Experts Go Toe-to-Toe Over Esketamine Depression Study

Deborah Brauser

May 21, 2019

SAN FRANCISCO — The ongoing debate over the risks and benefits of recently approved esketamine nasal spray (Spravato, Janssen Pharmaceuticals) for treatment-resistant depression (TRD) spilled over into a heated toe-to-toe discussion here at the American Psychiatric Association (APA) 2019 Annual Meeting.

Michael E. Thase, MD

In March, the US Food and Drug Administration (FDA) approved  the drug based, in large part, on a pivotal phase 3 trial. The study findings, which were presented at last year's APA meeting, were published online today in the American Journal of Psychiatry (AJP), along with an accompanying editorial. The trial was also the subject of a fully dedicated press briefing at this year's meeting.

Investigator Michael E. Thase, MD, professor of psychiatry at the University of Pennsylvania Perelman School of Medicine, told attendees that the drug was not only effective but also fast-acting, with some improvement evident within the first 24 hours.

Alan F. Schatzberg, MD, Stanford University School of Medicine, California, then made a presentation based on his accompanying editorial, noting that the data are somewhat "worrisome" and that questions remain — particularly with respect to dosing, risk, and the potential for withdrawal symptoms.

Alan F. Schatzberg, MD

Following the two presentations, Medscape Medical News asked whether Thase had any response to Schatzberg's concerns prompting an extended, sometimes heated, debate between the two physicians.

Thase said he "took issue" with some of the Schatzberg's criticisms.

"The fact that you can do some good for a large group of people that haven't been helped by other treatments is the exciting thing," said Thase, who is also a staff member at the Corporal Michael J. Crescenz VA Medical Center.

"We deal with desperate people every day and any effort to improve their lives should be lauded; but this is coming against a backdrop that will have a significant impact," Schatzberg responded, noting that desperation is leading to increased use of drugs with abuse potential.

"As a society, we're going to need to make decisions about what constitutes a reasonable risk-benefit ratio," he said.

AJP Editor-in-Chief Ned H. Kalin, MD, department of psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, noted that although the trial findings were presented in a poster last year, the journal "isn't just about new findings" but is also about opening up discussions of current trends in the field of psychiatry.

"We want to be on the forefront of this in relation to the recent FDA approval and wanted to pair it with the commentary. It's not just the paper but the combination of the two," Kalin said.

Esketamine is a glutamatergic N-methyl-D-aspartate receptor antagonist.

In the phase 3 study, more than 200 adult patients with TRD were enrolled at 39 sites in five countries. They were randomly assigned to receive daily for 4 weeks a newly initiated open-label, oral antidepressant plus either twice weekly esketamine starting at 56 mg and possibly titrating up to 84 mg (n = 114) or matching intranasal placebo (n = 109).

The newly initiated antidepressant was either duloxetine, escitalopram, sertraline, or extended-released venlafaxine.

The mean baseline scores on the Montgomery–Åsberg Depression Rating Scale (MADRS) were 37.0 and 37.3, respectively; and follow-up continued for all patients to week 24.

The primary efficacy outcome was change on MADRS total score from baseline to day 28. Results showed that the active treatment group had a significantly greater change at this endpoint vs the placebo group (adjusted mean difference, –4.0 points; 95% confidence interval [CI], –7.31 to –0.64; P = .02). The effect size from baseline to day 28 was 0.3.

Remission, which was defined as a total score of 12 or less at day 28 on the MADRS, was achieved by 52.5% of the active treatment group vs 31.0% of the placebo group (P = .001). A 50% improvement over baseline on the MADRS, signifying the response rate, was achieved by 69.3% vs 52.0%, respectively.

Dizziness, dissociation, dysgeusia, nausea, and vertigo were the most commonly reported adverse events (AEs) in the esketamine group and ranged from 20.9% to 26.1%. Although there was a transient increase in blood pressure up to 40 minutes after each dose of esketamine was administered, it commonly returned to normal ranges about an hour and a half after dosing.

Abuse Potential Concerning

IV ketamine has been shown to be effective for refractory depression but has not been approved by the FDA. Ketamine has also been used for decades as a recreational party drug.

The new agent, on the other hand, represents a novel administration method for ketamine and has grabbed wide attention in the field, Schatzberg notes in his accompanying editorial, which is titled "A Word to the Wise About Intranasal Esketamine."

"Rarely has there been so much anticipation for a new antidepressant as has been seen for intranasal esketamine," he writes.

He notes that the phase 3 study showed rapid separation compared with placebo and showed continued separation with repeated administration up to 28 days. However, during the FDA approval process, which included data from this trial, "a number of worrisome findings were revealed that should give potential users some pause and call for a concise framework for assessing the risk-benefit balance for using this formulation of ketamine," Schatzberg writes in his editorial.

