The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder

This post-approval, double-blind, placebo-controlled study (n=223, TRANSFORM-2) finds that those with comorbid anxiety (72%) responded just as well as those without anxiety to esketamine (56-84mg, 4 weeks, combined with SSRI) treatment.


Background: Comorbid anxiety is generally associated with poorer response to antidepressant treatment. This post hoc analysis explored the efficacy of esketamine plus an antidepressant in patients with treatment-resistant depression (TRD) with or without comorbid anxiety.

Methods: TRANSFORM-2, a double-blind, flexible-dose, 4-week study (NCT02418585), randomized adults with TRD to placebo or esketamine nasal spray, each with a newly-initiated oral antidepressant. Comorbid anxiety was defined as clinically noteworthy anxiety symptoms (7-item Generalized Anxiety Disorder scale [GAD-7] score ≥10) at screening and baseline or comorbid anxiety disorder diagnosis at screening. Treatment effect based on change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and response and remission were examined by presence/absence of comorbid anxiety using analysis of covariance and logistic regression models.

Results: Approximately 72% (162/223) of patients had baseline comorbid anxiety. Esketamine-treated patients with and without anxiety demonstrated significant reductions in MADRS (mean [SD] change from baseline at day 28: -21.0 [12.51] and -22.7 [11.98], respectively). Higher rates of response and remission, and a significantly greater decrease in MADRS score at day 28 were observed compared to antidepressant/placebo, regardless of comorbid anxiety (with anxiety: difference in LS means [95% CI] -4.2 [-8.1, -0.3]; without anxiety: -7.5 [-13.7, -1.3]). There was no significant interaction of treatment and comorbid anxiety (p = .371). Notably, in the antidepressant/placebo group improvement was similar in those with and without comorbid anxiety.

Conclusion: Post hoc data support efficacy of esketamine plus an oral antidepressant in patients with TRD, regardless of comorbid anxiety.”

Authors: Ella J. Daly, Ibrahim Turkoz, Giacomo Salvadore, Maggie Fedgchin, Dawn F. Ionescu, H. Lynn Starr, Stephane Borentain, Madhukar H. Trivedi, Michael E. Thase & Jaskaran B. Singh

Study details

Compounds studied

Topics studied
Anxiety Depression

Study characteristics
Placebo-Controlled Double-Blind Randomized



Institutes associated with this publication

Johnson & Johnson
One of the largest pharmaceutical companies in the world, Johnson & Johnson are responsible for bringing esketamine to market in the form of Spravato.

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Evaluation of Individual Items of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) in Adults with Treatment-Resistant Depression Treated with Esketamine Nasal Spray Combined with a New Oral Antidepressant
This posthoc analysis of the TRANSFORM-2 trial assessed the effects of esketamine plus an oral antidepressant (AD) using the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS). The odds of improving in those treated with esketamine plus AD were at least two times greater than with placebo plus AD.