In treatment-resistant depression, adding esketamine nasal spray to an oral antidepressant improved symptoms at 28

Question In adults with treatment-resistant depression, does adding flexibly dosed esketamine nasal spray to a newly started oral antidepressant reduce symptoms at 28 days? Methods Design: Randomized controlled trial (RCT). ClinicalTrials. gov NCT02418585. Allocation: {Concealed}*.dagger Blinding: Blinded dagger (patients, investigators, center staff, outcome assessors, and data analysts). Follow-up period: 28 days (treatment period). Setting: 39 outpatient referral centers in the Czech Republic, Germany, Poland, Spain, and the USA. Patients: 227 patients 18 to 64 years of age (mean age 46 y, 62% women) who had moderate-to-severe nonpsychotic major depressive disorder and were nonresponsive to an adequate trial (dose, duration, and adherence) of >= 2 oral antidepressants during the current depression episode. Nonresponse was defined as <= 25% improvement to >= 1 oral antidepressant documented retrospectively at the start of the 4-week prerandomization screening period and <= 25% improvement to 1 oral antidepressant used for >= 2 prescreening weeks and assessed prospectively during the 4-week screening period, with a minimum score at weeks 2 and 4. Exclusion criteria included suicidal behavior in the past year; homicidal or active suicidal ideation or intent in the past 6 months; borderline, antisocial, histrionic, or narcissistic personality disorder; current obsessive-compulsive disorder; autism spectrum disorder; intellectual disability; seizures; uncontrolled hypertension; or moderate or severe substance use disorder in the past 6 months. Intervention: Esketamine nasal spray, 56 or 84 mg twice/wk, plus a daily, investigator-selected, oral antidepressant (escitalopram, sertraline, duloxetine, or venlafaxine extended-release) not previously associated with nonresponse in the current depression episode (n = 116) or placebo nasal spray plus an oral antidepressant (n = 111). Outcomes: Primary outcome was the Montgomery-Asberg Depression Rating Scale score. Secondary outcomes included onset of clinical response by day 2 with maintenance of response to day 28 Patient follow-up: 87% completed the 28-day treatment period; 98% received >= 1 study drug dose and were included in the analyses. Main results 54% of patients received duloxetine as the oral antidepressant, 17% escitalopram, 14% sertraline, and 14% venlafaxine extended-release. The main results are in the Table. Conclusion In treatment-resistant depression, adding esketamine nasal spray to a new oral antidepressant improved symptoms at 28 days.