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

Abstract

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.

Keywords: anxiety; anxious depression; comorbid anxiety; esketamine; treatment-resistant depression.

Conflict of interest statement

Ella J. Daly, Ibrahim Turkoz, Giacomo Salvadore, Maggie Fedgchin, Dawn F. Ionescu, H. Lynn Starr, and Stephane Borentain are employees of Janssen Scientific Affairs, LLC or Janssen Research & Development, LLC and are stockholders of Johnson & Johnson, Inc. While employed by Janssen Research & Development, LLC, Jaskaran B. Singh worked on the clinical development program of esketamine for TRD; he is currently employed by Neurocrine Biosciences. Madhukar H. Trivedi has consulted for or served on the advisory board of Acadia Pharmaceuticals, Alto Neuroscience, Axsome Therapeutics, Boegringer Ingelheim, Engage Health Media, GreenLight VitalSign6 Inc., Janssen Research & Development, Lundbeck Research USA, Medscape, Merck & Co. Inc., Myriad Neuroscience, Navitor Pharmaceutical Inc, Neurocrine, Otsuka America Pharmaceutical Inc., Perception, Pharmerit International, Sage Therapeutics, Signant Health, and Takeda Global Research. Dr. Trivedi has received research support from the Agency for Healthcare Research and Quality, the Cancer Prevention and Research Institute of Texas, Janssen Research & Development, LLC, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Drug Abuse, National Institute of Mental Health, and the Patient‐Centered Outcomes Research Institute; and he has received editorial compensation from Engage Health Media, Healthcare Global Village, and Oxford University Press. Michael E. Thase reports that The Perelman School of Medicine of the University of Pennsylvania received grants from Johnson & Johnson to conduct the research protocol described in this report at his site. Dr. Thase also is a consultant to Johnson and Johnson and Janssen and is a member of several advisory boards sponsored by these companies. In addition, over the past three years Dr. Thase reports the following additional relationships:

1. Advisory/Consultant—Acadia, Akilii, Alkermes, Allergan (Forest, Naurex), AstraZeneca, Axsome, Cerecor, Clexio, Eli Lilly, Fabre‐Kramer, Gerson Lehrman Group, Guidepoint Global, Jazz Pharmaceuticals, Lundbeck, MedAvante, Merck, Moksha8, Nestlé (PamLab), Novartis, Otsuka, Pfizer, Sage, Seelos, Shire, Sunovion, and Takeda.

2. Grant Support—Acadia, Agency for Healthcare Research and Quality, Alkermes, Allergan (Forest), Avanir, Axsome, Intracellular, National Institute of Mental Health, Otsuka, PCORI, and Takeda.

3. Royalties—American Psychiatric Press, Guilford Publications, Herald House, and W.W. Norton & Company, Inc.

Dr. Thase's spouse, Diane M. Sloan, PharmD, is a senior medical director for Peloton Advantage, which does business with a number of pharmaceutical companies.

© 2021 The Authors. Depression and Anxiety Published by Wiley Periodicals LLC.

Figures

Figure 1

Least square mean change (SE) in Montgomery–Åsberg depression rating scale total score over time in the double‐blind treatment phase. Note: Treatment effect based on change in Montgomery–Åsberg depression rating scale (MADRS) total score from baseline to day 28 was not statistically significantly different (interaction term p = .371) between the without/with anxiety groups (difference in LS means 3.3, 95% CI −4.0 to 10.6), with a greater improvement in MADRS scores among those treated with esketamine/antidepressant as compared to antidepressant/placebo (patients without comorbid anxiety: −7.5, −13.7 to −1.3; p = .017; patients with comorbid anxiety: −4.2, −8.1 to −0.3; p = .036). Abbreviations: AD, antidepressant; ESK, esketamine; LS, least squares; PBO, placebo; SE, standard error

Figure 2

Response and remission rates at day 28 based on Montgomery–Åsberg depression rating scale total score.  *p < .05 from CMH test. Note: Response was defined as a ≥50% improvement in MADRS total score from baseline. Remission was defined as MADRS total score ≤12. For both response and remission rates at day 28, treatment‐by‐subgroup interactions were formally tested using logistic regression models. p values for testing the interactions were .136 and .088 for response and remission rate differences, respectively. CI, confidence interval; CMH, Cochran–Mantel–Haenzsel; MADRS, Montgomery–Åsberg depression rating scale