Esketamine-induced dentate gyrus plasticity in treatment resistant depression: First-in-human evidence
Alice Le Berre
Research Square preprint DOI: 10.21203/rs.3.rs-8196324/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort |
|---|---|
| Sample size | 12 |
| Population | Adults with treatment-resistant depression |
| Intervention | Esketamine |
| Duration | Two weeks between baseline and first follow-up MRI, with treatment completion at an unspecified later time point |
| Topics | Depression Esketamine |
| Key findings | Esketamine was associated with early dentate gyrus microstructural changes (reduced fractional anisotropy and increased orientation dispersion index), and baseline dentate gyrus diffusion metrics predicted early clinical improvement. |
Abstract
Abstract
Background: Treatment-resistant depression (TRD) involves impaired hippocampal plasticity. Preclinical work showed synaptic potentiation and dendritic spine growth in the dentate gyrus (DG) after esketamine (ESK), but human evidence is lacking. We aimed to detect early DG changes after ESK using advanced diffusion MRI, and to test whether baseline MRI metrics predict clinical response.
Methods: Twelve adults with TRD and 24 matched controls were enrolled. TRD patients were assessed at baseline (V1), two weeks after ESK initiation (V2), and at treatment completion (V3). Depression severity was rated with the Montgomery-Åsberg Depression Rating Scale. MRI (3D-T1, multi-shell diffusion) was acquired at V1 and V2 in TRD and at V1 in controls. DG volumes were computed with FreeSurfer; diffusion tensor, Q-ball and Neurite Orientation Dispersion and Density Imaging metrics were extracted with the Ginkgo-Toolbox. Linear mixed-effects models tested time, age, and sex effects (FDR-corrected). Pearson correlations assessed MRI-symptom change associations.
Results: DG volumes were stable from V1 to V2. Right-DG fractional anisotropy (FA) decreased (χ²=9.38, P FDR =0.01) and left-DG orientation dispersion index (ODI) increased (χ²=10.65, P FDR =0.003). Lower baseline left-DG FA correlated with greater improvement at V2 (r=–0.57, p=0.05), and FA reduction from V1 to V2 correlated with improvement (r=0.74, p=0.01). No significant correlations were observed at V3.
Conclusion: ESK was associated with early DG microstructural changes - reduced FA and increased ODI - consistent with greater dendritic complexity. Baseline DG diffusion metrics predicted early improvement, supporting their potential as in-vivo markers of plasticity and candidate biomarkers for TRD treatment. Larger studies are needed.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.