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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.

Introduction L’efficacite a court terme d’esketamine dans la depression resistante (DRT) a ete largement demontree, mais il n’etait pas encore etabli si les effets antidepresseurs etaient maintenus a long terme. Methode Etude de phase 3 multicentrique randomisee, double aveugle, evaluant l’efficacite et la tolerance d’esketamine intranasal (ESK) administre en continu ou discontinu, associe a un antidepresseur oral (AD), chez des adultes souffrant de DRT en remission stable apres 16 semaines d’ESK + AD. Les patients ont ete randomises 1 :1 : poursuivre ESK + AD ou Placebo intranasal (PLB) + AD. Le critere d’evaluation principal d’efficacite etait le delai avant rechute chez les patients en remission stable. Le critere secondaire d’efficacite etait le delai avant rechute chez les repondeurs stables. ESK (56 ou 84 mg) etait administre 1×/semaine ou 1×/2 semaines. Resultats Sept cent cinq patients adultes ont ete directement recrutes (n = 437) ou transferes d’une des etudes de phase 3 a court terme (etude a dose fixe, n = 150 ; ou dose flexible, n = 118). Le temps median avant rechute n’a pas pu etre estime chez les patients traites par ESK + AD (taux de rechute de 50 % non atteint) ; le temps median avant rechute dans le groupe PLB + AD etait de 273,0 jours, demontrant la superiorite significative d’ESK + AD. Parmi les patients en remission stable, le risque de rechute a reduit de 51 % par ESK + AD (26,7 % traites par ESK + AD ont rechute vs 45,4 % traites par PLB + AD, p = 0,03). Parmi les repondeurs stables, le risque de rechute a reduit de 70 % avec ESK + AD (25,8 % traites par ESK + AD ont rechutes vs 57,6 % traites par PLB + AD, p 10 %) rapportes dans le groupe ESK + AD etaient : dysgueusie (26,3 %), vertiges (25,0 %), somnolence (21,1 %), etourdissements (20,4 %), cephalees (17,8 %), nausees (16,4 %), vision floue (15,8 %) et troubles dissociatifs (13,2 %). Ces EI ont ete majoritairement observes le jour de l’administration, generalement transitoires, de gravite legere ou moderee et ont disparu le jour meme. Aucun deces n’a ete rapporte. Aucun EI n’a ete rapporte chez ≥ 10 % des patients traites par PLB + AD. Conclusion Chez les patients en remission stable ou repondeurs stables apres 16 semaines de traitement par ESK + AD, continuer le traitement par ESK + AD demontre une efficacite significativement superieure a un traitement PLB + AD pour retarder la rechute. Les donnees de tolerance etaient coherentes avec les donnees des precedentes etudes de phases 2 et 3.

Objective: To compare hospitalization rates in patients with schizophrenia treated prospectively with aripiprazole once-monthly 400 mg (AOM 400; an extended-release injectable suspension) vs the same patients’ retrospective rates with their prior oral anti-psychotic therapy. Research design and methods: Multi-center, open-label, mirror-image, naturalistic study in a community setting in North America. Patients who required a change in treatment and/or would benefit from long-acting injectable anti-psychotic therapy were treated prospectively for 6 months with AOM 400. Retrospective data on hospitalization rates were obtained. Clinical trial registration: ClinicalTrials.gov: NCT01432444. Main outcome measures: The proportion of patients with ≥1 psychiatric inpatient hospitalization with oral anti-psychotic therapy examined retrospectively (months –4 to –1 before oral conversion) and after switching to AOM 400 (months 4–6 after initiating AOM 400). Results: Psychiatric hospitalization rates were significantly lower when patients were treated with AOM 400 compared with oral anti-psychotic therapy both in the 3-month primary efficacy sample (2.7% [n = 9/336] vs 27.1% [n = 91/336], respectively; p 1 and

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

Long-term maintenance treatment with an antipsychotic is often required to prevent relapse and mitigate functional deterioration in patients with schizophrenia. This study assessed the long-term safety, tolerability, and maintenance of the therapeutic effect of aripiprazole once-monthly 400 mg (AOM 400) in patients with schizophrenia. This 52-week, open-label study included patients previously enrolled in 1 of 2 AOM 400 randomized controlled trials (RCTs) and de novo patients. Safety endpoints included adverse events (AEs), suicidality, extrapyramidal symptoms, injection-site pain, and clinically relevant changes in clinical and laboratory values. The primary efficacy endpoint was the percentage of stable patients at baseline who remained stable at the last visit of the AOM 400 maintenance phase. All endpoints were assessed with descriptive statistics; there were no formal planned statistical analyses. Of 1,247 patients screened, 1,178 enrolled in the study (194 de novo and 984 patients from the RCTs) and 1,081 received maintenance treatment with AOM 400. The maintenance phase completion rate was 79.4% at 52 weeks. Treatment-emergent AEs in ⩾5% of patients during open-label AOM 400 treatment were headache (7.6%), nasopharyngitis (7.0%), anxiety (6.8%), and insomnia (6.6%). There were no clinically relevant changes in safety parameters of interest. Ninety-five percent of stable patients at baseline remained stable at their last visit during the AOM 400 maintenance phase. The long-term safety and tolerability profile of AOM 400 was comparable to the RCTs, and the long-term therapeutic effect was maintained. A once-monthly injection to treat schizophrenia proves well-tolerated and clinically effective in a long-term trial, scientists in the USA report. Safe, long-term treatments are critical for patients with schizophrenia to help prevent relapse and maintain functioning. Long-acting, injectable forms of antipsychotic drugs, including Aripiprazole once-monthly 400mg (AOM 400), only need to be taken once a month. Timothy Peters-Strickland at Otsuka Pharmaceutical Development & Commercialization Inc. and co-workers conducted a year-long extension study to verify the safety and effectiveness of AOM 400. 1081 patients received AOM 400 as a once-a-month dose; 6.3% of patients experienced side-effects that led to study discontinuation, and 95% of patients who were stable at baseline remained stable at their last visit. The researchers show that AOM 400 is a reliable, effective and long-term alternative to daily treatment for patients with schizophrenia.