Esketamine Rapidly Curbs Suicidal Thoughts in Depressed Patients

By Anne Harding

NEW YORK—Depressed, suicidal patients show improvements in their symptoms four hours after receiving a dose of intranasal esketamine, a new proof-of-concept study shows.

Patients given 84 mg of esketamine, the S-enantiomer of ketamine, had significantly greater improvements in Montgomery-Aasberg Depression Rating Scale (MADRS) scores at four and 24 hours after administration compared to those given placebo, Dr. Carla M. Canuso of Janssen Research and Development in Titusville, New Jersey, and colleagues found.

"There's a potential opportunity for further development of a drug that could have dramatic effects in reducing symptoms of depressive and suicidal patients who are in crisis," Dr. Canuso told Reuters Health by phone. "The treatment options at this point in time are really limited. Typically patients are hospitalized as a way to keep them in a safe environment and monitored, and antidepressants are started . . . There really is not much you can do except to provide for that safe environment while you're waiting for that antidepressant to kick in."

Antidepressants typically take four to six weeks to reach their optimal effect, Dr. Canuso and her team note in the American Journal of Psychiatry, online April 16. Small studies have found that ketamine, an NMDA antagonist, improved mood and reduced suicidal symptoms within hours, they add. The drug is approved by the U.S. Food and Drug Administration (FDA) as a pediatric anesthetic, and is also abused as a "party drug" by people seeking its dissociative effects.

Janssen is developing esketamine for treating suicidal, depressed patients, and reported earlier this year in a phase 2 study in JAMA that the drug reduced symptoms as soon as two hours after administration.

In the new study, Dr. Canuso and her colleagues randomly assigned 68 patients with severe depression who were at imminent risk of suicide to receive 84 mg of esketamine or placebo intranasally twice a week for four weeks. All study participants were also started on a new antidepressant regimen. Forty-nine patients finished the double-blind phase of the study and 44 completed follow-up at day 81.

At four hours, MADRS (scale, 0-60) scores had improved by a mean of 13.4 in the esketamine group and by 9.1 in the placebo group (P=0.015). The difference remained significant at 24 hours after treatment, but by day 25 there was no statistical difference between the two groups in MADRS score improvement.

There were also significant improvements in the MADRS item measuring suicidal ideation four hours after administration, but not at 24 hours or at day 25.

A post-hoc analysis found 21.2% of patients in the active-treatment group had resolution of their suicide risk at four hours after treatment, compared to 9.7% of the placebo group. At 24 hours, suicide risk had resolved in 40% of the esketamine group and 6.5% of the placebo group.

Five patients in the esketamine group developed adverse events that led them to withdraw early from the study, and three had to reduce their dose due to intolerance. One patient in the placebo group had an adverse event.

Several phase 3 studies of esketamine for acute treatment of suicidal depression, and in patients with treatment-resistant depression, are underway, Dr. Canuso told Reuters Health.

To help prevent misuse of the drug, patients self-administer the medication in a physician's office, hospital or clinic, she added. It is dispensed in single-use nasal spray devices, in amounts too small for people seeing a ketamine-like high, Dr. Canuso said.

While such measures would help prevent misuse of esketamine at the level of individual practitioners, system-wide steps must also be taken if the drug shows clinical benefit in phase 3 trials, Dr. Robert Freedman, the editor-in-chief of the American Journal of Psychiatry, told Reuters Health by phone. Dr. Freedman and several colleagues wrote an editorial published with the new study.

"We need to help the regulatory agencies set up a framework in which the drug can be safely prescribed without causing another epidemic," Dr. Freedman said.

Janssen's efforts to prevent abuse "will be helpful for most physicians and most patients," he said. "But as we saw with the Oxycontin experience, once the drug is on the market there are all kinds of possibilities for diversion, and we also need to take steps to prevent that from happening again."

Examples of how esketamine might be regulated include scheduled drugs such as methadone, which is tightly controlled and rarely abused, and clozapine, which is only prescribed to patients after lab tests show they can safely take it, Dr. Freedman said. Ketamine is on the market, he added, "because it already has a very legitimate and important use as a pediatric anesthetic, and so the possibility of diversion actually exists, and there have been case reports of diversion."

SOURCE: https://bit.ly/2HNgJCo and https://bit.ly/2JZ5APd

Am J Psychiatry 2018.

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