DOI: 10.1192/j.eurpsy.2026.11630 ISSN: 0924-9338

Esketamine-induced dentate gyrus plasticity in treatment resistant depression: first-in-human evidence

A. Le, Berre, D. Attali, I. Uszynski, P. Piche, C. Debacker, M. Lui, S. Charron, C. Paolillo, M. Moyal, F. Ramon, A. Henensal, J. Benzakoun, M. Danon, L. Mekaoui, P. Gorwood, C. Poupon, A. Cachia, C. Oppenheim, M. Plaze
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Introduction

Treatment-resistant depression (TRD) is marked by impaired hippocampal synaptic plasticity, potentially reversible with intranasal esketamine (ESK). Preclinical studies have demonstrated robust synaptic potentiation and dendritic spine growth in rodent hippocampus after ESK, but in-human evidence is lacking.

Objectives

To detect early post-ESK microstructural changes in the dentate gyrus (DG) using advanced diffusion MRI in TRD patients, and to assess whether baseline MRI metrics predict clinical response.

Methods

Twelve adults with TRD and 24 matched healthy controls were enrolled (ethics-approved; ClinicalTrials.gov NCT06661616). TRD patients were assessed at baseline (V1), 2 weeks after ESK initiation (V2), and and at treatment completion (V3). Depression severity was rated with MADRS. MRI (3DT1, multi-shell diffusion) was acquired at V1 and V2 in TRD, and at V1 in controls. DG volumes were computed with FreeSurfer; conventional diffusion metrics and Neurite Orientation Dispersion and Density Imaging (NODDI) metrics were extracted with Ginkgo. Linear mixed-effects models tested effects of group, time, age, and sex; Pearson correlations examined associations between MRI metrics and MADRS improvement. P-values were FDR-corrected.

Results

Between V1 and V2, DG volumes remained stable while right DG fractional anisotropy (FA) decreased (χ² = 9.38, PFDR = 0.01) and left-DG orientation dispersion index (ODI) increased (χ² = 10.65, PFDR = 0.003) (Figure 1). No other hippocampal measures showed changes with time. Lower baseline FA in left DG correlated with greater symptom improvement at V2 (r=–0.57, p=0.05) (Figure 2), and FA decrease from V1 to V2 correlated with symptom improvement at V2 (r=0.74, p=0.01). No significant correlations were observed at V3.

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Image 1: Long description.

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Image 2: Long description.

Conclusions

ESK was associated with early microstructural remodeling in the human DG, reflected by decreased FA and increased ODI after two weeks of treatment, without detectable volumetric changes. This pattern - reduced FA and increased ODI - is consistent with increased dendritic complexity. Baseline DG diffusion metrics correlated with clinical improvement, suggesting their potential as in vivo proxies of synaptogenesis and ultimately as candidate biomarkers to guide TRD treatment. These first-in-human data support further validation in larger, longer-term cohorts.

Disclosure of Interest

A. Le Berre Grant/Research from: received a research fellowship grant from the Servier Institute., D. Attali Consultant/speaker’s bureau/advisory activities: has been invited to scientific meetings, served as a speaker, and received compensation from Janssen. DA has been invited to scientific meetings by Neuraxpharm., I. Uszynski: None Declared, P. Piche: None Declared, C. Debacker: None Declared, M. Lui: None Declared, S. Charron: None Declared, C. Paolillo: None Declared, M. Moyal: None Declared, F. Ramon: None Declared, A. Henensal: None Declared, J. Benzakoun: None Declared, M. Danon Financial support from: received meals from Janssen-Cilag and Eisai SAS., L. Mekaoui Speakers Bureau of: served as a speaker and received compensation from Johnson & Johnson., P. Gorwood Consultant/speaker’s bureau/advisory activities: received during the last 5 years fees for presentations at congresses or participation in scientific boards from Biogen, Johnson & Johnson, Lundbeck, MindMed, MS Pharma, Newron, Otsuka, Richter and Viatris., C. Poupon: None Declared, A. Cachia: None Declared, C. Oppenheim Consultant/speaker’s bureau/advisory activities: served as speaker for Canon medical and Guerbet and received compensation fees for a scientific advisor board from Olea Medical., M. Plaze Consultant/speaker’s bureau/advisory activities: has been invited to scientific meetings, served as a speaker, and received compensation from Janssen.

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