Psychiatric Annals

CME Article 

Ketamine, Esketamine, and A New Generation of Antidepressants

Samuel T. Wilkinson, MD; Brandon M. Kitay, MD, PhD

Abstract

Since the discovery of its rapid-acting antidepressant properties, ketamine has helped stimulate a new line of research in the development of rapid-acting antidepressants based on the glutamate and gamma-aminobutyric acid neurotransmitter systems. An intranasal version of the S-enantiomer of ketamine (esketamine) recently received regulatory approval as a therapy for treatment-resistant depression (TRD). Here we review the clinical evidence of esketamine for TRD, challenges to its adoption in clinical practice, and the regulatory requirements imposed by the US Food and Drug Administration (FDA) through a risk evaluation and mitigation strategy (REMS). Brexanolone, an exogenous formulation of allopregnanolone, also recently received FDA approval for the treatment of postpartum depression and is likewise subject to a REMS. Other compounds in late-stage development, including AXS-05 and SAGE-217, are also reviewed. [Psychiatr Ann. 2020;50(2):54–61.]

Abstract

Since the discovery of its rapid-acting antidepressant properties, ketamine has helped stimulate a new line of research in the development of rapid-acting antidepressants based on the glutamate and gamma-aminobutyric acid neurotransmitter systems. An intranasal version of the S-enantiomer of ketamine (esketamine) recently received regulatory approval as a therapy for treatment-resistant depression (TRD). Here we review the clinical evidence of esketamine for TRD, challenges to its adoption in clinical practice, and the regulatory requirements imposed by the US Food and Drug Administration (FDA) through a risk evaluation and mitigation strategy (REMS). Brexanolone, an exogenous formulation of allopregnanolone, also recently received FDA approval for the treatment of postpartum depression and is likewise subject to a REMS. Other compounds in late-stage development, including AXS-05 and SAGE-217, are also reviewed. [Psychiatr Ann. 2020;50(2):54–61.]

In 2000, Berman et al.1 published a groundbreaking study with the then-surprising result that exposure to a single, subanesthetic dose of ketamine could produce rapid and robust antidepressant effects in individuals with major depressive disorder (MDD). This finding has since been replicated many times by several different groups, with generally robust effects (number-needed-to-treat for response of 3–4; for remission 5–6).2 These results have also stimulated a new line of research investigating the development of other rapid-acting antidepressants, with purported mechanisms acting through the glutamate and gamma-amino-butyric acid (GABA) systems (extensively reviewed elsewhere3). This line of research achieved a milestone in March 2019 when the US Food and Drug Administration (FDA)4 approved intranasal esketamine (the S-enantiomer of ketamine) as an adjunctive therapy for treatment-resistant depression (TRD), creating the possibility that this drug could be used to treat millions of people who suffer from TRD.

Racemic Ketamine

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. Traditionally, its antidepressant action has been thought to be mediated through this NMDA receptor antagonism, which leads to downstream upregulation of synaptic protein synthesis and neuroplasticity.5 More recently, theories have arisen that ketamine can enhance glutamate release and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid activation independent of its effects on the NMDA receptor6 or that its antidepressant properties may be mediated by opioid neurotransmission.7

Many ketamine randomized trials in MDD have been single-dose studies conducted in academic centers. The largest, multidose randomized trial was conducted to achieve data answering the question of the optimal dosing schedule. This study randomized 68 people with TRD to receive intravenous ketamine (0.5 mg/kg given over 40 minutes) or intravenous placebo 3 times per week or 2 times per week. The study found that there was no difference in clinical outcomes based on these two different dosing schedules.8 A few additional open-label trials have examined the utility of multiple dosing protocols using intravenous ketamine (reviewed elsewhere9).

The discovery and replication of ketamine's rapid-acting antidepressant effects has provided hope for patients with MDD and especially for those with TRD who have not been able to achieve remission despite attempts with standard therapies. This hope combined with the limited efficacy or tolerability of existing therapies for TRD and the wide availability of ketamine has created a setting in which a number of providers began offering ketamine as an off-label treatment for psychiatric disorders.10 The number of these providers has grown substantially since the early 2010s. Although most of these providers report primarily using ketamine to treat depression, some also offer this as a treatment for other psychiatric disorders including posttraumatic stress disorder or obsessive-compulsive disorder.

