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Home , Arketamine, Esketamine, Lanicemine, Naltrexone

Commentary HOW WORKS

Ketamine/: Putative mechanisms of action

Details of how these agents produce rapid effects have been misrepresented

ince the FDA approved intranasal esketamine, there has understandably been significant dialogue, debate, and Sdiscussion about the possible mechanisms of action of its antidepressant effects. Ketamine, the racemate of esket- and , has been used off-label since the late 1990s. The first study of IV ketamine’s rapid antidepressant activity was published in 2000.1 In that study, 7 patients with major depressive disorder (MDD) were treated in a double- blind/placebo-controlled manner with IV ketamine or pla- cebo. Researchers found a significant antidepressant effect within 72 hours with the administration of IV ketamine. There is a tremendous number of publications related to ketamine, which creates a large reservoir of information to ZERBOR review in an attempt to piece together what we currently know John J. Miller, MD about the mechanisms of action of ketamine/esketamine Medical Director, Brain Health (K/ESK). A search of PubMed using the search word “ket- Editor-in-Chief, Psychiatric Times amine” (October 8, 2019; www.ncbi.nlm.nih.gov/pubmed) Staff Psychiatrist, Seacoast Mental Health Center Consulting Psychiatrist, Exeter Hospital produced a list of 4,869 articles just in the last 5 years; and the Exeter, New Hampshire search words “ketamine and ” produced a list of Consulting Psychiatrist 1,221 publications over the same time period. Insight Meditation Society Barre, Massachusetts The FDA approval of intranasal esketamine in March 2019 was based on 5 phase III clinical studies (albeit not all were positive studies) and >9 years of intensive pre- clinical and clinical research on the efficacy and safety of intranasal esketamine in treatment-resistant depres- sion (TRD). At the time the FDA approved it, esketamine had been studied in 1,700 patients with TRD, with 1-year safety data on approximately 800 patients. Despite this

Disclosure Current Psychiatry Dr. Miller is a consultant to Janssen and Sunovion, and a speaker for Allergan, Janssen, Neurocrine, 32 January 2020 Otsuka, Sunovion, and Teva. established data portfolio, critics of K/ESK ketamine’s mechanisms of action. Ketamine continue to opine that we do not have was discovered in 1962 by chemist Calvin enough long-term experience with these L. Stevens, who was experimenting with , and some key opinion leaders con- novel molecular structures to find a replace- MDedge.com/psychiatry tinue to voice caution about the clinical use ment for as a safer dissocia- of K/ESK until we obtain more information tive . After successful experiments and experience. in human prisoners in 1964, ketamine was An article in the September 2019 issue further studied and became FDA-approved Currrent Psychiatry by Epstein and in 1970 as a anesthetic. Lacking Farrell2 exemplifies my concern regarding respiratory depression and hypotension, the misrepresentation of significant details which were common adverse effects of about what we know about the mechanism other , ketamine became com- of action of K/ESK. Both K/ESK are cer- monly used on the battlefield in the Vietnam tainly not “miracle cures,” and although I War, and continues to be used as a dissocia- understand the use of this term in the arti- tive anesthetic. cle’s title, the continued use of this term to Following the publication of the Berman describe K/ESK in the article is detrimental. article1 in 2000 that demonstrated appar- Clinical Point The authors caution about “miracle cures” ent RAAD activity of IV ketamine, interest Ketamine/ ultimately proving to be harmful, and sug- in ketamine’s use for TRD—a huge unmet gest that K/ESK could end up in the trash need in psychiatry—skyrocketed. Since esketamine may heap with Freud’s 1884 positive descrip- the FDA approval of (a mono- rapidly improve tion of for depression and inducing amine oxidase inhibitor) as the first medi- depression by insulin comas to treat patients with schizo- cation approved to treat major depression ultimately increasing phrenia, a treatment used until 1960. These in 1958, and the FDA approval of imipra- synaptogenesis in rogue treatments were used in the infancy mine in 1959, all subsequent FDA-approved of psychiatry, at a time when there was a have shared iproniazid/ the prefrontal cortex paucity of treatments available in psychia- ’s properties of modulating the try, and only a primitive understanding of monoamines serotonin, , and the brain. norepinephrine. The infamous Sequenced Of greater concern to me is the authors’ Treatment Alternatives to Relieve Depression simplistic and flawed description of the (STAR*D) trial concluded that only 37% of of ketamine. They patients with a major depressive episode state “based on available research, ket- achieve remission with their first antide- amine’s long-lasting effects seem to come pressant trial, and only 49% respond (50% from 2 mechanisms… activation of endog- improvement in symptoms).3 Ketamine/ enous receptors… [and] blockade esketamine offered a novel mechanism of of N-methyl-d-aspartate receptors.” In the action, presumed to be related to the gluta- spirit of scientific inquiry, I would like to mate system, that demonstrated a clinical explore the current evidence base of the improvement in depressive symptoms in as putative mechanisms of action of K/ESK. few as 4 hours, with benefits that lasted up to 1 week after a single dose.

