麻豆传媒

Esketamine nasal spray (Spravato) paired with oral antidepressants remained effective long-term for patients with treatment-resistant depression who responded to the therapy, according to a withdrawal trial by the product's manufacturer.

After 16 weeks of esketamine nasal spray (56 or 84 mg) plus antidepressants, 176 patients achieved stable remission, defined as scores of ≤12 for at least 3 out of 4 of the last weeks. Among this group in remission, the continued use of esketamine and antidepressants decreased the risk of relapse by 51% compared to patients on antidepressants and placebo (hazard ratio 0.49, 95% CI 0.29-0.84), reported Ella Daly, MD, of Janssen Research and Development in Titusville, New Jersey, and colleagues.

No deaths were reported, but six patients in the esketamine-antidepressant arm did experience serious adverse events (AEs), including autonomic nervous system imbalance, disorientation, hypothermia, lacunar stroke, sedation, simple partial seizures, and suicidal ideation, all of which occurred during an induction phase that determined which patients responded to the therapy, they wrote in .

"This is an important finding given that this patient population are known to be very resistant and refractory in terms of their ability to respond and maintain response," Daly told 麻豆传媒 in an interview with a media relations person present. "So learning that you can not only get a response in this difficult-to-treat patient population, but that you can maintain the response, is really important."

In March, the FDA approved esketamine, the S-enantiomer of ketamine, leading to mixed responses in the psychiatric care community. Many were excited by the new therapy's rapid onset of action for this population, but others expressed concern about the lack of long-term safety data and whether coming off the drug would be problematic for patients.

Esketamine shares the dissociative effects seen with its parent drug, ketamine, prompting the latter's illicit use as a party drug ("Special K"). The Spravato label carries a for risk of sedation and problems with attention, judgment, thinking, abuse, misuse, and suicidal thoughts and behaviors. Because of its potential for abuse, the nasal spray is administered in a clinical setting under supervision for at least 2 hours. It was also approved with a that requires prescribers and patients to sign an enrollment form, and patients to avoid driving or using heavy machinery on treatment days.

Long-Term Data

The current study, , comes after a that showed esketamine at 56 or 84 mg twice weekly, in addition to antidepressants, improved MADRS scores at 28 days versus placebo and antidepressant therapy.

In an , Alan Schatzberg, MD, of the Stanford University School of Medicine in California, said that although efficacy was achieved, the effect size was "mild" (0.3) and certain questions remained, such as how long clinicians should continue the therapy beyond an acute course and which patients respond best to treatment.

"Unfortunately, the long-term discontinuation study that demonstrates efficacy may not be the best paradigm for a drug of abuse where coming off the drug may be more important and informative than the period when taking it," Schatzberg wrote.

As part of the safety assessment in the current trial, researchers included a 20-item Physician Withdrawal Checklist, and found "no evidence of a distinct withdrawal syndrome" 2 weeks after esketamine treatment was stopped.

In terms of duration of treatment, that needs to be determined by the clinical judgment of the provider, Daly said.

Both the short-term study and SUSTAIN-1 were included in the for the drug's approval to support proof of efficacy, which was a "somewhat unusual application in proof of efficacy," Schatzberg noted.

Although Daly and colleagues provided positive long-term data on the use of esketamine and concurrent antidepressants in this study, clinicians may still be concerned about the nature of the trial and the dosing frequency used in the protocol, the authors noted.

It's possible, for example, that an increased rate of depression that occurred after switching to placebo in the maintenance phase of the study was caused by antidepressant withdrawal, leading to a high relapse rate early on or a "rebound effect," they noted.

"In this study, although there were a high number of relapses in the first month in those switched to placebo nasal spray, it is unlikely that a pharmacologic withdrawal effect contributed given that the decrease in esketamine plasma concentrations is rapid for the initial 2 to 4 hours and more gradual thereafter (mean terminal half-life, 7-12 hours), with steady state never reached with intermittent dosing," they wrote.

Also, of those patients who relapsed after switching to placebo nasal spray, further analysis showed that over half were patients who had required a weekly versus biweekly dosing regimen to sustain stable remission before randomization, “reflecting the higher vulnerability in this subpopulation,” they added.

"Taken together, the evidence suggests that relapses seen in the first weeks after discontinuing esketamine treatment are likely attributable to more vulnerable patients and not a withdrawal or rebound phenomenon," they wrote.

SUSTAIN-1 Details

Patients were enrolled directly or transferred in from two other short-term blinded studies across 99 sites in the U.S., Canada, and Europe from 2015 to 2018. Patients (ages 18-64 years) were included if they had moderate to severe depression (MADRS score of at least 28; recurrent or at least 2 years of major depressive disorder; or a score of at least 34 on the Clinician-Rated Inventory of Depressive Symptomatology).

Initially, all patients received 56 mg esketamine spray, which was adjusted to a higher dose if deemed clinically appropriate by site investigators. Individuals who responded to the therapy in the induction phase entered a 12-week optimization period where the same dose (56 or 84 mg) was administered for 4 weeks, and then either weekly or every other week based on patient symptoms.

Participants who achieved remission or stable response at week 16 continued to the maintenance phase, during which they were randomized to continue esketamine or switch to placebo. They were then followed-up for 2 weeks after esketamine treatment was stopped, during which antidepressants were continued if necessary.

Of 297 patients (66.3% female, mean age 46.3) in the maintenance phase of the study, median exposure to esketamine was 17.7 weeks for those in remission and 18.4 for those in stable response, defined as at least a 50% reduction in MADRS scores from baseline without remission.

For patients in stable response, the risk of relapse was reduced by 70% with antidepressants and esketamine versus placebo (HR 0.30, 95% CI 0.16-0.55), the authors reported.

The most common reported AEs in the active arm of the maintenance phase were dysgeusia, vertigo, dissociation, somnolence, and dizziness. The same group also experienced increased transient blood pressure and dissociative symptoms on treatment days, though maximum blood pressure values and peak symptoms usually occurred 40 minutes after administration and returned to normal within 1.5 hours after treatment.

Also, while 85% of patients entered the trial without suicidal ideation or behavior, 11.6% of patients in the esketamine arm had higher scores after baseline during the induction phase, 5.7% did in the optimization phase, and 2.4% did in the maintenance phase, the authors reported.

They noted that while the evaluation of the primary endpoint, MADRS, was conducted by remote independent raters, the dissociative, sedative symptoms of esketamine are "difficult to blind," and "could have biased the staff who observed treatment administration," which was a study limitation.

Daly added that further long-term safety data in real-world settings will need to be monitored as well.

Comment