Baseline Response Criterion and Changes in Emotional Bias as Markers of Esketamine Response in Treatment-Resistant Depression
Chlöé Müh, Pauline Favre, Isabel Karen Lütkenherm, Juan Zambrano, Chantal Henry, Lucie Berkovitch
medRxiv October 15, 2026 preprint DOI: 10.64898/2026.10.14.26365535 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort |
|---|---|
| Sample size | 106 |
| Population | 53 patients with treatment-resistant depression and 53 healthy controls |
| Intervention | Esketamine |
| Duration | 4 weeks of treatment, with assessments at baseline, 24 hours after the first esketamine administration, and after 4 weeks |
| Measures | Emotional Facial Expression Morphing task, MADRS |
| Topics | Depression Esketamine |
| Key findings | Patients with treatment-resistant depression showed altered facial-emotion processing at baseline: they required greater happy-face intensity for detection, more often categorized neutral faces as negative, and had a more conservative response criterion without impaired discrimination sensitivity. Esketamine responders showed an early increase in discrimination sensitivity and, by week 4, less negative categorization of neutral faces than non-responders. A lower baseline response criterion was associated with responder status and, in secondary analyses, with greater subsequent MADRS improvement. |
Abstract
Abstract Negative emotional bias, including reduced processing of positive information and negative interpretation of ambiguous stimuli, is a core feature of depression. Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist with rapid antidepressant effects in treatment-resistant depression (TRD), reduces depressive symptoms, but its effects on distinct components of emotional processing remain unclear. Fifty-three patients with TRD and 53 healthy controls performed an Emotional Facial Expression Morphing task. Patients were assessed at baseline, 24 hours after the first esketamine administration, and after 4 weeks of treatment. Statistical models examined detection thresholds for happy and sad faces, negative categorisation of neutral faces, and signal detection indices separating emotion–neutral discrimination sensitivity ( d′ ) from response criterion ( c ), indexing the evidence required to report the presence of an emotion. At baseline, patients required greater happy-face intensity for emotion detection and were more likely to categorise detected neutral faces as negative. They also showed a more conservative response criterion without group difference in discrimination sensitivity. Responders showed an early increase in d′ and, by week 4, less negative categorisation of neutral faces than non-responders. A lower baseline response criterion was associated with responder status and, in secondary continuous analyses, with greater subsequent MADRS improvement. These findings indicate that TRD involves abnormalities across detection-related, valence-related, and decisional aspects of facial-emotion processing that are differently associated with esketamine response: baseline response criterion emerged as a candidate prognostic marker, whereas negative categorisation of neutral faces tracked clinical response. Assessing these domains may inform clinical evaluation, pending independent replication.
In the evidence
This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.
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Esketamine responders showed early increases in emotion discrimination sensitivity and less negative categorization of neutral faces by week 4 than non-responders, and a lower baseline response criterion was associated with responder status.
Synthesized
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Esketamine responders showed early increases in emotion discrimination sensitivity and, by week 4, less negative categorization of neutral faces than non-responders; lower baseline response criterion was associated with responder status.
Synthesized
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.