Clinical Topics

Debate Continues on Esketamine Efficacy and Safety for Depression Treatment

by Annette Boyle

August 12, 2019

VA Panel Puts Limits on Use of Drug

PHILADELPHIA—Is esketamine a revolutionary treatment for depression or just another moderately effective adjunctive medication with some potentially serious risks? The VA’s Medical Advisory Panel leaned toward the latter position when it decided in June to approve the use of esketamine on a nonformulary basis for individuals who have previously failed at least two trials of other antidepressants.

The formulary committee’s decision has done little to tamp down debate about the drug, however.

That esketamine is the first medication in a new drug class approved for treatment of depression in three decades remains undisputed. N-methyl-D-aspartate receptor antagonists, esketamine and its parent drug, ketamine, stimulate glutamate production, which in turn triggers development of new neural connections, according to Gerard Sanacora, MD, PhD, a psychiatrist at Yale Medicine and ketamine researcher.1 

Glutamate is far more prevalent in the brain than the neurotransmitters targeted by most current antidepressants, serotonin and norepinephrine. Its central role in neuronal excitation means it significantly impacts critical brain functions, including cognition, emotions, sensory perception and motor coordination. Esketamine and ketamine’s ability to act on a molecule with such a broad portfolio and prevalence might explain their ability to relieve depression in some of the 30% of people with major depression who have not responded to other therapies.

That same broad impact on the brain has made ketamine an effective anesthetic for decades and a powerful painkiller used by battlefield medics. It also drives ketamine’s abuse as a hallucinogenic—and much of the debate on the safety of esketamine, the s-enantiomer of ketamine.

Efficacy Questions

But first, does it work?

The pivotal Phase 3 study of the drug found that esketamine started reducing depression symptoms within 24 hours. Notably, all 227 participants in the study started a new antidepressant along with either esketamine or a placebo (saline) nasal spray.2 

Participants in the esketamine arm of the study saw a 4 point greater reduction in score on the 60-point Montgomery-Asberg Depression Rating Scale than those in the placebo arm at Day 28 of the study. The effect size was 0.3 for esketamine. More than half (52.5%) of the patients in the esketamine arm achieved remission, and 69.3% responded to the treatment compared to 31% and 52%, respectively, of those receiving placebo.

The 4 point improvement was a better result achieved in less time than seen in other studies of U.S. Food and Drug Administration-approved adjunctive medications for treatment-resistant depression, said study co-author Michael E. Thase, MD, staff physician at the Corporal Michael J. Crescenz VAMC in Philadelphia and professor of psychiatry at the University of Pennsylvania Perelman School of Medicine. 

“The drugs of greatest comparability, aripiprazole, brexpiprazole and olanzapine had just 2- to 3-point differences at six weeks,” Thase told U.S. Medicine

“Studies using intravenous ketamine showed a greater difference, so there’s some disappointment that esketamine is not as strong and powerful. Still, it’s better than other comparative options,” he said.

The FDA’s requirement that participants start a new antidepressant coincident with the start of esketamine might also have affected the results. “In studies of other drugs, patients stayed on their previous antidepressant. Based on earlier studies of intravenous and intranasal esketamine using the more conventional designs—in which patients stayed on an ineffective antidepressant—there was reason to expect a larger effect size, on the order of 0.5 or 0.6,” he added.

More participants responded to esketamine than previous adjunctive medications as well, he noted. “A 20% improvement [compared to placebo] is remarkable; other drugs showed only a 10% improvement or less.”

The speed with which esketamine acts is a significant advantage. “What I like best about esketamine is that it shows itself very quickly. If it’s not going to help, you can close it down in two weeks and not wait six or eight weeks as you would with other antidepressants,” Thase noted. The study showed separation between placebo and esketamine within two days.

“The effect of esketamine isn’t as large or quite as fast as IV ketamine, but a form of treatment that doesn’t require an IV is a good thing when you have to gauge and marshal cost and efficacy,” he said. Ketamine does not have FDA approval for treatment of depression, but is increasingly used off-label for that purpose.

Esketamine may not be as effective as its parent, but is it effective enough? While the Phase 3 trial showed positive results, two other trials run by the manufacturer failed to demonstrate a statistically significant separation from placebo. Further, more than 20% of the participants in the successful trial had failed only one class of oral antidepressants prior to the study.

Questions about how truly blinded patients were in the study have also arisen, as the saline nasal spray had none of the signature side effects of esketamine, such as brief dissociation and perceptual disturbances.

Suicide Issues

Still, for advocates of esketamine, the more people with hard to treat depression who can start treatment with the new intranasal spray formulation, the better. 

