DEPRESSION AND ANXIETY 33:685–688 (2016)
Editorial WHITHER KETAMINE AS AN ANTIDEPRESSANT: PANACEA OR TOXIN? D. Jeffrey Newport, M.D., M.S., M.Div.,1,2 Alan F. Schatzberg, M.D.,3 and Charles B. Nemeroff, M.D., Ph.D.1,4 ∗
1 Department
of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida 2 Department of Obstetrics and Gynecology, University of Miami Miller School of Medicine, Miami, Florida 3 Stanford University School of Medicine, Stanford, California 4 Center on Aging, University of Miami Miller School of Medicine, Miami, Florida Disclosures: Dr. Newport has received research support from Eli Lilly & Company (Lilly), Glaxo SmithKline (GSK), Janssen, National Alliance for Research on Schizophrenia and Depression (NARSAD), National Institutes of Health (NIH), SAGE, Takeda Pharmaceuticals, and Wyeth. He has served on speakers’ bureaus for Astra-Zeneca (AZ), Lilly, GSK, Pfizer and Wyeth, and advisory boards for GSK. Dr. Schatzberg has served as a consultant for Alkermes, Cervel, Clintara, Forum Pharmaceuticals, McKinsey and Company, Myriad Genetics, Neuronetics, Naurex, One Carbon, Pfizer, Takeda, Sunovion, and X-Hale and as a speaker for Merck and Pfizer; he holds equity in Corcept (cofounder), Gilead, Incyte Genetics, Intersect ENT, Merck, Neurocrine, Seattle Genetics, Titan, and X-Hale; and he is listed as an inventor on pharmacogenetic and mifepristone patents from Stanford University. In the last 3 years, Dr. Nemeroff has received research support from NIH. He has served on scientific advisory boards for the American Foundation for Suicide Prevention (AFSP), Anxiety and Depression Association of America (ADAA), Brain and Behavior Research Foundation, Skyland Trail, and Xhale, on the board of directors for AFSP, ADAA, and Gratitude America, and as a consultant to Bracket, Lilly, Lundbeck, Mitsubishi Tanabe Pharma Development America, Roche, SK Pharma, Sunovion, Taisho, Takeda, and Xhale. He has equity in Xhale and stock holdings with Titan Pharmaceuticals, Seattle Genetics, etc. He has received honoraria, royalties, and expert witness fees from various sources. His income sources or equity of $10,000 or more include American Psychiatric Publishing, Xhale and Bracket. He holds patents for Method and devices for transdermal delivery of lithium (US 6,375,990B1) and Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2). ∗ Correspondence
to: Charles B. Nemeroff, University of Miami Miller School of Medicine, Clinical Research Building, 1120 NW 14 Street, Suite 1440, Miami, FL 33136. E-mail:
[email protected] Received for publication 25 April 2016; Accepted 26 April 2016 DOI 10.1002/da.22535 Published online in Wiley Online Library (wileyonlinelibrary.com).
C 2016 Wiley Periodicals, Inc.
Well they say that time loves a hero But only time will tell If he’s real he’s a legend from heaven If he ain’t he was sent here from hell Little Feat
Against the backdrop of an antidepressant pharmacopoeia beset by limited efficacy and delayed therapeutic action and a stagnant developmental pipeline for new antidepressants,[1, 2] ketamine therapy, celebrated as “the most important breakthrough in antidepressant treatment in decades”,[3] emerged to fanfare typically reserved for a rookie phenom ballplayer or presidential candidate du jour. The contents of this special issue of Depression and Anxiety offer instead a sober examination of the extant evidence regarding ketamine’s antidepressant efficacy, mechanism of action, and potential for abuse. As the following compendium will show, ketamine as an antidepressant is an evolving story. Whether ketamine will ultimately revolutionize antidepressant pharmacotherapy or wither under sustained scrutiny remains debated.