Ketamine: A plethora of studies An impressive body of literature is A model of how ketamine works attempting to piece together the complex Numerous publications from preclinical and multidimensional neurophysiologi- and clinical research collectively have Discuss this article at cal mechanisms that result in ketamine’s woven a putative model of how K/ESK www.facebook.com/ MDedgePsychiatry rapid-acting antidepressant (RAAD) effect, may rapidly improve depression by ulti- which occurs as soon as 4 hours post-dose. mately increasing synaptogenesis in the A plethora of pre-clinical and clinical stud- human prefrontal cortex—a part of the brain ies, including functional connectivity MRI known to atrophy in states of chronic stress scans in individuals with MDD, have pro- and depression.4 What is well established is Current Psychiatry vided a rough outline, albeit incomplete, of the noncompetitive antagonism of K/ESK Vol. 19, No. 1 33 at the N-methyl-d-aspartate (NMDA) glu- The demonstration of increased global con- tamate , but this pharmacodynamic nectivity in the prefrontal cortex of patients property may or may not be responsible, or with MDD, both during ketamine infusion even required, for the ultimate antidepres- and at 24 hours post-infusion, supports sant effect 4 hours after administration. the clinical observations in clinics treating It has been shown that unlike anesthetic patients with K/ESK. doses of K/ESK that inhibit glutamate, sub- How ketamine anesthetic doses activate neuronal gluta- works mate transmission in the prefrontal cortex.5 Opioid receptors and ketamine A significant body of evidence supports During the past year, there has been sig- agonism of the glutamate -amino- nificant discussion in psychiatry about the 3-hydroxy-5-methyl-4-isoxazolepropionic possible role of the mu acid (AMPA) receptor as an important step and opioid system activation in ketamine’s in the cascade of events that ultimately RAAD effect. Remarkably, the literature increases levels of the mammalian target supporting this hypothesis in humans is of rapamycin (mTOR), which unleashes based on a single study by Williams et al.15 Clinical Point protein synthesis in synapses facilitating The authors’ claim: “We now present the Evidence that synaptogenesis. Pretreatment with AMPA first evidence in humans that opioid recep- receptor antagonists blocks the downstream tors are necessary for ketamine’s acute anti- opioid receptors effect of synaptogenesis.6,7 In support of this depressant effect.” In fact, in my opinion, are necessary putative mechanism, , this single study, which has not been repli- for ketamine’s a metabolite of racemic ketamine that has cated, is highly flawed. It included 30 adults antidepressant effect also demonstrated RAAD activity in a with TRD, but only 12 of the 14 participants ketamine-like manner, is dependent upon who qualified for the planned interim comes from a single AMPA upregulation analysis completed the double-blind cross- study and activation, while not requiring activity over. The population studied was quite at the NMDA-glutamate receptor.8,9 treatment-refractory; the average duration A comprehensive model on the putative of MDD was 24.1 years, the average age at molecular cascade of events contributing onset was 17.3 years, and the duration of to the antidepressant effect of ketamine the current depressive episode at the time has recently been published10 and mirrors of the study was 8.6 years. Most significant the excellent previous review by Abdallah to me was the reason the study was termi- et al.11 Hirota and Lambert10 propose that nated: “At the interim analysis, given the antagonism of interneuronal NMDA- finding that the combination of ketamine glutamate receptors on GABAergic inter- and naltrexone was not only ineffective neurons may result in a prefrontal cortex but also noxious for many participants, surge of glutamate, which increases ago- we decided to stop enrolling patients in nism of the AMPA-glutamate receptor. This the study.” A distinct possibility is that the AMPA-glutamate receptor agonism has noxious adverse effects from the naltrexone been shown to increase expression of brain- impacted the participants’ experience in derived neurotrophic factor (BDNF) and a negative manner, dampening down any vascular endothelial growth factor (VEGF),12 antidepressant effect from ketamine. both of which converge on increasing lev- In the August 2019 issue of Molecular els of mTOR, and the subsequent activation Psychiatry, these same authors published of mTOR, which putatively plays a role in a second article16 with conclusions based increased production of scaffolding pro- solely on “a secondary analysis of” the data teins and increased synaptogenesis, espe- from the same 12 participants in their first cially in the prefrontal cortex. In support of publication. Williams et al16 concluded that this model, during infusion and at 24 hours naltrexone also