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

Esketamine-induced dentate gyrus plasticity in treatment resistant depression: First-in-human evidence | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Esketamine-induced dentate gyrus plasticity in treatment resistant depression: First-in-human evidence Alice Le Berre This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8196324/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version 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. depression imaging esketamine neuroplasticity hippocampus treatment-resistance Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Treatment-resistant depression (TRD) represents a major clinical challenge due to its multifactorial etiology, heterogeneous treatment approaches, and public-health impact ( 1 ). The high prevalence of TRD - affecting 30–55% of individuals with major depressive disorder ( 2 ) - underscores both the limitations of conventional antidepressant treatments and the complexity of its underlying pathophysiology. TRD reflects intricate interactions among multiple neurotransmitter systems, genetic vulnerabilities, environmental factors and impaired neuroplasticity ( 3 , 4 ). Specifically, TRD is increasingly viewed as a disorder of synaptic plasticity - the brain’s ability to form, strengthen, and prune connections. Consistent with this view, chronic stress-induced atrophy of glutamatergic synapses in hippocampal and prefrontal regions is thought to disrupt mood regulation and cognitive function ( 4 – 10 ). Traditional monoaminergic antidepressants rescue synaptic plasticity slowly - requiring weeks of treatment to increase BDNF expression, adult neurogenesis, and dendritic spine formation ( 6 ). This delay highlights the need for fast-acting interventions that directly target neuroplasticity. Intranasal esketamine (ESK) has emerged as such a therapy for TRD, producing rapid antidepressant effects, reducing suicidal ideation and relapse risk ( 11 – 14 ), with a favorable tolerability profile ( 13 ). As an NMDA-receptor antagonist, ESK disinhibits glutamatergic transmission, activates mTORC1-dependent protein synthesis, elevates BDNF levels, and induces robust synaptic potentiation and spine growth in the prefrontal cortex and hippocampus in mouse models ( 8 , 15 , 16 ). These microstructural changes - spine enlargement, new spine formation, and dendritic branching - occur preferentially within the dentate gyrus (DG) and CA1–3 subfields of the murine hippocampus ( 17 – 19 ). Validating this mechanistic model in humans requires in-vivo markers of microstructural plasticity. In heathy volunteers, an MRI performed 65 minutes after the start of an IV S-ketamine infusion detected rapid and significant increases in hippocampal subfield volumes - most notably a trend toward left CA1 enlargement ( 20 ). However, volumetric MRI cannot directly assess the underlying microstructural changes. We previously showed that neurite orientation dispersion and density imaging (NODDI) detects increases in dendritic density and complexity in the hippocampus of TRD patients after electroconvulsive therapy (ECT) ( 21 ). Because the orientation dispersion index (ODI) and the neurite density index (NDI) reflect, respectively, neurite fanning and volume fraction ( 22 ), they provide complementary indices of dendritic spine proliferation and maturation. The primary objective of this study was to assess longitudinal changes in hippocampal volume and microstructure using anatomical T1, diffusion tensor imaging (DTI) and NODDI in patients with TRD treated with ESK, with healthy controls serving as a baseline reference. We focused specifically on the DG - a region critically involved in adult neurogenesis and synaptic remodeling, and consistently reported as reduced in volume in depressed patients compared to controls ( 23 , 24 ). We hypothesized that ESK would induce rapid macro- and microstructural modifications in the human DG, reflecting spine growth and dendritic remodeling consistent with its proposed synaptogenic effects. We also examined, post hoc, whether baseline and early changes in DG MRI metrics predicted clinical improvement after ESK treatment. Methods Participant recruitment and study framework Adults (≥ 18 years) were consecutively enrolled at Sainte-Anne Hospital (GHU‑Paris Psychiatry & Neurosciences, Paris, France) between February 2022 and February 2024. The inclusion criteria were (i) a DSM-5 diagnosis