Esketamine

Considering that the S-enantiomer had more potent action as an antagonist at the NMDA receptor11 and that NMDA receptor antagonism was a critical mechanism underlying the antidepressant effects of the drug,5 researchers began developing an isolate of the S-ketamine enantiomer (esketamine) that could be further concentrated and packaged into a convenient nasal spray obviating the need for intravenous administration. In March 2019, the FDA approved esketamine as the first-in-class rapid-acting antidepressant indicated specifically for TRD.4 It should be noted that esketamine was approved as a treatment to be used in conjunction with an oral antidepressant and not as a monotherapy.

FDA Registration Trials

Five Phase 3 clinical trials formed the basis of esketamine's new drug application to the FDA (Table 1). These trials were comprised of (1) a fixed-dose randomized trial in adults age 18 to 64 years (TRANSFORM-1, TRD3001); (2) a flexible-dose randomized trial in adults age 18 to 64 years (TRANSFORM-2, TRD3002); (3) a flexible-dose randomized trial in adults age 65 years and older (TRANSFORM-3, TRD3005); (4) a randomized withdrawal trial wherein esketamine responders/remitters were randomly assigned to continue receiving esketamine or saline nasal spray (SUSTAIN-1, TRD3003); and (5) a long-term, single-group, open-label study (SUSTAIN-2, TRD3004). Two additional Phase 2 trials were also discussed by the FDA Advisory Committee. Notably, in the randomized trials, study participants were assigned to receive esketamine nasal spray plus a new oral antidepressant or to receive placebo nasal spray plus a new oral antidepressant. Hence, all participants started a new antidepressant.

Results of Short-Term, Randomized Studies of Esketaminea

Table 1.

Results of Short-Term, Randomized Studies of Esketamine

Two of the randomized trials achieved their primary outcomes, whereas two others did not. In one of the short-term studies (TRD3002, ClinicalTrials.gov Identifier: NCT02417064), non-elderly adult participants with TRD were randomly assigned esketamine (flexible dose of 56–84 mg) nasal spray plus an oral antidepressant or placebo spray plus antidepressant. Patients received nasal treatments twice per week for 4 weeks. This study showed a greater improvement among patients in the esketamine/antidepressant group compared to the placebo/antidepressant group by the end of the 4-week treatment period (P = .02), with a Cohen's d effect size of approximately 0.34. The separation between groups was as early as day 2, which is more rapid than previous antidepressant interventions.

In another positive trial, patients who achieved stable remission (Montgomery–Åsberg Depression Rating Scale [MADRS] ≤12 for ≥3 of the preceding 4 weeks) or response (≥50% reduction in MADRS score from baseline in the preceding 2 weeks, but without remission) continued to receive esketamine/antidepressant for a period of 12 weeks (TRD3003, ClinicalTrials.gov Identifier: NCT02782104). After this optimization phase, the patients were randomly assigned to continue receiving esketamine or to begin receiving placebo nasal spray (randomized withdrawal). All patients continued to receive an oral antidepressant. Among patients who achieved stable remission, 26.7% in the esketamine group experienced a relapse versus 45.3% in patients randomized to withdrawal (placebo); among stable responders, 25.8% of patients in the esketamine group experienced a relapse versus 57.6% in the placebo group. In both remitter and responder groups, the time to relapse was significantly longer among those who continued to receive esketamine compared to those who switched to receive placebo. Overall, ongoing treatment with esketamine significantly delayed relapse when compared with randomized withdrawal, decreasing relapse risk by 51% among stable remitters and 70% among stable responders.12

The fixed-dose short-term trial (TRD3001, ClinicalTrials.gov Identifier: NCT02417064) of non-elderly adults showed greater improvements in the esketamine/antidepressant group compared to placebo/antidepressant group in continuous outcomes (depression severity, score difference of 3.2 points on the Montgomery-Asberg Depression Rating Scale) and response (53.1% high-dose esketamine, 54.1% moderate-dose esketamine, 38.9% placebo) and remission (38.8% high-dose esketamine, 36% moderate-dose esketamine, 30.6% placebo) but did not achieve its primary endpoint (P = .088). The short-term trial in geriatric patients (TRD3005, ClinicalTrials.gov Identifier: NCT02422186) also did not meet its primary outcome (P = .058).

