Esketamine – the S-enantiomer of the anesthetic ketamine – continues to look promising as an adjunctive treatment for refractory depression, phase 2 results of a four-phase multicenter trial suggested.

“We observed a significant and clinically meaningful treatment effect (vs. placebo) with 28-mg, 56-mg, and 84-mg doses of esketamine,” reported Ella J. Daly, MD, of Janssen, and her associates. The results were apparent 1 week after treatment, and they persisted over the follow-up phase, which lasted 8 weeks.

Results support further investigation of intranasal efficacy of esketamine for the management of [treatment-resistant depression] in larger trials,” Dr. Daly and her associates wrote in JAMA Psychiatry (2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3739).

In the study, patients aged 20-64 years with a diagnosis of major depressive disorder were recruited from several outpatient referral centers. All of the participants had treatment-resistant depression, defined by the study as an inadequate response despite the use of two or more antidepressants. Overall, 67 patients were randomized to receive one of the three doses of intranasal esketamine or a placebo nasal spray. In addition, participants continued to take oral antidepressants during the study period. People with a history of psychotic symptoms, use of substances such as alcohol and cannabis, or significant medical comorbidities were excluded.

Among participants in the treatment groups, the mean total score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) surpassed the MADRS score changes among those on placebo. Specifically, the mean MADRS score change for those on the 28-mg dose was –4.2 (P = 0.2), on the 56-mg dose was –6.3 (P = .001), and on the 84-mg dose was –9 (P less than .001).

The most common side effects among participants treated with esketamine were dizziness, headache, and dissociative symptoms. However, most adverse events were transient and “either mild or moderate in severity,” the investigators reported.

Dr. Daly and her associates cited several limitations, including the small sample size and the study’s exclusion criteria. Despite those limitations, Dr. Daly and her associates said, the results support further investigation of intranasal esketamine for treatment-resistant depression. They said a phase 3 study aimed at evaluating the frequency needed for dosing and duration of effect is underway.

Janssen funded the study. Dr. Daly and several of the other investigators are Janssen employees.

SOURCE: Daly et al. JAMA Psychiatry. 2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3739


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