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When the FDA to treat patients with treatment-resistant depression last March, the decision was met with waves of enthusiasm and concern within the psychiatric community, ripples of which are still being felt today.

The nasal spray, to be used alongside standard oral antidepressants, was touted as a "game changer" for a notoriously difficult-to-treat population, but critics were quick to point out irregularities in the evidence used to support the drug's approval and highlighted increased risks for dissociation, abuse, and suicidality observed in the trials.

Their concerns came to the forefront in a series of editorials published in The Lancet Psychiatry in October. Now the debate's next chapter opens with a response from drugmaker Janssen, a Johnson & Johnson subsidiary.

"Overall, the program provides substantial evidence that esketamine nasal spray plus oral antidepressant acts rapidly, shows robust efficacy in treatment resistant depression, and maintains this benefit over time," wrote Janssen's Ella Daly, MD, and colleagues in a published Thursday.

Expedited Approval Criteria

Just two positive trials formed the basis of the FDA approval: one short-term trial that demonstrated efficacy up to 4 weeks, and -- in an unusual move by the FDA -- a maintenance withdrawal trial designed to assess time-to-relapse.

Daly and co-authors acknowledged this nonstandard approach, but noted the FDA required both short and long-term data in the drugmaker's initial application "because of the novelty of the product."

"The study's objective was to assess time to relapse in patients whose symptoms remit or respond to esketamine, and hence the population was necessarily enriched for those achieving stable remission or stable response, respectively," they stated.

In the short-term trial, esketamine treatment yielded a mean four-point improvement on the 60-point Montgomery-Åsberg Depression Rating Scale (MADRS) relative to placebo, and 69% of those receiving the active drug were considered responders.

A relatively high proportion (52%) of the placebo group also achieved at least a 50% improvement in MADRS scores from baseline and were designated as responders as well.

"Although the sponsor argues that this difference is clinically meaningful, clinicians who have heard esketamine referred to as a game-changer might be disappointed to calculate that 81% of the response to esketamine was observed with placebo," wrote former FDA reviewer Erick Turner, MD, of Oregon Health and Science University in Portland, in his .

In their recent correspondence, Daly and colleagues acknowledged the large MADRS improvements in both groups, but said this finding may be due to placebo participants being started on new antidepressants at baseline -- as opposed to placebo alone -- as well as things like high expectations of receiving a novel drug.

Nonetheless, this trial did achieve statistical significance and, although two short-term efficacy studies failed to meet their primary endpoint, patients in the esketamine arm did experience a "clinically meaningful" two-point change in MADRS scores, Daly and colleagues said. They also noted that the FDA had approved the study plan and, obviously, the drug itself after the data were in.

Turner had also questioned the robustness of the maintenance trial's findings and cautioned that one site in Poland, in which 100% of participants in the placebo arm relapsed, was driving the results.

But neither the sponsor nor the FDA found "any reason to exclude data from the site" after performing a site inspection and reviewing the data, said the Janssen group.

In the most recent correspondence, Daly and colleagues presented an additional sensitivity analysis excluding data from the Polish site. Updated Kaplan-Meier estimates that used a "statistical method appropriate for time-to-event data" showed that statistical significance for the primary endpoint was maintained (HR 0.57, P=0.048).

On the other hand, Turner's own "back of the napkin" calculation (as he put it) from publicly available data indicated a non-significant difference.

"In the spirit of open science, it is hoped that the sponsor will share the patient-level data so that unconflicted academics might resolve these questions and attempt independent replication," Turner wrote.

Regardless, among patients with treatment-resistant and severe depression, rapid-but-modest symptom changes would need to stabilize over time to be meaningfully effective, said Ioana Cristea, PhD, of the University of Pavia in Italy, who co-authored another with Florian Naudet, MD, PhD, of Universitaire de Rennes in France.

In the short-term efficacy trial, clinical responses were not maintained 24 hours after dosing.

"Anyone who works with depression, especially chronic depression, can tell you this is not something you'll solve with three [sprays]," Cristea told 番茄社区app. "This is something that interacts with your personality and everyday functioning and everything else. This search for quick fixes is worrying."

Daly and colleagues acknowledged that esketamine in the two efficacy trials failed to initiate a clinical response by day 2 that persisted to day 28, but noted that this was a novel endpoint and that a sustained response "is recognized as a high hurdle in this patient population."

An Unmet Need, a Vulnerable Population

There has not been a new drug approved specifically for treatment-resistant depression in close to three decades.

As such, esketamine's novel mechanism quickly scored it a "breakthrough therapy" designation based on findings from a that demonstrated rapid and significant antidepressant effects. Previously, case reports and -- best known alternatively as an anesthetic agent and as a party drug due to its dissociative effect on perception -- had shown that some severely depressed individuals obtained relief within hours, even minutes, of dosing. Anecdotally, some of these responses were considered near-miraculous.

Perhaps it was this novel effect that also "encouraged leniency" regarding some of these concerns throughout the approval process, Turner noted.

"In the case of esketamine, you have this unmet need, this drum that gets pounded over and over again: People are dying and we don't have anything for them," Turner told 番茄社区app. "But that actually makes the data all the more disappointing."

In the esketamine trials, treatment-resistant depression was defined as patients who had failed two or more antidepressants, which "has been endorsed by health authorities" including the European Medicines Agency's Committee for Medicinal Products for Human Use and the FDA, Daly said.

But clinically, "vanishingly few" clinicians would consider patients to have treatment-resistant depression after failing to respond to two selective serotonin reuptake inhibitors (SSRIs), Turner noted in his most recent correspondence.

Instead, this diagnosis is often confirmed after patients have failed to respond to two different classes of pharmacologic treatment and commonly involves treatment with cognitive behavioral therapy or other nonpharmacologic strategies, he added.

In the phase III Spravato trials, 22% had failed just one class of antidepressants, Turned noted in his editorial, citing Janssen's FDA briefing packet.

"In the real world, you're going to have a level of treatment resistance that is much higher than what was used in the clinical trial program, so these data, as weak as they are, represent a best-case scenario," he told 番茄社区app.

Currently, esketamine can only be administered through facilities registered in its Risk Evaluation and Mitigation Strategy (REMS), and patients must be monitored for two hours after dosing due to the adverse events that occurred in the clinical trial program.

Overall, six patients assigned to the intervention , of which three were suicides. Deaths by suicide occurred four, 12, and 20 days after patients' last dose of esketamine. No deaths were seen with placebo.

Regardless of the statistical method used, the patient population selected, and the robustness of the findings, these events and esketamine's potential for harm should raise the bar for the evidence required for approval, Cristea noted in her recent editorial.

"This is a drug that will be expensive, has a high potential for abuse, and has a problematic safety profile, if anyone has doubts about that," Cristea said. "This is compensated by very modest benefits."

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