Depression’s Journey From Monoamines to Glutamate

From the Editor

March 5, 2019 turned out to be an important day for psychiatric providers as well as individuals suffering from treatment resistant depression (TRD). This was the day that esketamine (Spravato) was FDA approved as an intranasal spray to combine with a traditional oral antidepressant to treat individuals that, despite aggressive and adequate traditional psychopharmacological treatments, remained severely depressed. There are many stories within this story that I would like to explore.

Ketamine’s story

Ketamine was discovered by chemist Calvin Stevens in 1962. After studies in animals demonstrated ketamine’s anesthetic effect, it was studied in human prisoners in 1964. Once ketamine proved itself to be an effective dissociative anesthetic, it was FDA approved in 1970. Unlike many anesthetics, ketamine demonstrated properties that were advantageous in acute trauma situations-specifically it did not cause respiratory depression and hypotension-and it was found to be quite useful for injured soldiers during the Vietnam War. Since that time it has continued to be used in medicine for the induction and maintenance of anesthesia, often in combination with other medications. Additionally, ketamine is commonly used in veterinary anesthesia, and is used as a first-line agent in equine surgery. In 2000, Berman and colleagues,¹ at Yale University reported a significant antidepressant effect within 72 hours when 7 depressed individuals were treated with intravenous ketamine in contrast to a saline placebo.

This rapidly acting antidepressant effect of ketamine was replicated by numerous studies and led to significant excitement in the psychiatric community for the possibility of a novel mechanism of action for the treatment of depression. Up until esketamine’s FDA approval for TRD this year, all other FDA-approved antidepressants-monotherapy and augmentation agents-shared mechanisms of action that acted on the monoamine system, including the neurotransmitters serotonin, norepinephrine, and dopamine.

The monoamine hypothesis of depression dates to 1952 when both reserpine (used to treat hypertension) and iproniazid (used to treat tuberculosis) were shown to increase brain levels of the monoamines serotonin, norepinephrine and dopamine, and simultaneously treated symptoms of depression. Ultimately iproniazid was FDA approved as our first antidepressant medication in 1958, followed by imipramine in 1959. Although these and all subsequent antidepressants showed clinical effectiveness in the treatment of depression, it often takes 2 to 8 weeks to achieve improvement. Hence, the observation in 2000 that ketamine appeared to reduce depressive symptoms within 72 hours of the first treatment was a true and welcome paradigm shift.

An explosion of research on ketamine and its 2 isomers, esketamine and arketamine, ensued. A search on PubMed (April 12, 2019; https://www.ncbi.nlm.nih.gov/pubmed) listed 4669 articles published with the search word “ketamine” in the past 5 years. Although ketamine has been FDA approved as an anesthetic since 1970, its use in depression has been off label, greatly limiting its access to most depressed individuals. Ketamine remains off label for the treatment of TRD but is administered throughout the US by physicians of various specialties in ketamine clinics, where it is usually administered intravenously, and with no consistent protocol.

Long-term studies are lacking to quantify duration of treatment, frequency of treatment, dosing, and long-term safety. A recent publication did monitor long-term tolerability in 14 patients who received from 12 to 45 IV ketamine infusions over a period of 14 to 126 weeks with no significant long-term serious side effects reported.²

Esketamine’s story: chirality and stereoisomerism

All proteins, enzymes, and receptors are constructed of a core sequence of amino acids. As life evolved on our planet, a random choice was made whenever an amino acid had at least one carbon atom with 4 unrelated groups attached-resulting in a subset of amino acids having mirror image structures, one found in living systems and the other absent. This results in the phenomena of chirality, whereby when you look at the attached groups on the carbon atom, the smallest to largest groups rotate either clockwise or counterclockwise.

Many drugs, when synthesized, contain a 50:50 mixture of these chiral compounds, and some drugs can have numerous chiral carbon sites. Depending on the arrangement of these 4 attached groups on the carbon atom, the drug is classified as either “es” or “S” for left rotating, or “ar” or “R” for right rotating. The common analogy used is “handedness.” Although the left hand and right hand look identical at first glance, they are not superimposable. Rather, they are mirror images of each other. If you had a lock that required your hand’s 3-dimensional structure to open it, only one hand would work. These basic chemical principles create the phenomena of stereoisomerism, and in most cases the “es” or the “ar” isomer of a drug binds much tighter and cleaner to its associated receptor.

