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

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}*. Blinding Blinded (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 obsessivecompulsive 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 MontgomeryAsberg 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. Esketamine vs placebo nasal spray added to a new oral antidepressant in adults with treatment-resistant depression Outcomes Mean change from baseline At 28 d Esketamine Placebo Mean difference (95% CI) MontgomeryAsberg Depression Rating Scale score 21 17 4.0 (7.3 to 0.64) Event rates RBI (CI) Onset of clinical response by day 2 with maintenance of response to day 28 7.9% 4.6% 73% (42 to 367) Abbreviations defined in Glossary. RBI and CI calculated from placebo event rate and odds ratio in article. Score range 0 to 60; higher scores = greater depression severity. Adjusted for country and antidepressant class. MontgomeryAsberg Depression Rating Scale score reduction 50% at 2 d and maintained to 28 d with 1 excursion allowed. Commentary The phase 3, multicenter RCT by Popova and colleagues used esketamine to address treatment resistance in patients with depression and substantial nonresponse to traditional oral anti-depressant medications. It found that adding esketamine nasal spray, 56 or 84 mg twice weekly, to a new antidepressant improved depression scores assessed by blinded raters over the 4-week treatment period. In a post hoc analysis, the proportion of responders at day 28 was 69% vs 52%, with a number needed to treat of 6. During the treatment period, adverse effects were more frequent in the esketamine vs placebo groups; most notable were dizziness (21% vs 4.6%), dissociation (26% vs 3.7%), dysgeusia (24% vs 12%), vertigo (26% vs 2.8%), and nausea (26% vs 6.4%). Blood pressure increased after each administration of esketamine and mostly returned to near predose levels within 2 hours. No esketamine abuse was recorded during the 24-week posttreatment follow-up. The trial did not address the longer-term efficacy of esketamine or maintenance of beneficial effects beyond the 28-day treatment period (1). It found a high response rate with the placebo and antidepressant combination. The strict exclusion criteria will affect the generalizability of the results, and the need for clinic-based administration of esketamine may affect the potential for widespread uptake due to costs and monitoring needs (2). Given these constraints, add-on esketamine should only be prescribed in secondary care and specialist services.