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Esketamine nasal spray (Spravato) monotherapy was helpful in improving symptoms of treatment-resistant depression, a randomized, double-blind trial found.

Among 379 participants in the efficacy analysis, those who received one of two strengths of esketamine had a significantly greater improvement in average Montgomery-Åsberg Depression Rating Scale (MADRS) total score compared with placebo by day 28, with least-square mean differences of -5.1 with the 56-mg dose and -6.8 with 84 mg (both P<0.001 vs placebo).

For the key secondary endpoint of the trial, esketamine monotherapy was significantly better than placebo by day 2, about 24 hours after the first dose. This was marked by a 3.8-point and 3.4-point greater improvement than placebo in the 56-mg and 84-mg groups, respectively, reported Adam Janik, MD, of Janssen Research and Development in San Diego, and co-authors at Psych Congress in Boston.

Approved in March 2019, esketamine is currently indicated for use alongside an oral antidepressant for treatment-resistant depression and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior.

"This data gives patients the option to benefit from esketamine treatment either with or without an antidepressant," said Gregory Mattingly, MD, president of Midwest Research Group and Founding Partner of St. Charles Psychiatric Associates in Missouri, who was involved with the study but not listed as an author on the poster.

He told MedPage Today that his group was "extremely excited" by the findings. "For many patients with treatment resistant depression who have not benefited from standard antidepressants, this allows them to 'unchain' themselves from antidepressants that have often provided little benefit but are often associated with unwanted side effects."

"The esketamine benefits without an antidepressant give patients and clinicians the opportunity to truly individualize treatment for their best outcomes," he added.

Study participants had to be medically stable and considered non-responders (defined as 25% or less improvement of symptoms) to two or more oral antidepressants for the current depressive episode. All adults also had to have recurrent or a single episode of major depressive disorder lasting 2 years or longer according to DSM-5 criteria without psychotic features and an Inventory of Depressive Symptomatology-Clinical rated 30-item (IDS-C30) total score of 34 or more (ranges from 0 to 84).

Prior ketamine or esketamine users were excluded. Other exclusion criteria included non-responsiveness to electroconvulsive therapy for the current episode, vagal nerve or deep brain stimulation for the current episode, medical or anatomical inability to use a nasal spray, moderate or severe substance or alcohol use disorder, and homicidal or suicidal ideation in the prior 6 months.

After screening and randomization, 95 patients received 84 mg esketamine, 86 patients received 56 mg esketamine, and 197 received placebo. About 61% were female, 86.8% were white, and 65.6% were on an antidepressant at screening. Average duration of the current depressive episode was 348.3 weeks.

Baseline MADRS total score averaged 37.3 (ranges from 0 to 60), Clinical Global Impression-Severity score averaged 4.9 (ranges from 1 to 7), mean Patient Health Questionnaire 9 item score was 20 (ranges from 0-27), and mean IDS-C30 score was 45.9.

Prior to study treatment, the screening period lasted up to 7 weeks, which involved a mandatory 2-week drug-free period. The double-blind treatment phase involved twice-weekly treatment sessions for 4 weeks.

By day 28, twice as many participants on esketamine achieved treatment response -- a 50% or more improvement in MADRS score -- compared with placebo (30.5% on 56 mg, 29.2% on 84 mg, and 15.1% on placebo). Also at the end of the trial, more patients who received esketamine monotherapy achieved remission, defined as a MADRS score of 10 or under (14.6%, 21.3%, and 6.5%, respectively).

In addition to the 379 participants in the efficacy analysis set who met the prior treatment non-response criteria, another 98 who didn't meet this criteria still received the study medication and were included in the safety analysis. No new safety signals emerged, and no deaths occurred. The most common adverse events during the double-blind phase were nausea (24.8% on either esketamine dose vs 8.4% with placebo), dissociation (24.3% vs 2.8%), dizziness (21.7% vs 7.2%), and headache (19% vs 8.8%).

Based on the data, in July the submission of a supplemental new drug application to the FDA seeking approval for esketamine as a monotherapy for adult treatment-resistant depression.

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