In the long-term, open-label trial (TRD3004, ClinicalTrials.gov Identifier: NCT02497287) participants received intranasal esketamine (in addition to a new oral antidepressant) twice weekly for 4 weeks (induction phase), then weekly for 4 weeks (optimization phase), and then weekly or every other week depending on clinical status (maintenance phase) for up to 52 total weeks of esketamine exposure. In total, data from 802 participants were enrolled and received one or more doses of esketamine. By the end of the 4-week induction phase, 78.4% of the participants achieved response (≥50% reduction from baseline MADRS) and 47.2% achieved remission (total MADRS ≤12). The most common non-serious adverse events experienced by ≥10% of participants in the induction or optimization phase of treatment included nausea, dizziness, headache, hypoesthesia, somnolence, and dissociation.

Risk Evaluation and Mitigation Strategy Program and Challenges to the Adoption of Esketamine

Although esketamine has been developed as an easily self-administered nasal spray, the risks of sedation, dissociation, abuse/misuse, and diversion of this drug have prompted the FDA to require the institution of a risk evaluation and mitigation strategy (REMS). This REMS includes a provider/patient registry designed to monitor long-term administration outcomes and serious adverse events, and also places restrictions on how esketamine is accessed by providers and settings where it can be administered.

Providers, clinical institutions, and pharmacies must become certified with the REMS to carry and dispense medication. Although there is no specialty training required for certification per se, the REMS specifies that to become certified a provider must agree to (1) ensure a prescriber is onsite during esketamine administration and monitoring; (2) ensure that health care provider(s) are onsite to monitor each patient for at least 2 hours after medication administration; (3) ensure that the medication is not dispensed for use outside the health care facility; and (4) train all relevant staff involved in prescribing, dispensing, and administering medication and establish processes and procedures to ensure that appropriate counseling and REMS patient enrollment/verification occurs prior to medication administration.

For patients, registration in the esketamine REMS further involves a patient agreement that outlines the conditions of enrollment as well as affirms that the patient understands not only details of informed consent including anticipated medication benefits, known risks and side-effects, and treatment alternatives, but also specific requirement of esketamine administration including health care setting, 2-hour treatment observation, and need for safe transportation home as patients should not drive for the remainder of the day after medication administration (Table 2).

Key Points from the Esketamine Label

Table 2.

Key Points from the Esketamine Label

Current reimbursement models for delivery of esketamine, including the 2 hours of observation as mandated by the REMS, among both commercial and public insurance carriers remain poorly defined. For example, the medication is “self-administered” but must be given in a certified health care setting under direct provider supervision, a model for which a current procedural terminology code and precedent codes do not exist. Administration and compensation models will therefore need to evolve in these early days of public esketamine availability,13 especially as more safety data and practice data become available through the REMS.

Notably, the Institute for Clinical and Economic Review conducted an independent cost-effectiveness study suggesting that the esketamine price exceeds traditional cost-effectiveness thresholds of $50,000 to $150,000 per quality adjusted life year, costing approximately $198,000 per quality adjusted life year.14 The estimated cost for the first year of esketamine (excluding physician, facility, and other nondrug charges) is $36,500.14

