Intranasal Esketamine Found to Rapidly Reduce Symptoms of Depression, Suicidality

Intranasal esketamine appears to rapidly improve depression scores and measures of suicidality among depressed patients at imminent risk of suicide, according to a report published April 16 in AJP in Advance.

The proof-of-concept study is important because it shows efficacy of esketamine in the clinical management of a potentially lethal condition for which there are no approved pharmacotherapies. Ketamine itself has been in use since 1970 as an anesthetic; esketamine is a derivative that can be used intranasally in relatively small doses.

“This is a significant and important study because it provides early evidence demonstrating that esketamine produces antidepressant effects greater than those found with intensive standard of care approaches over the first hours and days of treatment in patients believed to be at imminent risk of suicide requiring hospitalization,” co-author Gerard Sanacora, M.D., Ph.D., told Psychiatric News. “If confirmed, this type of rapid onset antidepressant effect could potentially shorten hospital stays or possibly even allow patients to avoid hospitalization altogether and more rapidly return to their normal lives.”

Sanacora was the lead author of a consensus statement on ketamine for depression and suicide produced by a work group of the APA Council on Research Task Force on Novel Biomarkers and Treatments. Work group members, in addition to Sanacora, included past APA Presidents Alan F. Schatzberg, M.D., and Paul Summergrad, M.D. Other authors on the consensus statement were Mark A. Frye, M.D., William McDonald, M.D., Sanjay J. Mathew, M.D., Mason Turner, M.D., and Charles Nemeroff, M.D.

In the study, sponsored by Jansen Research and Development LLC, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for four weeks, in addition to comprehensive standard-of-care treatment. (The latter included hospitalization for five days after randomization, unless a longer or shorter period was clinically warranted, and initiation of one or more antidepressants.)

Candidates for the study were screened shortly after presenting to an emergency department or an inpatient psychiatric unit in the previous 24 hours and found to be in clinical need of acute psychiatric hospitalization due to imminent risk for suicide.

The study participants were asked about depressive symptom severity (using Montgomery-Åsberg Depression Rating Scale, or MADRS) before receiving their initial dose of ketamine or placebo as well as 4 and 24 hours later. Depressive symptoms were reassessed at visits during the double-blind and posttreatment follow-up phases of the study. Clinicians were also asked to evaluate the suicide risk of the study participants throughout the trial (using the Suicide Ideation and Behavior Assessment Tool).

A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours and at 24 hours. Participants in the esketamine group also had significantly greater improvement on the MADRS suicidal thoughts item score at 4 hours.

Additionally, a significantly greater proportion of patients in the esketamine group achieved resolution of suicide risk 24 hours after the first dose, as defined by a clinical global judgment of suicide risk score of 0 to 1. This finding is consistent with results of a meta-analysis of intravenous ketamine, also published in the American Journal of Psychiatry, which found a single infusion of ketamine significantly reduces suicidal thoughts in depressed patients in as little as one day, with benefits lasting for up to one week.

Intranasal esketamine was generally well tolerated. Adverse events leading to early termination occurred in five participants in the esketamine group, and three were given a lower dose of the medication over the course of the trial due to intolerance. (Adverse events included agitation, aggression, unpleasant taste, irregular heartbeat, dizziness, labored breathing, and nausea.)

Ketamine has been used recreationally as a “party” drug and carries with it the risk of abuse. “The limited, controlled use of the medications, such as in this study, markedly mitigates most of those risks,” Sanacora told Psychiatric News. “There is always some risk/benefit analysis that needs to be performed when making any clinical decision. In this case, clinicians and patients will need to consider the benefits of a more rapid reduction in depressive symptoms (that may allow for a faster hospital discharge and return to normal life), against the risks associated with ketamine use under these controlled conditions.”

The benefits of esketamine, as shown by the study, appear to be primarily for rapid reduction of symptoms and suicidality in the acute period, rather than for long-term efficacy. At one month, patients in both the treatment and placebo arms had met remission criteria, defined as a MADRS score of 12 or less, but the statistically significant advantage of esketamine over placebo disappeared on measures both of depressive symptoms and suicidality at Day 25.

Sanacora emphasized that the study was specifically designed to assess the efficacy of esketamine for rapidly reducing depressive symptoms and suicidality among individuals with major depressive disorder. He noted that all the patients in the trial received ongoing follow-up care regardless of treatment group, making it difficult to discern a significant benefit of esketamine over placebo.

“All patients received intensive standard of care treatment, including inpatient hospitalization and extremely close outpatient follow-up care on discharge, at some of the leading depression treatment centers in the U.S.,” he said.

Sanacora added that patients were not required to have treatment-resistant depression, so it should not be surprising that even the placebo patients did well over the course of a month with intensive standard of care treatment.

“My interpretation of the data is that, in this patient population, esketamine provided a significant benefit early in the treatment course that gradually became less apparent over time as the antidepressant effects of the standard treatment approaches had more time to take effect.”   

In an editorial accompanying the report in AJP, Editor Robert Freedman, M.D., and members of the AJP Editorial Board wrote, “If positive, longer-duration results emerge for intranasal esketamine, it is possible that this treatment will help a significant number of patients who do not respond adequately to existing antidepressant therapies.”

They added, “The FDA and the pharmaceutical companies marketing ketamine have the primary ability to control how the drug is distributed and in what circumstances it can be used, but input from psychiatrists and other interested professional groups as well as the Centers for Disease Control and Prevention and the National Institute on Drug Abuse, should inform the development of effective controls. … [T]he aim is to establish the risk for abuse and the framework within which that treatment will continue to be available to those with need, while the population that is at risk for abuse is protected from an epidemic of misuse.” ■

“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” can be accessed here. “Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial” is available here. “A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders” is located here.