of a major depressive episode (unipolar or bipolar disorder) and (ii) a clinical indication for ESK treatment, as determined by the treating psychiatric team. Exclusion criteria comprised any comorbid psychiatric condition (e.g., schizophrenia, pervasive developmental disorders), any substance‑use disorders other than nicotine, any neurological condition (e.g. Parkinson disease, dementia), ECT within the preceding six months, contraindication to brain MRI, compulsory psychiatric care, protected adults, people under legal protection, and pregnant or breastfeeding women. Clinical and MRI assessments were conducted at baseline (V1) and after two weeks of treatment (corresponding to four to five ESK administrations) (V2), with a final clinical evaluation conducted at the end of the treatment course (V3). Each patient underwent two MRI scans, at V1 and V2. An age- and sex-matched healthy control (HC) group, free of psychiatric and neurological illness, was scanned for reference in the neuroimaging analyses. Healthy control participants were part of a previously published dataset (21). The sample size was based on prior cross‑sectional and longitudinal NODDI studies that detected microstructural changes with comparable group sizes (25,26) . Ethical Approval The study protocol was approved by the Comité de Protection des Personnes Sud‑Méditerranée (ID-RCB number: 2017-A01812-51) and registered at ClinicalTrials.gov (NCT06661616). All participants provide written informed consent prior to inclusion. All procedures were conducted in accordance with the Declaration of Helsinki and relevant national regulations. Esketamine treatment Esketamine was administered intranasally twice weekly, either during daytime outpatient visits or inpatient hospitalization. Treatment was continued until sustained remission - defined as a Montgomery–Åsberg Depression Rating Scale (MADRS) (27) score ≤10 for at least two consecutive weeks - or discontinued at the treating psychiatrist’s discretion if no further benefit was observed. Concomitant medications were made by the clinical team, and detailed medication data for each visit are provided in Supplementary Table 10 . Clinical assessments Depressive symptom severity and treatment response were evaluated using the MADRS and the 21‑item Hamilton Depression Rating Scale (HDRS‑21) (28) at V1, V2, and V3. Response was defined as a ≥50 % reduction in MADRS, and remission as a MADRS ≤10. MRI data acquisition All imaging was performed on a 3-Tesla General Electric MR750 scanner fitted with a 16‑channel head coil. Each participant underwent the same protocol at V1 and V2. High‑resolution structural images were acquired using a 3D T1‑weighted spoiled gradient‑echo sequence incorporating inversion recovery (isotropic resolution = 1 mm, TE/TR/TI = 3.2/8.2/400 ms, flip angle = 11°). Diffusion-weighted images were acquired with a multi‑shell echo‑planar sequence optimized for NODDI: three b‑value shells (200, 1500, and 2500 s mm⁻²) were sampled with 30, 45, and 60 diffusion‑encoding directions, respectively along with three b = 0 s mm⁻² images for reference (isotropic resolution = 2 mm, TE/TR = 80/4400 ms). To correct for susceptibility-induced distortions, a scan with reversed phase‑encoding (b = 2500 s mm⁻², 6 directions) was also collected. Image processing Structural and diffusion datasets were processed with the Ginkgo Toolbox (CEA; https://framagit.org/cpoupon/gkg). First, susceptibility artefacts were removed by pairing the forward and reverse phase‑encoded images in FSL (29), after which all shells were concatenated. Outlier detection, eddy‑current correction, and rigid‑body motion correction were then applied in a unified Ginkgo framework. The T1‑weighted volume was skull‑stripped, rigidly aligned to the averaged b = 0 s mm⁻² image, and used to generate an accurate brain mask. NODDI parameter maps - neurite density index (NDI), isotropic volume fraction (Fiso), and orientation dispersion index (ODI) - were estimated with the intrinsic and isotropic diffusivities fixed at 1.7 × 10⁻³ mm² s⁻¹ and 3 × 10⁻³ mm² s⁻¹, respectively. Conventional diffusion‑tensor metrics (fractional anisotropy, axial, radial, and mean diffusivities) were also computed, and a Q‑ball reconstruction (spherical‑harmonics order 8, regularization λ = 0.006) yielded generalized FA maps. FreeSurfer 7.0.0 was used to segment the T1 images, delineated the hippocampi, and compute subfield parcellations. In line with earlier