Ketamine/Esketamine and Suicidal Ideation

From its initial discovery as a rapid-acting antidepressant, ketamine has been noted for its ability to rapidly alleviate suicidal ideation. Overall, the data from randomized controlled trials of racemic ketamine studies (single dose) suggest that ketamine has a rapid effect on suicidal ideation that is at least partly independent of its general antidepressant effects.15 Two moderate-sized clinical trials have shown benefit of ketamine (N = 80, significant reduction in scale for suicidal ideation score 24 hours post single infusion over placebo)16 and esketamine (N = 68, significant reduction in the suicidal thoughts item of the MADRS assessment 4 hours post treatment over placebo, but not at 24 hours)17 among patients from a variety of care settings who had presented due to suicide risk. Two Phase 3 studies of esketamine as a treatment for patients with MDD who are assessed to be at imminent risk for suicide and in need of hospitalization were recently reported as positive18 and may form the basis of a new drug application to acquire another FDA indication for esketamine in this population (NCT03039192; NCT03097133). Given that suicidal ideation is not a reliable predictor of suicide death or suicide attempts, the chief limitation of the current state of research in this area is that no study has examined the effect of ketamine/esketamine on suicidal behaviors. Furthermore, concerns have been raised about the number of deaths that occurred in the esketamine development programs.19 A deeper understanding of the relationship between ketamine/esketamine and suicidal behaviors will likely require large observational datasets with rigorous pharmaco-epidemiologic designs to minimize confounding of treatment with pre-existing suicide risk.

Unanswered Questions Regarding Ketamine/Esketamine

Despite the recent FDA approval of esketamine and the vast clinical experience with racemic ketamine in anesthesia settings, several questions of significant clinical relevance remain unanswered.

Cognitive Functioning and Delusions

The use of ketamine in anesthesia settings has generally been limited to one-time use for procedural sedation. In contrast, the FDA label of esketamine is somewhat open-ended, with a recommended dosing frequency of weekly or every other week when patients enter the maintenance phase of treatment at week 9. It is unclear whether patients can taper off the esketamine treatments or whether some of them may need treatment indefinitely. This issue is relevant because high doses of long-term ketamine use have been shown to have negative health outcomes with respect to cognition and the propensity for the development of delusions. These data are extrapolated from observational studies of ketamine substance abusers and it is unclear whether pre-existing traits or characteristics may have in some way contributed to these negative health outcomes. Although it may be perceived that lower doses of ketamine/esketamine with less frequency may be safe in the long-term, the dosing and frequency threshold necessary for long-term safety is a key question that remains unanswered.

Potential strategies for maintaining the antidepressant effects of ketamine/esketamine in ways that minimize the ongoing use of the drug would be desirable. Clinical trials of lithium20 and riluzole21,22 after ketamine treatment have not shown promise. A small, open-label trial of cognitive-behavioral therapy combined with four doses of intravenous ketamine in 16 participants shows promise,23 but these findings need replication and testing in well-powered clinical trials.

The Abuse Liability of Ketamine

Although ketamine is not widely abused in the US, parts of southeast Asia and areas in the United Kingdom have alarming rates of ketamine abuse. For instance, in Hong Kong, ketamine is thought to be the most common drug of abuse, and in Taiwan, it is the third most common drug of abuse.24 Data are sparse regarding the prevalence and characterization of ketamine abuse in the US. Although the REMS program linked with nasal esketamine will greatly limit the potential for direct abuse, it is unclear to what extent patients might begin seeking ketamine illicitly after being introduced to it in a clinical setting. At least one report of iatrogenic ketamine abuse has been documented, with catastrophic results.25 A recent report by Williams et al.7 suggests that opioid system activation is required for ketamine's antidepressant effects although this remains controversial as conflicting reports exist.26 Whereas reports of ketamine inducing a classic withdrawal syndrome similar to that of opioids are lacking, concern exists that long-term therapeutic use may predispose people to a greater risk of ketamine abuse.

Blinding of Ketamine/Esketamine Studies

Many placebo-controlled trials for ketamine/esketamine conducted thus far have used saline as a comparator. Given the well-documented dissociative side effects of ketamine, functional unblinding may occur if research participants realize to what arm they have been randomized. To improve the blinding, a few trials have used the short-acting benzodiazepine midazolam as an “active” placebo. There are at least three single-dose studies that have used this design, and a composite patient-level analysis of this data has shown that the 24-hour effect size of these trials is roughly half the magnitude of those trials using a saline comparator.27 This finding is driven by a more realistic “placebo response” in midazolam-controlled studies, suggesting that functioning unblinding may account for a substantial part of the large effect sizes seen in saline-controlled ketamine studies.