He notes that the small effect size of 0.3 was in the mild range "and there was no further gain in advantage beyond the initial separation." In addition, the "known abusability of ketamine in humans" is reason for concern, as is a potential suicide risk.

There were three suicides reported in the esketamine group, "but were these drug related?" said Schatzberg.

Data from a drug relapse prevention/discontinuation study, which was mentioned in the FDA's briefing document, also showed a rapid relapse rate, he added during the press briefing.

"We need a better sense of how the drug works," Schatzberg said. "We haven't answered many questions for a drug of potential abuse."

Heated Debate

Following the presentations, Thase and Schatzberg were joined by Kalin for a question-and-answer session with the press that morphed into a point-counterpoint debate between the two physicians.

Thase noted that both men agree that esketamine "is known to be a controlled substance. There is a risk evaluation and mitigation strategy [REMS] in place to minimize some of the things that Alan mentioned."

He added that in a longer-term study, the investigators did not see "patients divert and switch out to get black market ketamine. We did not see examples of people using other drugs to increase the effect or chase the effect," he said.

"Our patients didn't behave like people who are drug seeking. They behaved like depressed people who were responding to a treatment," Thase said. "That doesn't mean that other people don't get into trouble with ketamine, they do."

He noted that in some countries, it's a major drug of abuse and that in the United States, it can be a recreational drug that some individuals have serious problems with. "So I'm entirely in agreement that we must be cautious and reasonable and careful," he said.

"My own opinion about this is that the endogenous opioid system is part of what makes life worth living. We have it for reasons that include the ability to enjoy, to consume, to have fun, to pursue, and so forth. It works in fine balance with the other neurotransmitter systems and our placebo responses in part [are] mitigated by the opioid system," said Thase.

"At a receptor level, the drug is not an opiate. It just isn't. But I do agree that it has some releasing or other effect that is part of why we need to be cautious," he added.

Small Effect Size

Thase noted that while Schatzberg was not impressed with the 0.3 effect size, "that's the most significant improvement we've seen in 20 years. At the end of the day, if you look at the last five, six, seven treatments that have come out, they were approved with 2- to 3-point differences after 8 weeks and the effects emerged more slowly.

"I wish the effect size was larger, but it is larger than every other recently approved antidepressant," he added.

"The effect size is mild, no matter what," Schatzberg countered. However, he noted that the number needed to treat was very low at about 5, "which is good and very encouraging."

Thase added that he also "took issue" with Schatzberg's point that the difference between 2 and 4 weeks in terms of relapse was important. "In all of our studies of effectiveness, when treatments are abruptly discontinued, people start relapsing — and they start relapsing fairly quickly." Whether the relapse occurs a 2 weeks or 4 weeks is relatively insignificant, he added.

He noted that the relapse curves in his relapse-prevention study, which has results that have not yet been published, "look every bit like the relapse curves in the STAR-D study," where those who have responded to treatment for chronic depression often do relapse.

"Michael raises a couple of interesting points," said Schatzberg. First, the blood levels attained with esketamine are lower than those seen with the intravenous form of the drug, he said.

"With esketamine, you don't get to those same blood levels, but you also don't get as much efficacy probably, which is good and bad," Schatzberg said. "If the drug in fact mobilizes the opioid system, God bless and this may be a very good thing to do. We may have found a good way to mobilize the opioid system in a safe way.

"However, at the same time, the data that are out there about several deaths and several suicides, regardless of the exact explanation, are worsening and somewhat worrying. I think there needs to be more caution rather than less," he added.

Schatzberg noted that patients come in every day asking whether his center is providing IV or intranasal ketamine. "There's a lot of interest in it, so we need to be thoughtful as to what we're going to recommend to patients. We'll get the data, but that data will take a while," he said.

The REMS program "will help us get that data," said Thase. "This is my life's work and arguing for more careful and longer study with a novel treatment with some issues is the most reasonable approach here."

Cautious and Careful Exploration

Kalin noted that there is a "level of desperation that is out there" in many patients with TRD, as well as a lot of pressure on the clinicians that care for them to provide effective treatments.

"Our concern and what you're hearing isn't necessarily that the scientific approach won't be there over time, but that when all the excitement, all the demand, all the desperation, and all the pressure [decreases], there's the potential for using this in ways that is not necessarily in the best interest of patients, as we understand it now," he said.

"My motivation is to make sure we are as cautious and as careful as possible; but at the same time, being positive and optimistic about exploring this and providing it in appropriate ways to our patients," Kalin added.

