treatment-resistant depression. As for which treatment ought to come first in patients with severe, treatment-resistant depression--ketamine or ECT?--here
I think we need to consider and balance competing priorities. The very early "read out" that may emerge from a ketamine trial is one reason to place ketamine ahead of ECT in the TRD treatment sequence; but the incomparably long and compelling ECT data base, over more than 50 years of experience, is arguably a more persuasive factor--at least, from the standpoint of "evidence-based medicine." That said, I agree with Dr. Feifel that for some TRD patients who do not want to assume the potential cognitive risks and long-term "commitment" entailed in ECT treatment, a ketamine trial is a rational alternative. And,yes, Dr. Feifel is right--I have not observed ketamine-treated patients, so it is hard for me to share in Dr. Feifel's enthusiasm. On the other hand, I suspect that we have both seen the impressive efficacy of carefully-conducted ECT treatment, in severely depressed, suicidal patients [Kellner CH, Greenberg RM, Murrough JW, et al. ECT in treatment-resistant depression. Am J Psychiatry. 2012;169:1238-1244]

Finally, I agree with Dr. Feifel that, "If it turns out that we cannot find a practical way to maintain the prodigious acute benefits in patients over long-periods, than ketamine too, despite its remarkable acute efficacy, may fizzle as a treatment." But I'm sure I share with Dr. Feifel the hope that ketamine or related NMDA-active drugs do indeed produce enduring benefits for our TRD patients.

Respectfully,
Ron Pies MD

P.S. I just noticed that the references in the online version of my article
were "off by one", beginning with ref. 4. The correct listing follows, and I
apologize for any confusion:

4.http://clinicaltrials.gov/ct2/show/NCT01700829
5.Kellner CH, Greenberg RM, Murrough JW et al: ECT in Treatment-Resistant
Depression. Am J Psychiatry 2012;169:1238-1244
6.McIntyre RS, Muller A, Mancini DA et al. What to do if an initial antidepressant
fails? Can Fam Physician. 2003; 49: 449-457.
7.Brown WA.Treatment response in melancholia. Acta Psychiatr Scand Suppl.
2007;(433):125-9.
8.Trivedi RB, Nieuwsma JA, Williams JW: Examination of the Utility of Psychotherapy
for Patients with Treatment Resistant Depression: A Systematic Review. J Gen Intern
Med. 2011; 26(6): 643-650.
9.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. The Lancet, Early Online
Publication, December 7, 2012

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References

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.

Ketamine, Cum Grano Salis

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