decreases the anti-suicidal- after a single ketamine infusion in individu- ity effects of ketamine. Without any addi- als with MDD, functional connectivity MRI tional data or clinical research, these same demonstrated an increase in global brain authors extrapolated their hypothesized Current Psychiatry 34 January 2020 connectivity in the prefrontal cortex.13,14 opioid receptor activity of ketamine to include it being responsible for ketamine’s pretreatment group, at 2 weeks post IV established anti-suicidal effects. ketamine infusion, patients treated with Mathew and Rivas-Grajales17 recently rapamycin-ketamine had a longer dura- published a thoughtful critique and analy- tion/greater improvement in their depres- MDedge.com/psychiatry sis of the study design and conclusions of sive symptoms compared with the patients the original Williams paper.15 They con- receiving placebo-ketamine (improvement of cluded that insufficient evidence exists to 41% vs 13%, respectively, P = .04). Abdallah answer the question of how ketamine may et al22 hypothesized that the pretreatment interface with the opioid system, and they with rapamycin provides anti-inflammatory encourage further research into this impor- benefits to the synaptogenesis resulting tant topic. from ketamine, which protects the newly Two additional recent publications18,19 formed synapses and prolongs ketamine’s reported that naltrexone pretreatment did antidepressant effect. Schatzberg21 came to not attenuate the antidepressant effects of a different conclusion than Abdallah et al,22 ketamine in their participants. Additionally, opining that because the rapamycin “failed a recent publication in the anesthesiol- to decrease ketamine response,” this result ogy literature20 concluded that esketamine debunks the role of mTOR as a mediator Clinical Point reversed respiratory depression that was in the antidepressant effect of ketamine Two additional recent induced by . From a clinical through synaptogenesis. perspective, the most compelling argument publications reported against a direct mu opioid receptor mecha- that naltrexone nism for K/ESK is the lack of any craving, Much more to learn pretreatment did tolerance, or withdrawal in patients with We still have a great deal to learn about the not attenuate the TRD treated with K/ESK in numerous clin- mechanism of action of K/ESK. However, antidepressant effects ical publications comparing K/ESK with clinics that are augmenting antidepressants placebo. In the case of esketamine, during with K/ESK in patients with TRD report of ketamine the 5 phase III clinical trials—including significant and rapid symptom improve- both short- and long-term studies—there ment in some patients (personal commu- was no signal for an opioid-like pharma- nications). We still do not understand the cology. Significantly, both K/ESK are rap- actual mechanisms of action of antidepres- idly metabolized by the human body, and sants and , but this does not the typical dosing is 2 doses/week for the curtail their use and clinical benefits to our first month, then 1 dose/week for the next patients. Ketamine has been extensively month, then 1 dose every week or less for studied. In the current appropriate climate the remainder of treatment. of concern about the pervasive and lethal Curiously, in the May 2019 issue of the in the United States, we American Journal of Psychiatry, Schatzberg21 must remain on solid scientific ground (one of the co-authors of the prior 2 stud- before attributing an opioid mechanism to a ies opining that ketamine has direct opioid novel treatment that has already benefitted system activation) wrote a “Reviews and many of our most depressed and refractory Overviews” article in which he misrepre- patients. sents the conclusions of an elegant study by Looking at the extensive published Abdallah et al22 published in December 2018. data over the past 20 years, a consistent Abdallah et al22 added rapamycin, an model has emerged whereby glutamate immunosuppressant and a known inhibitor agonism of the AMPA-glutamate receptor, of mTOR, as a pretreatment to patients in a both with and without antagonism of the major depressive episode prior to infusion NMDA-glutamate receptor, appears to set with IV ketamine. Their hypothesis was to in motion a molecular cascade involving see if the rapamycin decreased ketamine’s BDNF and VEGF, and ultimately increasing rapid antidepressant response—putatively the activity of mTOR, with resulting synap- by inhibiting the effect of mTOR. Rather togenicity that increases global brain con- than decreasing ketamine’s antidepres- nectivity in the human prefrontal cortex. As Current Psychiatry sant effect, and in contrast to the placebo we continue to understand the complexities Vol. 19, No. 1 35 8. Zanos P, Moaddel R, Morris PJ, et al. NMDA inhibition- independent antidepressant actions of ketamine metabolites. Related Resources Nature. 