Positive Results of Analysis of Esketamine Nasal Spray on Emotional Blunting in Patients With Treatment Resistant Depression

Andrii Lysenko/Adobe Stock

Johnson & Johnson reported post hoc analysis focused on the effect of esketamine (Spravato) monotherapy on emotional blunting in patients with treatment resistant depression. The analysis measured an emotional blunting composite score, ultimately finding these scores to significantly improve from baseline in patients receiving esketamine.¹

This analysis used data from a phase 4 multicenter, double-blind, randomized, placebo-controlled study (NCT0455855) and used Montgomery-Asberg Depression Rating Scale (MADRS) items 7 and 8 along with Patient Health Questionnaire (PHQ) item 1 to evaluate a composite emotional blunting score. Analysis included 378 patients, with 86 receiving esketamine 56 mg, 95 receiving esketamine 84 mg, and 197 receiving placebo. MADRS scores were evaluated on days 2, 8, 15, 22, and 28. PHQ was evaluated on days 15 and 28. On day 28, least squares mean change in emotional blunting score was -2.7 for patients receiving esketamine 56 mg, -3.3 for patients receiving esketamine 84 mg, and -1.5 for placebo (P<0.01). Least squares mean change in MADRS items 7 and 8 were both −1.4 for esketamine 56 mg, −1.5 and -1.8 for esketamine 84 mg, and −0.8 and -0.7 for placebo (P < 0.01). PHQ scores in patients receiving esketamine also improved at day 28, with least squares mean change of -0.7,-1.0, and -0.3 for esketamine 56 mg, 84 mg, and placebo, respectively.

Most common treatment-emergent adverse effects were nausea (24.8%), dissociation (24.3%), dizziness (21.7%), and headache (19%). Serious adverse events occurred in 6 patients: 1 ankle fracture, 1 ophthalmic migraine, 1 suicide attempt, 1 self-injurious ideation, 1 suicidal ideation, and 1 acute myocardial infarction; none of these events were considered to be related to the study medication.

Esketamine nasal spray is an S-enantiomer of racemic ketamine and is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. The drug is currently approved by the US Food and Drug Administration for treatment resistant depression as monotherapy or adjunctive with oral antidepressant, and in conjunction with oral antidepressant for depressive symptoms in major depressive disorder with acute suicidal ideation or behavior.²

Limitations of this post hoc analysis were noted surrounding emotional blunting measurements. MADRS was not developed with the intention of measuring emotional blunting, and MADRS items 7 and 8 and PHQ item 1 have not been validated as assessments of emotional blunting. The larger study that this data was taken from for post hoc analysis found that esketamine monotherapy resulted in improvement in MADRS total score and improvement in all MADRS item scores at day 28.³

Authors concluded that “esketamine nasal spray monotherapy significantly reduced emotional blunting vs placebo through day 28 and as early as day 2 as measured by MADRS items 7 and 8 and PHQ-9 item 1. No new safety signals were identified.”

References

1. Fu DJ, Turkoz I, Cabrera P, et al. Effect of esketamine nasal spray monotherapy on emotional blunting in adult patients with treatment-resistant depression: a post hoc analysis. Poster presented at: Psych Congress; September 17-21, 2025; San Diego, CA. Accessed September 18, 2025.

2. SPRAVATO® (esketamine) nasal spray, CIII. Prescribing information. Janssen Pharmaceuticals, Inc.; 2025. Accessed September 19, 2025. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf

3. Janik A, Qiu X, Lane R, et al. Esketamine monotherapy in adults with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2025;82(9):877-887.