January 03, 2018
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Esketamine rapidly improves symptoms in treatment-resistant depression

Ella J. Daly

Patients with treatment-resistant depression who received intranasal esketamine alongside their oral antidepressants experienced significant and rapid improvement of depressive symptoms, according to phase 2 data published in JAMA Psychiatry.

“Major depressive disorder affects nearly 300 million people of all ages globally and is the leading cause of disability worldwide,” lead author Ella J. Daly, MD, from the department of neuroscience at Janssen Research & Development, said in an interview. “Although currently available antidepressants are effective for some patients, about one third of patients do not respond to treatment, highlighting a substantial unmet need in this therapeutic area.”

Researchers conducted a phase 2, double-blind, placebo-controlled study to determine the efficacy, safety and dose-response of intranasal esketamine in 67 adults with major depressive disorder and treatment-resistant depression.

The study included four phases: screening, two double-blind treatment periods (days 1-15), optional open-label treatment (days 15-74) and post-treatment follow-up at 8 weeks. Researchers randomly assigned 67 patients to receive treatment, and 60 completed both double-blind periods. In the first period, 33 participants were assigned to placebo, 11 to 28 mg esketamine, 11 to 56 mg esketamine, and 12 to 84 mg of esketamine, twice weekly. In the second period, 28 placebo-treated participants with more serious symptoms were rerandomized (1:1:1:1) to one of the four treatment arms, while those with mild symptoms continued to receive placebo. Dosing frequency was reduced gradually throughout the open-label phase.

Analysis showed that patients in all three esketamine groups experienced a superior change in depression scores compared with placebo (esketamine 28 mg: P = .02; 56 mg: P = .001; 84 mg: P < .001), indicating a significant ascending dose-response relationship (P < .001). Although dosing frequency gradually decreased during the open-label phase, researchers observed sustained improvement in depressive symptoms throughout the study. Overall, the average depression score decreased from baseline to day 8 in period one and from day 8 to day 15 in period two across all groups; however, participants receiving esketamine saw greater improvement compared with placebo.

Of 56 patients treated with esketamine, three experienced adverse events and discontinued participation during the double-blind phase, whereas no patients receiving placebo discontinued participation. Only one participant of 57 had adverse events that led to discontinuation during the open-label phase.

“The results of the study showed that treatment with intranasal esketamine produced a significant, rapid improvement of depressive symptoms in patients with treatment-resistant depression. These data support the need for more research in this area, and provide hope for people in need,” Daly told Healio Psychiatry. “These results suggest that with further research, intranasal esketamine may be a potential treatment option for patients with major depression who are not responding to current treatment. We look forward to seeing the results of our phase 3 clinical trials.”

In a related editorial, Daniel S. Quintana, PhD, from NORMENT K.G. Jebsen Centre for Psychosis Research, division of mental health and addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, in Norway, and colleagues wrote that the study findings show intranasal esketamine holds promise to be an effective antidepressant. Not only does esketamine helps rapidly reduce depressive symptoms in a faster way than current treatments, but it can also be delivered intranasally, a potentially advantageous delivery method compared with administering oral or IV treatments, they wrote.

“The results of the study by Daly and colleagues demonstrate the considerable promise of combining a compound with rapid antidepressant effects with intranasal delivery,” Quintana and colleagues wrote. “We look forward to further research developments of intranasal esketamine as a novel treatment for depression given the crucial need for better antidepressants.” – by Savannah Demko

Disclosures: Daly is an employee of Janssen Research & Development, LLC and holds company stock. Please see the study for all other authors’ relevant financial disclosures. Quintana is a coinventor on a patent application for an intranasal oxytocin administration delivery device. Please see the study for all other authors’ relevant financial disclosures.