2016;533(7604):481-486. • Mattingly GW, Anderson RH. Intranasal esketamine. Current 9. Collo G, Cavalleri L, Chiamulera C, et al. (2R,6R)- Psychiatry. 2019;18(5):31-38. Hydroxynorketamine promotes dendrite outgrowth in human inducible pluripotent stem cell-derived neurons • Thase M. Ketamine and esketamine for treating unipolar through AMPA receptor with timing and exposure depression in adults: Administration, efficacy, and adverse compatible with ketamine infusion in effects. UpToDate. www.uptodate.com/contents/ketamine- humans. Neuroreport. 2018;29(16):1425-1430. and-esketamine-for-treating-unipolar-depression-in-adults- 10. Hirota K, Lambert DG. Ketamine and depression. Br J administration-efficacy-and-adverse-effects. Anaesth. 2018;121(6):1198-1202. How ketamine Brand Names 11. Abdallah CG, Adams TG, Kelmendi B, et al. Ketamine’s mechanism of action: a path to rapid-acting antidepressants. works Esketamine nasal spray • Naltrexone • Vivitrol, ReVia Depress . 2016;33(8):689-697. Spravato Rapamycin • Rapamune 12. Deyama S, Bang E, Wohleb ES, et al. Role of neuronal VEGF Imipramine • Tofranil Remifentanil • Ultiva signaling in the prefrontal cortex in the rapid antidepressant Ketamine • Ketalar effects of ketamine. Am J Psychiatry. 2019;176(5):388-400. 13. Abdallah CG, Dutta A, Averill CL, et al. Ketamine, but not the NMDAR antagonist , increases prefrontal global connectivity in depressed patients. Chronic Stress (Thousand Oaks). 2018;2. doi: 10.1177/2470547018796102. 14. Abdallah CG, Averill LA, Collins KA, et al. Ketamine treatment and global brain connectivity in major depression. and additional circuitries that are involved Neuropsychopharmacology. 2017;42(6):1210-1219. 15. Williams NR, Heifets BD, Blasey C, et al. Attenuation Clinical Point in the RAAD effect of K/ESK, the hope is of antidepressant effects of ketamine by opioid receptor that novel molecular targets for future drug antagonism. Am J Psychiatry. 2018;175:1205-1215. A better 16. Williams NR, Heifets BD, Bentzley BS, et al. Attenuation of development will emerge. antidepressant and antisuicidal effects of ketamine by opioid understanding of receptor antagonism. Mol Psychiatry. 2019;24(12):1779-1786. the antidepressant References 17. Mathew SJ, Rivas-Grajales AM. “Does the opioid 1. Berman RM, Cappiello A, Anand A, et al. Antidepressant system block or enhance the antidepressant effects of effects of ketamine effects of ketamine in depressed patients. Biol Psychiatry. ketamine?” Chronic Stress. (Thousand Oaks). 2019;3. doi: 2000;47:351-354. 10.1177/2470547019852073. 18. Yoon G, Petrakis IL, Krystal JH. Association of combined might lead to novel 2. Epstein K, Farrell HM. ‘Miracle cures’ in psychiatry? Current naltrexone and ketamine with depressive symptoms in Psychiatry. 2019;18(9):13-16. molecular targets for a case series of patients with depression and use 3. Valenstein M. Keeping our eyes on STAR*D. Am J Psychiatry. disorder. JAMA Psychiatry. 2019;76:337-338. 2006;163:1484-1486. drug development 19. Marton T, Barnes DE, Wallace A, et al. Concurrent use 4. Abdallah CG, Sanacora G, Duman RS, et al. The of , , or naltrexone does not neurobiology of depression, ketamine and rapid-acting inhibit ketamine’s antidepressant activity. Biol Psychiatry. antidepressants: is it glutamate inhibition or activation? 2019;85(12):e75-e76. Pharmacol Ther. 2018;190:148-158. 20. Jonkman K, van Rijnsoever E, Olofsen E, et al. Esketamine 5. Moghaddam B, Adams B, Verma A, et al. Activation of counters opioid-induced respiratory depression. Br J neurotransmission by ketamine: a novel Anaesth. 2018;120(5):1117-1127. step in the pathway from NMDA receptor blockade to 21. Schatzberg AF. Scientific issues relevant to improving and cognitive disruptions associated with the the diagnosis, risk assessment, and treatment of major prefrontal cortex. J Neurosci. 1997;17(8):2921-2927. depression. Am J Psychiatry. 2019;176(5):342-347. 6. Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse 22. Abdallah C, Averill LA, Gueorgueiva R, et al. Rapamycin, formation underlies the rapid antidepressant effects an immunosuppressant and mTORC1 inhibitor, triples of NMDA antagonists. Science. 2010;329(5994): the antidepressant response rate of ketamine at 2 weeks 959-964. following treatment: a double blind, placebo-controlled, 7. Hoeffer CA, Klann E. mTOR signaling: at the crossroads cross-over, randomized . bioRxiv. December 19, of plasticity, memory, and disease. Trends Neurosci. 2018. https://www.biorxiv.org/content/10.1101/500959v1. 2010;33(2):67-75. Accessed December 5, 2019.

Bottom Line Extensive published data over the past 20 years has produced a consistent model to explain the putative mechanisms of action for the rapid antidepressant effects of ketamine and esketamine. We must remain on solid scientific ground before attributing an opioid mechanism to a novel treatment that has already benefitted Current Psychiatry 36 January 2020 many of our patients with treatment-resistant depression.