CAUSE FOR OPTIMISM Ketamine’s antidepressant activity is generally believed to be mediated by a truly novel antidepressant mechanism, antagonism of the N-methyl-D-aspartate (NMDA) glutamate receptor. This represents a stark and welcome departure from the mechanism of action of existing antidepressant agents, which are all believed to exert their therapeutic actions via modulation of monoaminergic neurotransmission. Initial suggestions that glutamatergic agents might hold antidepressant efficacy date back nearly six decades.[4] Numerous lines of evidence subsequently pointed to aberrant NMDA receptor mediated glutamate neurotransmission as a viable target for antidepressant pharmacotherapy, including alterations in central NMDA receptor binding profiles in rodent models of depression and postmortem tissue from suicide victims, as well as changes in NMDA receptor activity produced by chronic treatment with conventional antidepressants.[5] Even more encouraging is the consistent realization of the antidepressant potential of NMDA antagonism in randomized clinical trials of subanesthetic ketamine
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infusion. Indeed, existing data provide compelling evidence that ketamine’s antidepressant effects are both rapid and robust with an odds ratio for symptom remission of 14.47 [95% CI: 2.67–78.49] 24 hr after infusion.[6] Moreover, ketamine infusion has also been reported to rapidly alleviate suicidal ideation[7] and to be well tolerated with only transient dissociative and psychotomimetic effects on the day of infusion.[6] Finally, used as an antidepressant, ketamine may confer neuroprotective benefit, activating intracellular signaling pathways linked to synaptic plasticity. For example, ketamine administration has been associated with a cascade of increased phosphorylation of eukaryotic elongation factor 2 (eEF2), increased synthesis of brain-derived neurotrophic factor (BDNF), and heightened activation of mammalian target of rapamycin (mTOR). It has, in fact, been argued that ketamineinduced synaptogenesis is crucial to its antidepressant effects.[8]
CAUSE FOR SKEPTICISM Existing clinical trials indicate that the antidepressant effects of ketamine are as transient as they are rapid. Specifically, 1 week after ketamine infusion, the odds ratio for remission of depressive symptoms is no longer statistically significant and the odds ratio for therapeutic response, though significant, has fallen from a peak of 24.7 to 4.6.[6] Moreover, the extant literature has not demonstrated that serial ketamine infusions provide sustained therapeutic benefit beyond 2 weeks after the final infusion.[9, 10] For example, relapse rates within only 1 month following serial ketamine infusions range from 55 to 89%,[6] whereas relapse rates in 6 months following electroconvulsive therapy (ECT) approach 50%.[11] Existing data, therefore, indicate that the therapeutic response to ketamine lacks the durability of ECT treatment response, failing to support ketamine infusion as an alternative to ECT for acute treatment of depression. The solution to extending ketamine’s early therapeutic benefit arguably lies in ketamine maintenance therapy. However, there are currently no data regarding the efficacy and safety of ketamine maintenance therapy delivered intravenously, intranasally, or via other routes. In existing controlled studies, the longest duration of ketamine treatment has been only 6 weeks.[10] Instead, there is reason to be concerned regarding potential perils of long-term ketamine administration. For example, despite evidence supporting neuroprotective benefit of ketamine, in some contexts, ketamine may be neurotoxic. In particular, extended exposure has been posited as a risk factor for ketamine-induced neurotoxicity.[12] Ketamine’s addictive liability also warrants concern, particularly if, as some have speculated, the psychotomimetic and dissociative effects of ketamine are necessary for its antidepressant efficacy.[13, 14] Ketamine abuse is a widely recognized social problem in many countries, particularly in Asia,[15] but also in Europe and the United States.[16] Widespread dissemination of keDepression and Anxiety
tamine therapy, particularly as a maintenance treatment, could readily produce physiological and psychological dependence. Furthermore, diversion of prescribed ketamine for illicit use could rival problems encountered with prescription opiates and sedative hypnotics. In Hong Kong, for example, ketamine has supplanted heroin as the primary drug of abuse.[15] Finally, some have questioned whether the prevailing assumption that ketamine’s antidepressant mechanism of action, or at least its sole mechanism of action, is NMDA antagonism. It is noteworthy that no other NMDA antagonist has as yet provided consistent evidence of antidepressant efficacy approaching that of ketamine, and some (e.g., memantine) have provided no evidence whatsoever of antidepressant benefit,[6] though such differences could be attributable to distinctions in pharmacodynamic properties (e.g., high vs. low trapping) within the NMDA ion channel. Yet, it is also true that ketamine possesses a rich pharmacology, and its antidepressant activity has been variously attributed to modulation of sigma,[17] dopamine, [18] and serotonin[19] activity. Furthermore, ketamine also binds to mu opioid receptors,[8] which may also contribute to its antidepressant effects.[20] Ultimately, the lack of clarity regarding ketamine’s putative antidepressant mechanism hinders efforts to develop alternative glutamatergic antidepressants devoid of ketamine’s safety concerns and abuse liability. Recently, the identical dose of ketamine most commonly used to treat depression was shown to model schizophrenia-like symptoms in volunteers, and in that study, ventral striatal responses to reward were markedly attenuated by ketamine, hardly a desirable profile for an antidepressant.[21]