Brexanolone

At the time of this writing, brexanolone is the only other compound that acts via glutamate or GABA neurotransmitter systems in addition to esketamine that has received FDA approval28 for the treatment of a mood disorder. Indicated for the treatment of postpartum depression, brexanolone is chemically identical to allopregnanolone, an endogeneous compound that acts as a positive allosteric modulator at the GABA-A receptor. Allopregnanolone is the major metabolite of progesterone; during pregnancy, levels rise gradually. At the time of parturition, the majority of allopregnanolone is made in the placenta; hence, levels fall abruptly during the postpartum period, which may be a driving factor in the pathophysiology of postpartum depression. Brexanolone is given over a slow, 60-hour intravenous drip (Table 3). The medication is subject to a REMS and essentially can only be given to hospitalized patients. The unwieldy administration requirements and the high price ($34,000, excluding physician, facility, and other nondrug charges)29 will likely limit the adoption of this compound.

Key Points from the Brexanolone Label

Table 3.

Key Points from the Brexanolone Label

Other Drugs in Development

The discovery that subanesthetic doses of ketamine could lead to rapid antidepressant effects, in concert with advances in our understanding of the neurobiology of mood disorders,30 has motivated a deeper search for antidepressant targets outside of the traditional monoaminergic system. Increasingly, several lines of evidence demonstrate that both the glutamate and GABA neurotransmitter systems play a key role in the neurobiology of depression and may offer better targets for antidepressant therapeutic development. Hence, several other companies have attempted to develop antidepressant therapies that operate within these systems. In addition to ketamine and esketamine, these have included lanicemine (AZD6765/BHV-5500), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), riluzole, ganaxolone, and SAGE-217. The progress and clinical development of these compounds has been reviewed extensively elsewhere.3 Below we discuss two drugs in late-stage clinical development.

AXS-05 is in Phase 3 trials for the treatment of MDD (NCT04019704, NCT04039022) and TRD (NCT02741791) after reporting positive Phase 2 results.31 AXS-05 is a combination of dextromethorphan (60 mg) and bupropion (210 mg) and is posited to act as an NMDA receptor antagonist. The purpose of adding bupropion is to increase the bioavailability of dextromethorphan through inhibiting CYP2D6.

Similar to brexanolone, SAGE-217 is a positive allosteric modulator at the GABA-A receptor. However, unlike brexanolone, SAGE-217 is administered orally, which may greatly facilitate adoption of the medicine if it receives regulatory approval. SAGE-217 is in Phase 3 clinical trials (NCT03672175, NCT03864614) for the treatment of MDD after a positive Phase 2 trial.32 One Phase 3 study (NCT02978326) with SAGE-217 was positive in postpartum depression.33

Conclusions

Ketamine has generated considerable excitement as the first rapid-acting antidepressant. The recent FDA approval of esketamine, the S-enantiomer, or ketamine as a therapy for TRD was a significant milestone, yet several questions regarding the safety and abuse liability of the drug remain unanswered. Esketamine's approval offers hope to millions of patients whose depressive symptoms have not resolved with standard treatments. Additional potential therapies based on the glutamate and GABA neurotransmitter systems may also offer significant improvements over existing treatments.