For this camp, increasing access for veterans has a particular advantage—possible reduction in veteran suicides. A proof-of-concept study published in the American Journal of Psychiatry last year showed esketamine rapidly and dramatically reduced the risk of suicide in suicidal, depressed patients. 

The study compared esketamine to placebo in 68 acutely suicidal patients. Esketamine resolved suicide risk in 21.2% of those patients in four hours and in 40% within 24 hours compared to 9.7% and 6.5% of those who received a placebo, respectively.3

Experts who urge greater caution with the drug also cite suicide risk, however. Three participants committed suicide in the esketamine arm of one of the studies provided by the manufacturer on which the U.S. Food and Drug Administration based its approval. None died in the placebo arm. The study evaluated drug relapse and discontinuation following 16 weeks of treatment with esketamine plus an antidepressant, tapering to once every two weeks, before transitioning to antidepressant plus placebo or continued treatment with esketamine plus the antidepressant.4

The three suicides occurred between four and 20 days after the participants received their last dose of esketamine. Two of the individuals had not demonstrated signs of suicidal activity at baseline or at their last visit. 

“This suggests a protracted withdrawal reaction, as has been reported with opioids, and one that is different from the more physical withdrawal symptoms seen acutely with opioids,” said Alan Schatzberg, MD, director of the Stanford Mood Disorders Center and professor of psychiatry and behavioral sciences at Stanford University School of Medicine in a commentary in the June issue of the American Journal of Psychiatry.5

In its briefing document on esketamine, the FDA addressed the suicides and three other deaths in esketamine arms of clinical trials saying, “it is difficult to consider these deaths as drug-related” because of the small number of cases, severity of participants’ illness and inconsistent pattern in the suicides. 

Schatzberg called the FDA conclusion “misguided,” as “discontinuation reactions can certainly be due to the drug, even though patients are not taking them at that time” and because it failed to factor in the drug’s known abuse potential.

Abuse Potential

Ketamine has been abused as a party drug for decades for its hallucinatory and dissociative effects.

Schatzberg and his colleagues have reported that oral naltrexone blocks the antidepressant effects of ketamine, indicating the drug’s effect arises in part either through a release of endogenous opioids or binding to the mu opioid receptor.6

“The opioid properties may explain the drug’s abusability and raise concerns regarding liability with longer-term use,” Schatzberg noted in his editorial.

The FDA approval established a restricted distribution system for esketamine under a Risk Evaluation and Mitigation Strategy that limits its administration to certified medical offices. Patients self-administer the spray under supervision of a healthcare provider and stay in the facility to be monitored for side effects. VA guidelines call for veterans to remain for observation for at least two hours. The spray cannot go home with a patient. 

“There’s an obligation with a new treatment that in other forms have abuse potential to make sure that treatment is done in a safe and reasonable way,” Thase said. 

In his view, the REMS program creates effective safeguards. “If you were using ketamine as a party drug, just 50% would be esketamine or the s-form,” he said, so the amount needed would be much higher.

Further, “users must take progressively higher doses to continue to get the euphoric effect. The two therapeutic doses given for antidepressant effect are just at the edge of the illusions or dissociation response that people sometimes have and doctors are not permitted to go above those levels, so they’re not at the dose that would lead to abuse,” he explained. “And, the restricted distribution system means patients don’t have access to the drug to self-administer.”

Caution is still in order, though. “In the VA setting, we have to be especially mindful of risk. We’re treating mostly older men with long-standing illness,” Thase noted. “None of the esketamine research has been done at VAMCs and the benefits for older people are not clearly established.”

1. Chen J. How New Ketamine Drug Helps with Depression. Yale Medicine. https://www.yalemedicine.org/stories/ketamine-depression/

2. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, Mazzucco C, Hough D, Thase ME, Shelton RC, Molero P, Vieta E, Bajbouj M, Manji H, Drevets WC, Singh JB. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry 2019; 176:428–438 

3. Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, Pinter C, Hough D, Sanacora G, Manji H, Drevets WC. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018 Jul 1;175(7):620-630.

4. US Food and Drug Administration: Briefing information for the Feb 12, 2019 joint meeting of the Psychopharmacologic Drugs Advisory Committee (PDAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM). 

5. Schatzberg AF. A Word to the Wise About Intranasal Esketamine. Am J Psychiatry. 2019 Jun 1;176(6):422-424. 

6. Williams NR, Heifets BD, Blasey C, Sudheimer K, Pannu J, Pankow H, Hawkins J, Birnbaum J, Lyons DM, Rodriguez CI, Schatzberg AF. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry 2018; 175:1205–1215.



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