Ketamine is a racemic mixture, so when it is synthesized it contains 50% esketamine and 50% arketamine. It is well established that esketamine binds approximately 4 times tighter to the NMDA-glutamate receptor than arketamine. However, both molecules have relevant and significant effects on receptors in the human brain. Each isomer is metabolized by liver enzymes, and some of the metabolites retain chirality, while others do not. An evolving research literature continues to expand our understanding of the differences between these 2 isomers, but much remains to be learned.

Janssen, the manufacturer of Spravato, chose to develop its intranasal spray with the isomer esketamine. Initial dosing studies determined the IV doses of esketamine required to achieve similar rapid onset efficacy in TRD patients to that of IV ketamine. Once these serum concentrations were established for esketamine, Janssen developed an intranasal spray delivery system to achieve these same concentrations to allow for intranasal administration. At the time of FDA approval of Spravato, Janssen had studied it for 9 years, and in over 1700 patients with TRD.

The journey to FDA approval of esketamine

After significant preclinical research on esketamine, and the successful development of an intranasal spray delivery system, five phase 3 clinical trials (three short term; two long term) were completed investigating the efficacy of esketamine in patients with TRD. The esketamine doses that demonstrated efficacy were 56 mg and 84 mg. The primary short-term, randomized, double-blind, placebo controlled 4-week clinical trial required that patients with established treatment resistant MDD, with at least 2 failed adequate antidepressant treatments in the current episode, would be started on a novel antidepressant (sertraline, escitalopram, venlafaxine XR, or duloxetine) simultaneously with the onset of treatment with either intranasal ketamine or intranasal placebo.

The subjects in this trial were quite depressed, with a mean Montgomery-Asberg Depression Rating Scale (MADRS) score of 37 at the time of randomization. Moreover, one-third of the study participants had a history of suicidal ideation. The primary endpoint of this study was the change in the total MADRS score from baseline to study end at day 28. On day 1 of the study, subjects were started on a new oral antidepressant, which they continued daily throughout the study. Simultaneously, they received either esketamine spray or placebo spray twice weekly for the 4 weeks. By 24 hours after the first dose of esketamine, most of the treatment difference from placebo was seen. From 24 hours post-dose through day 28 both esketamine and placebo groups continued to improve. At day 28 esketamine spray/oral antidepressant had improved the MADRS score by an average of 4 points (P = .02) compared with placebo spray/oral antidepressant.

The second study was a long-term maintenance study in patients with TRD that began with 16 weeks of open-label treatment with a new oral antidepressant along with esketamine. Esketamine was administered twice weekly for the first 4 weeks (the Induction Phase), weekly for the next 4 weeks, and then weekly or biweekly for the remaining 8 weeks (the 12-week Optimization Phase).

At week 16, two sub-groups were identified: stable remitters (a MADRS ≤ 12) or stable responders (≥ 50% reduction in the baseline MADRS score). At that point, after 16 weeks of open-label esketamine spray/oral antidepressant, remitters and responders entered into separate maintenance phases, which involved double-blind, placebo spray-controlled randomization for up to 80 weeks. All patients were treated with either flexibly dosed esketamine spray (56 mg or 84 mg) weekly or every other week, or placebo spray weekly or every other week, as well as continuing on their original open label oral antidepressant.

The stable remitters on esketamine spray/oral antidepressant relapsed 51% less than placebo spray/oral antidepressant. The stable responders on esketamine spray/oral antidepressant relapsed 70% less than placebo spray/oral antidepressant.

At the time of FDA approval 1-year safety data had been collected on over 800 patients, and a subset of patients were continued on open-label maintenance treatment with esketamine spray/oral antidepressant for up to 96 weeks. Janssen and the FDA established a Risk Evaluation and Mitigation Strategy (REMS) program to minimize serious adverse effects and to minimize the potential for drug diversion, as well as to provide a readily accessible database of all treatment with Spravato.

Spravato is patient administered in REMS certified clinics, and the drug is provided by REMS certified pharmacies. Patients receiving Spravato are required to remain in a supervised setting at the health care provider’s clinic for 2 hours post-nasal infusion. This allows for ongoing monitoring of patients during the period when significant adverse effects (sedation, dissociation, and elevated blood pressure) are most likely to occur. The REMS protocol requires the patient to abstain from driving or engaging in any complex task until the following morning, after a night’s sleep. More information is available at www.spravatohcp.com, and in the FDA-approved product insert for Spravato.

