2026 ECNP Congress

PS02-2102

Emotional processing and neural correlates of esketamine response in depressive disorders: a longitudinal fMRI study

Chloe Muh — S. Charron, C. Henry, P. Favre · INSERM, u1266- IPNP- IMA-Brain, Paris, France

2026 ECNP Congress

Introduction: Depressive disorders — including major depressive disorder (MDD) and bipolar disorder (BD) presenting with a major depressive episode (MDE) — are characterised by a negative emotional bias: heightened sensitivity to negative stimuli and blunted reactivity to positive ones [1]. Amygdala hyperreactivity to negative content persists beyond remission as a trait marker [2]. Reduced engagement of the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) constitutes a neural correlate of anhedonia [3], and blunted positive affect predicts poor antidepressant response [4]. Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, demonstrates rapid antidepressant effects; yet neuroimaging biomarkers of differential response remain lacking [5]. This study aimed to (i) characterise baseline differences in behavioural and neural emotional processing between patients with an acute MDE and healthy controls (HC), and (ii) examine longitudinal modulation following repeated esketamine administration stratified by clinical response.

Methods: Hospitalised adults with an acute MDE (MDD or BD, DSM-5) underwent eight intranasal esketamine sessions over four weeks (Sainte-Anne Hospital, Paris). fMRI was acquired at baseline (S0) and post-treatment (S10) during an emotional valence task comprising 180 images across 18 blocks of 10 stimuli each, drawn from standardised affective databases and spanning positive, negative, and neutral valence categories. HC (n=35) completed one session; patient samples comprised n=35/33 (S0/S10) for behaviour and n=33/32 for fMRI. Response was defined as ≥50% MADRS reduction; groups had comparable baseline scores (27.6 vs 29.2; 15 responders, 20 non-responders at S0; 15 and 18 at S10). Percent signal change (PSC) in three a priori ROIs — amygdala, NAcc, mPFC — was analysed using linear mixed models controlling for age, sex, and depression subtype.

Results: At baseline, patients rated positive stimuli lower in valence (t(72.3)=2.21, p=.030) and arousal (t(72.8)=2.41, p=.019) than HC; no differences emerged for negative or neutral stimuli (all p>.09). No group differences in ROI PSC were found; however, amygdala reactivity was greater for negative than neutral stimuli (t(140)=−3.22, p=.005) and mPFC activation greater for positive than neutral (t(140)=−4.14, p<.001), regardless of group. Longitudinally, a response×valence interaction (F(2,1173)=7.14, p<.001) showed responders rating positive stimuli higher than non-responders at S0 (t(208)=−2.72, p=.007) and S10 (t(219)=−2.50, p=.013). A response×session×valence interaction for arousal (F(2,1165)=3.19, p=.042) showed higher arousal in responders for positive stimuli at S10 (t(102)=−2.61, p=.011) only. Non-responders exhibited NAcc PSC decrease from S0 to S10 (t(176)=3.36, p<.001), most pronounced for negative stimuli (t(173)=2.44, p=.016); responders showed no change (p=.418). Non-responders also showed mPFC PSC decrease across all valence conditions (t(174)=3.79, p<.001); responders did not (p=.601).

Conclusion: Blunted positive emotional processing characterises depressive disorders behaviourally, yet ROI activation patterns remain comparable to healthy controls. Strikingly, responders demonstrated heightened sensitivity to positive stimuli prior to treatment — despite equivalent depression severity — pointing to a stable trait marker rather than a treatment effect. Following esketamine, responders maintained NAcc and mPFC engagement while non-responders showed progressive neural disengagement. These findings suggest that baseline positive affect sensitivity may constitute a biomarker to stratify patients prior to esketamine initiation. Future work should examine task-based functional connectivity to delineate network-level mechanisms underlying these differential trajectories.

References

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