References

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Results of Short-Term, Randomized Studies of Esketaminea

Study/Clinical Trials Identifier Population Design Dose Sample Size (N) LS Mean Change in MADRSa P Value (Difference from PBO) Response Rate at Week 4 (%) Remission Rate at Week 4 (%)
TRANSFORM-1 (TRD3001)/NCT02417064 Adults, age 18 to 64 y with TRD Parallel-group: fixed dose ESK vs PBO, twice weekly dosing PBO IN 56 mg IN 84 mg 113 115 116 −14.9 (95% CI 17.4 to −12.4) −18.9 (95% CI −21.4 to −16.4) −18.2 (95% CI −20.9 to −15.6) .027 .088 39 54 53 31 36 39
TRANSFORM-2 (TRD3002)/NCT02418585 Adults, age 18 to 64 y with TRD Parallel-group: flexible-dose ESK vs PBO, twice weekly dosing PBO IN 56 mg IN 84 mg 110 114 −15.8 (SE 1.2) −19.8 (SE 1.3) - .020 52 69 31 53
TRANSFORM-3 (TRD3005)/NCT02422186 Geriatric, age ≥65 y with TRD Parallel-group: flexible-dose ESK vs PBO, twice weekly dosing PBO IN 56 mg IN 84 mg 65 72 −18.2 (95% CI −20.9 to −15.6) −10.1 (95% CI −13.1 to −7.1) - .058 13 27 7 18
SUI2001/NCT02133001 Adults, 18 to 65 y with severe MDD and SI at imminent risk of suicide Double-blind, randomized: ESK vs PBO, twice weekly PBO IN 84 mg 31 35 Day 2b: −12.8 (SD 9.8) Day 25: −23.0 (SD 10.8) Day 2b: −19.3 (SD 12) Day 25: −26.4 (SD 14.5) - Day 2b: .015 Day 25: .159 63 83 50 63

Key Points from the Esketamine Label

Black box warning that included the following <list-item>

Risk for sedation and dissociation after administration

</list-item><list-item>

Potential for abuse and misuse

</list-item><list-item>

Patients should be monitored for 2 hours after administration

</list-item><list-item>

Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants

</list-item>
Patients are not to drive or operate machinery until the next day after a restful sleep following esketamine administration Patients are to avoid food for at least 2 hours and liquids at least 30 minutes prior to administration Esketamine is to be administered in conjunction with an oral antidepressant Dosage recommendation <list-item>

Induction phase (weeks 1 to 4) <list-item>

Start at 56 mg

</list-item><list-item>

Subsequent doses (administered twice per week) of 56 or 84 mg

</list-item>

</list-item><list-item>

Maintenance phase <list-item>

Administer 56 or 84 mg weekly for weeks 5 to 8

</list-item><list-item>

Administer every 2 weeks or weekly from week 9 and after

</list-item>

</list-item>

Key Points from the Brexanolone Label

Black box warning that includes the following <list-item>

Warning of excessive sedation and sudden loss of consciousness

</list-item><list-item>

Patients must be monitored for sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring

</list-item><list-item>

Patients must be accompanied during interactions with their children

</list-item>
A health care provider must be on site to continuously monitor the patient for the duration of the infusion Brexanolone is administered as a continuous intravenous infusion over 60 hours (2.5 days) Most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush
Authors

Samuel T. Wilkinson, MD, is an Assistant Professor of Psychiatry. Brandon M. Kitay, MD, PhD, is an Assistant Professor of Psychiatry. Both authors are affiliated with the Yale Depression Research Program, Yale School of Medicine.

Address correspondence to Samuel T. Wilkinson, MD, Yale Depression Research Program, Yale School of Medicine, 100 York Street, STE 2J, New Haven, CT 06511; email: samuel.wilkinson@yale.edu.

Grant: To support this work, a grant (K12HS023000) was received from the Agency for Healthcare Research and Quality (AHRQ) as well as support from the Brain and Behavior Research Foundation, the Robert E. Leet and Clara Guthrie Patterson Trust, and the American Foundation for Suicide Prevention.

Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ.

Disclosure: Samuel T. Wilkinson has received contract funding from Janssen (the developer of esketamine) and Sage Therapeutics for the conduct of clinical trials administered through Yale University; anticipates receiving contract funding from LivaNova for conducting clinical trials; and has received consulting fees from Janssen, Oui Therapeutics, and Biohaven Pharmaceuticals. Brandon M. Kitay has received contract funding from Janssen and Sage Therapeutics for the conduct of clinical trials administered through Yale University.

10.3928/00485713-20200113-02

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