This post hoc analysis of two Phase III double-blind studies assessed the effects of baseline irritability on clinical outcomes in participants with treatment-resistant depression (TRD) (n=560) treated with intranasal ketamine (esketamine) plus an oral antidepressant (ESK + AD). ESK + AD improved symptoms of depression regardless of baseline irritability level and increased odds of achieving a response in all participants.
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 (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
Authors: Manish K. Jha, David J. Williamson, Ghazal Magharehabed, Ibrahim Turkoz, Ella J. Daly & Madhukar H. Trivedi
Summary of Intranasal esketamine effectively treats TRD in adults with irritability
In a post hoc analysis of two 4-week, double-blind, phase 3 studies, adults with treatment-resistant depression (TRD) treated with fixed or flexible doses of esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD) had similar rates of irritability at screening and baseline, but more significant improvement with ESK+AD versus AD+placebo at day 28.
The TRANSFORM-1 and TRANSFORM-2 trials showed that intranasal esketamine effectively treated treatment-resistant depression in adults regardless of baseline irritability.
Study details
Topics studied
Depression
Treatment-Resistant Depression
Study characteristics
Placebo-Controlled
Double-Blind
Randomized
Re-analysis
Participants
560
Humans
Institutes
Institutes associated with this publication
Johnson & JohnsonOne of the largest pharmaceutical companies in the world, Johnson & Johnson are responsible for bringing esketamine to market in the form of Spravato.
Linked Research Papers
Notable research papers that build on or are influenced by this paper
Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM StudiesThis pooled analysis of two phase III studies (n=518, TRANSFORM) finds that for those who didn’t respond, continued treatment may still be beneficial. This was both true for the esketamine group and the group that received a placebo.
Linked Clinical Trial
A Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression (TRANSFORM-1)The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) participants from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.
A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression (TRANSFORM-2)
The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) subjects from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.