Schatzberg noted his concern about the growing proliferation of drugs of potential abuse as potential treatments for psychiatric disorders, including MDMA, psilocybin, and even very low doses of opioids such as buprenorphine.

"How the field responds to this, and how public and regulators respond, is going to be a place of frank discussion. People will need to be educated about the risk and the benefit and we need to study more," he said.

Esketamine is the first of what may be other potential options on the horizon, Schatzberg added. "People need to understand that [this drug] isn't kooky but it does have some risk. In the end, we're trying to help the patients but we're also trying to keep people safe."

Hugging it Out

When Thase asked whether "it's not kooky" is the take-home message, both men laughed.

Remarkably, they also ended the session with a hug.

However, Thase told Medscape Medical News afterwards that his take-home message for clinicians is that "this is a treatment that really works" in patients who have failed other antidepressant therapies.

Thase said he was "cautiously optimistic" 8 years ago, before investigators started researching the drug.

"I have tempered optimism now," he said. "I know what to worry about and I'm reassured that our patients don't seek drugs and get into trouble like people who are addicted, and this delivery system will prevent that from happening."

He added that for REMS-managed esketamine, he's not worried about the concerns raised during the debate. "For intravenous ketamine done outside of FDA purview and formal follow-up, you could run into some concerns."

However, he added he believes esketamine is "really the story of the decade in depression therapeutics and maybe in psychiatric therapeutics," Thase said.

No "Silver Bullet"

Ned H. Kalin, MD

In an "Editor's Note" that will be published next month in the AJP, Kalin writes that "despite our best efforts," many psychiatric patients continue to suffer. "We simply need new treatments," he adds.

He told Medscape Medical News that his recommendation for clinicians is that "we should move forward with this and that it's an improved treatment that seems to help some patients pretty dramatically."

That said, Kalin noted that it's important to be cautious, especially in relation to some of the AEs and abuse potential "and maybe the discontinuations."

"We want to be cautious but we don't want to diminish that this is an advance and an opportunity for clinicians and for patients."

He added that it's important to keep in mind that this isn't a "silver bullet" treatment.

"It's a new bullet and it works differently from our other drugs. On the other hand, we alluded to the ketamine clinics that are out there where ketamine is used off-label and without regulation. So we just need to be very thoughtful and cautious about it," Kalin said.

A statement from Janssen sent to Medscape Medical News following the APA press conference stated that "healthcare providers have had limited options for adult patients with treatment-resistant depression" before the recent FDA approval of their intranasal spray.

"These findings, which represent part of the phase 3 clinical trial program of more than 1700 patients, reinforce the robust efficacy and safety profile of the medicine and the significant improvement of depression symptoms that Spravato may offer adults with TRD," the company writes.

The study was funded by Janssen Pharmaceuticals. Thase reported serving as a consultant or independent contractor to Acadia, Akili, Alkermes, Allergan (Forest, Naurex), AstraZeneca, Axsome, Cerecor, Eli Lilly, Fabre-Kramer, Gerson Lehrman Group, Guidepoint Global, Lundbeck, Johnson & Johnson, MedAvante, Merck, Moksha8, Nestlé (Pamlab), Neuralstem, Novartis, Otsuka, Pfizer, Shire, Sage, Sunovion, and Takeda; receiving grant or research support from Acadia, the Agency for Healthcare Research and Quality, Alkermes, Allergan (Forest), AssureRx Health, Avanir, Axsome, Intracellular, Janssen Pharmaceuticals, Johnson & Johnson (including for the present study), NIMH, Otsuka, the Patient-Centered Outcomes Research Institute, and Takeda; and receiving royalties from the American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton & Company. In addition, his spouse is employed by Peloton Advantage, which does business with a number of pharmaceutical companies. Disclosures for the other study authors are fully listed in the original article. Schatzberg disclosed receiving grant support from Janssen; serving as a consultant for Alkermes, Avanir, Brain Resource, Bracket, Compass, Delpor, Epiodyne, GLG, Jazz, Janssen Pharmaceuticals, Lundbeck/Takeda, McKinsey and Company, Merck, Myriad Genetics, Neuronetics, Owl Analytics, Pfizer, Sage, Sunovion, and Xhale; holding equity in Corcept (co-founder), Delpor, Dermira, Epiodyne, Gilead, Incyte Genetics, Intersect ENT, Madrigal, Merck, Owl Analytics, Seattle Genetics, Titan, and Xhale; and being listed as an inventor on patents for pharmacogenetics and antiglucocorticoid use in the prediction of antidepressant response. Kalin disclosed no relevant financial relationships.

American Psychiatric Association (APA) 2019 Annual Meeting. Presented May 20, 2019.

Am J Psychiatry. Published online May 21, 2019. Full text, Editorial

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