The mechanism of action (MOA) story

Ketamine, esketamine, and arketamine are all categorized as NMDA glutamate receptor antagonists, and on the surface this is an accurate description. Over the past 2 decades an impressive literature has evolved, including in vitro studies, animal studies, and studies in humans, including neuroimaging studies of subjects given ketamine or placebo. Although ketamine contains 50% esketamine and 50% arketamine, each of these 3 formulations demonstrates unique pharmacokinetic and pharmacodynamic properties, albeit with significant overlap. However, they should not be considered interchangeable. There is at least one secondary metabolite, hydroxy-nor-ketamine, that has demonstrated antidepressant activity in mice; it seems to be related to its downstream effect of increasing brain derived neurotrophic factor (BDNF). The majority of research on understanding the MOA to date has been done on racemic ketamine, which will be reviewed briefly.

A reasonable metaphor for our current understanding of ketamine’s MOA is that of the 6 blindfolded scientists who are all unknowingly placed in front of different parts of an elephant’s body and are asked to describe the object in front of them. They each accurately describe their different observations-the elephant’s back, leg, tail, trunk, ear, and tusk-and when placed in a room to discuss their conclusions each scientist was confused and perplexed by the findings of the others. Like the elephant, ketamine’s MOA remains elusive to us, but there exist significant clinical data that some day we hope to integrate into a comprehensive understanding.

A list of putative mechanisms that may contribute to ketamine’s antidepressant effect follows:

• Direct effects on the NMDA glutamate ionotropic receptor

• Effects on the AMPA glutamate ionotropic receptor

• Secondary glutamate synaptic release from interneurons in diverse circuits

• Secondary effects on GABA interneurons

• Activity of the secondary metabolite, hydroxy-nor-ketamine

• Inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase

• Increased expression of BDNF

• Increased expression of tropomyosin receptor kinase B (TrKB)

• Activation of the mammalian target of rapamycin (mTOR) signaling pathway

• Rapid decrease in the size of the amygdala and nucleus accumbens

• Rapid increase in the size of the hippocampus and prefrontal cortex

For me, the most exciting part of the ketamine story is a growing literature of neuroimaging studies looking at brain structural and functional changes (especially the hippocampus and prefrontal cortex) and increased global brain connectivity, which are observed in human studies to occur within hours and days of a single treatment dose of ketamine. As we untangle the mosaic of research data, it appears that ketamine ultimately improves brain connectivity with an associated rapid decrease in depressive symptoms that seems to result from a range of downstream cascades that culminates in the activation of mTOR, which plays a primary role in synaptogenesis. Remarkably, the brain’s structure appears to rewire in hours after a single dose of ketamine-wrap your brain around that!

I would be remiss not to mention a study published in 2018 that hypothesized opioid receptors played a primary role in ketamine’s antidepressant action.³ Williams and colleagues looked at pretreatment with naltrexone, followed by the IV administration of ketamine. Their study had a small number of participants. Of the 30 adults who were initially enrolled in this study, 12 completed the protocol to allow an interim analysis fraught with limitations. Two subsequent studies in 2019 demonstrated no interplay between the mu opioid receptor and ketamine’s rapidly acting antidepressant effect.^4,5

Conclusion

So, psychiatry has finally crossed into a new paradigm in the treatment of TRD, bringing the glutamate system on board to join the modulation of the monoamine systems. Esketamine is the first in what we hope will be a long list of non-monoamine-based treatments to help improve the lives and functioning of the many individuals suffering from TRD.

Disclosures:

Dr Miller reports that he is on Janssen’s Advisory Board and on the Speaker’s Bureau for Spravato.

References:

1. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.

2. Wilkinson ST, Katz RB, Toprak M, et al. Acute and longer-term outcomes using ketamine as a clinical treatment at the Yale Psychiatric Hospital. J Clin Psychiatry. 2018;79:pii:17m11731.

3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175:1205-1215.

4. Yoon G, Petrakis IL, Krystal JH. Association of combined naltrexone and ketamine with depressive symptoms in a case series of patients with depression and alcohol use disorder. JAMA Psychiatry. 2019; 76:337-338.

5. Marton T, Barnes DE, Wallace A, et al. Concurrent use of buprenorphine, methadone, or naltrexone does not inhibit ketamine’s antidepressant activity. Biol Psychiatry. March 26, 2019; Epub ahead of print. ❒