San Diego, CA – September 18, 2025 – A post hoc analysis presented at Psych Congress indicates esketamine nasal spray monotherapy significantly reduced emotional blunting in adults with treatment-resistant depression compared too placebo, as early as day 2 and through day 28 of treatment. The findings offer further support for the use of esketamine, currently approved by the US Food and Drug Administration for treatment-resistant depression both as monotherapy and adjunctive treatment, and for depressive symptoms with acute suicidal ideation or behavior.
Researchers evaluated changes in emotional blunting using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Patient Health Questionnaire-9 (PHQ-9). On day 28, least squares mean change in emotional blunting score was -2.7 for patients receiving esketamine 56 mg,-3.3 for those receiving 84 mg, and -1.5 for placebo (P<0.01). Improvements were also observed in MADRS items 7 and 8, with changes of −1.4 and −1.5 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 also improved with esketamine treatment, showing least squares mean changes of -0.7, -1.0, and -0.3 for the 56 mg, 84 mg, and placebo groups, respectively.
The most common treatment-emergent adverse effects were nausea (24.8%), dissociation (24.3%), dizziness (21.7%), and headache (19%).Six patients experienced serious adverse events – one ankle fracture, one ophthalmic migraine, one suicide attempt, one instance of self-injurious ideation, one case of suicidal ideation, and one acute myocardial infarction – but none were considered related to the study medication.
Esketamine is an S-enantiomer of ketamine and functions as a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist.
Researchers acknowledged limitations related to the measurement of emotional blunting, noting that the MADRS was not specifically designed for this purpose and that the utilized items (MADRS 7 & 8, PHQ-1) lack validation as assessments of emotional blunting. The larger study from which this data was derived previously demonstrated improvements in overall MADRS scores and all MADRS item scores at day 28 with esketamine monotherapy.
The study 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.”
