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Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group.Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (7%) treated with an antidepressant and placebo.For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.ClinicalTrials.gov identifier: NCT02493868.

Objective: To report the design and preliminary results of a mirror-image study comparing total psychiatric hospitalisation rates pre- and post-switch to aripiprazole once-monthly, an extended release injectable solution. Methods: A multi-center, open-label mirror-image study of patients (18–65 years) with schizophrenia to compare total psychiatric hospitalisation rates between retrospective treatment with oral standard-of-care (SOC) anti-psychotics and prospective treatment with aripiprazole once-monthly in a naturalistic community setting in North America. Total psychiatric hospitalisation rates were assessed between retrospective (Months −4 to −1) and prospective treatment periods (Months 4–6) for patients who completed ≥3 months aripiprazole once-monthly. Results: One hundred and eighty-three patients entered the prospective phase. After switching to aripiprazole once-monthly, total psychiatric hospitalisation rates for the 3-month prospective period were significantly lower (p