Intranasal esketamine effectively treats treatment-resistant depression in adults regardless of baseline irritability

Abstract

Objective: To evaluate the impact of baseline irritability on clinical outcomes in adults with treatment-resistant depression (TRD) treated with fixed or flexible doses of esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD) and to explore whether treatment with ESK affects irritability symptoms over time.

Methods: This was a post hoc analysis of pooled data from two 4-week, double-blind, phase 3 studies: TRANSFORM-1 (NCT02417064) and TRANSFORM-2 (NCT02418585). Adults with TRD (n = 560) were randomly assigned to ESK+AD or placebo nasal spray plus oral antidepressant (AD+PBO). Irritability was assessed with Item 6 of the 7-item Generalized Anxiety Disorder scale at screening and baseline. Changes in depression severity (Montgomery-Åsberg Depression Rating Scale [MADRS] total score) were evaluated by analysis of covariance (ANCOVA) models. Rates of MADRS response (≥50 % decrease from baseline total score) and remission (total score ≤ 12) were examined using multiple logistic regression models.

Results: Of 560 participants with TRD, 52.9 %, 23.2 %, and 23.9 % had high, low, and varying levels of irritability, respectively. No significant interaction between baseline irritability and treatment group was observed for change in MADRS total score, treatment response, or remission at day 28; numerically greater improvement was observed on all outcomes with ESK+AD versus AD+PBO at day 28 regardless of baseline irritability level. Percentages of patients reporting adverse events were similar across the three baseline irritability groups.

Limitations: TRANSFORM-1 and TRANSFORM-2 were not designed to prospectively evaluate predetermined irritability outcomes.

Conclusions: These post hoc results support efficacy of ESK+AD in patients with TRD, regardless of baseline irritability.

Trial registration: ClinicalTrials.gov identifiers: NCT02417064 (TRANSFORM-1), NCT02418585 (TRANSFORM-2).

Keywords: Antidepressant; Depression; Esketamine; Irritability; Major depressive disorder; Treatment-resistant depression.

Conflict of interest statement

Conflict of Interest Drs. Magharehabed and Turkoz are employees of Janssen Scientific Affairs, LLC (Dr. Magharehabed), and Janssen Research & Development, LLC (Dr. Turkoz), and hold stock in Johnson & Johnson, Inc. Drs. Williamson and Daly were employees of Janssen Scientific Affairs, LLC, when the study was conducted and hold stock in Johnson & Johnson, Inc. Dr. Jha has received contract research grants from Acadia Pharmaceuticals and Janssen Research & Development; an educational grant to serve as Section Editor of the Psychiatry & Behavioral Health Learning Network; consultant fees from Eleusis Therapeutics US, Inc., Janssen Global Services, and Guidepoint Global; and honoraria from the North American Center for Continuing Medical Education and Global Medical Education. Dr. Trivedi has served as a consultant or advisor for Acadia Pharmaceuticals, Inc., Alkermes Inc., Alto Neuroscience Inc., Axsome Therapeutics, GH Research Limited, GreenLight VitalSign6 Inc.; Janssen, Merck Sharp & Dohme Corp., Mind Medicine (MindMed) Inc., Neurocrine Biosciences Inc., Orexo US Inc., Otsuka, SAGE Therapeutics, Signant Health, and Titan Pharmaceuticals, Inc., has conducted research for NIMH, NIDA, Patient-Centered Outcomes Research Institute (PCORI), and Cancer Prevention Research Institute of Texas (CPRIT); and receives editorial compensation from Oxford University Press.

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