CAUSE FOR ALARM Truly alarming is the rapid proliferation of off-label ketamine administration in the absence of evidence of lasting therapeutic benefit or safety with long-term administration. For example, one ketamine provider recently notified us that he has managed many patients “on maintenance therapy for years”, administering 1,500 ketamine infusions annually, and routinely prescribing intranasal ketamine for outpatient use. Some depressed patients receive ketamine therapy in infusion centers directed by anesthesiologists, clearly practicing outside the scope of their training, in the absence of clinical monitoring by a psychiatrist. One active practitioner of ketamine therapy contends that “the wealth of clinical experience from treating hundreds of patients with ketamine has supplanted the preliminary data that emerged from . . . small doubleblinded studies” and “patients undergoing our protocols do not become addicted to ketamine and the “slippery slope” from treating depression to creating a ketamine addiction is not so precipitous as some would lead us to believe”.[22] Rather than providing reassurance, such statements serve to illustrate the ostensibly cavalier
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nature of current clinical practice with ketamine in some quarters. Ketamine neurotoxicity and ketamine abuse are factual not theoretical concerns. Indicated only for anesthesia, existing ketamine safety data are limited to its isolated use as an anesthetic agent. This simply does not address the frequency or magnitude of these concerns with repeated, long-term administration of ketamine. In fact, there are no systematic safety data regarding long-term ketamine administration. It may be debatable whether relying upon postmarketing surveillance in the aftermath of the proliferation of ketamine treatment centers to ascertain those risks will compromise public health, but doing so is certainly ethically dubious. Furthermore, outpatient ketamine therapy is currently administered in the absence of consensus therapeutic monitoring guidelines. A recent case report highlights the perils of poorly monitored ketamine therapy.[23] In this tragic case, an adult male with a long history of recurrent major depression was prescribed ketamine 75–150 mg intranasally every 4 hr as needed for depression but acknowledged using it 10–12 times daily. His family expressed concern that he used the prescribed ketamine while driving, and his ketamine abuse ultimately led to loss of employment. Despite these consequences, he continued to abuse ketamine until he was no longer able to obtain the drug. The following months were punctuated by worsening depression and increasing alcohol abuse, culminating in his death in a single automobile accident. The potential for such escalation from ketamine therapy to ketamine abuse is undeniable. Although a recent anecdotal report of 100 patients administered once weekly infusions denied that any patients requested additional infusions,[24] we were recently informed that one academic center in the United States closed its clinical ketamine program due to growing concerns regarding ketamine seeking behavior. One wonders whether the precipitous expansion of the ketamine infusion industry is being driven primarily by clinical need or financial incentive. Ketamine infusion therapy is clearly lucrative both acutely and with repeated administration. There is no scientific evidence, however, to support the use or safety of longer term maintenance.
THE FUTURE OF AN INFUSION Ketamine practitioners appear to be positioning it as an alternative to ECT to treat acute depression; however, current data do not support this role. The brevity of ketamine’s therapeutic benefit, in comparison to ECT, coupled with the absence of safety data for ketamine as a maintenance treatment, undermines any putative role for ketamine as an ECT alternative. At present, the only use justified by evidence from controlled studies is perhaps to address acute suicidality. If ketamine’s current role as an antidepressant is murky, its future is even more obscure. Our concern
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is that the too rapid spread of poorly monitored clinical use of ketamine, outpacing scientific scrutiny, may lead to dire public health consequences that will in turn invite legislative action that could curtail both clinical and research use of ketamine, hindering efforts to build upon the promise of current ketamine research. We invite the medical community to proactively expedite the establishment of guidelines for current clinical use of ketamine. Whether continuing research will more definitively clarify the clinical antidepressant utility and safety of ketamine remains to be seen, as does whether further research on ketamine’s mechanism of action will aid in follow on drug development. Our hope is that overly ambitious, or worse, poorly justified and potentially unscrupulous clinical practice, will not compromise future, rational use of ketamine and the study of NMDA antagonism as a potential target of antidepressant development. Ultimately, only time will tell whether ketamine as an antidepressant has a place in our pharmacological armamentarium.
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