work (21,30), the DG was defined by aggregating its thin internal labels within the ‘CA’ segmentation, mitigating boundary inaccuracies at 2 mm resolution. All segmentations and inter‑modality registrations were visually inspected by a neuroradiologist (ALB). Bilateral DG volumes and mean diffusion metrics were extracted. Statistical analysis All statistical analyses were conducted in R 3.4. Outlier removal Diffusion metrics outliers within the DG were removed using a mean absolute deviation (MAD) approach. The median and MAD were computed for each hemisphere (left/right), diffusion metric, study group (ESK vs. HC), and - within the ESK group - visit (V1, V2). Exclusion thresholds were set at ±2.5 MAD from the median, and values exceeding these limits were replaced with 'not available’. This procedure eliminated 63 outliers from 768 total observations. Longitudinal effects and group comparisons To assess treatment-related DG changes over time, separate univariate linear mixed-effects models were fitted for DG volume and each microstructural metric (DTI and NODDI) in each hemisphere. Models included fixed effects of time (V1 vs V2), age, and sex, with participants modeled as random intercepts. Wald χ² tests were used to evaluate the significance of fixed effects in the mixed models. At each visit, ESK patients were compared to age- and sex-matched healthy controls: normally distributed metrics were tested via independent t-tests, while skewed variables (e.g. GFA, volumes) used Mann–Whitney U tests. All p-values were adjusted for multiple comparisons using the Benjamini–Hochberg false discovery rate (FDR) procedure, with FDR-corrected two-tailed p < 0.05 considered significant. Clinical correlation This post-hoc analysis focused on the DG volume and diffusion metrics that show significant time effects in the linear mixed-effects model to examine their association with clinical response. For each participant and each selected metric, we extracted the baseline value (V1) and calculated its proportional change from V1 to V2: Only subjects with both V1 and V2 data were included in this analysis. We then assessed Pearson correlations separately for (1) baseline V1 metrics versus ΔMADRS and (2) Δmetrics versus ΔMADRS, in left and right DG. For each correlation test we report the correlation coefficient ( r ), the two-tailed p -value, and the 95% confidence interval. To control for 12 total comparisons (3 metrics × 2 timepoints × 2 hemispheres), we applied Benjamini–Hochberg FDR correction; uncorrected p < 0.05 were noted as significant or trend-level, with FDR-adjusted values presented alongside. The correlation analysis was also extended to test whether early MRI changes (ΔV1 → V2) were associated with longer-term clinical improvement (ΔMADRS V1 → V3). Post‑hoc metric‑change mapping Finally, we conducted an exploratory, ROI-based mapping of microstructural change. As in the previous step, the analysis was confined to the metrics that showed significant longitudinal effects under ESK. For each of the ten bilateral hippocampal subfields provided by the ‘CA’‑version FreeSurfer segmentation (CA1, CA2/3, CA4 -including the dentate gyrus-, subiculum, presubiculum, parasubiculum, fimbria, hippocampal tail, hippocampal fissure and the hippocampal‑amygdalar transition area), we extracted the subject‑level mean metrics at baseline (V1) and week 2 (V2). Percentage change was then calculated as For each subfield, we computed the mean ± SD of %Δmetric and mapped these average changes onto the hippocampal anatomy using a color-coded scale reflecting the direction and magnitude of the mean change. No statistical tests were applied in this exploratory analysis. Results Patients Twelve patients with TRD treated with ESK were included, along with 24 age- and sex-matched HC. In the ESK group, the median interval between the baseline MRI (V1) and post-ESK MRI scan (V2) was 20.5 days (range: 11–42), and the mean ± SD number of ESK sessions was 5 ± 0.3. At V2, three patients (25%) were both responders and remitters. The median interval between V1 and the final clinical evaluation (V3) was 56 days (range: 14–82). At V3, four patients (33%) were responders and 2 (17%) were remitters. Demographic and clinical characteristics of the ESK and HC groups are summarized in Table 1 . Pharmacological regimens at V1, V2, and V3 during ESK treatment are provided in Supplementary Table 1 . Longitudinal effects and group comparisons Volume change Mean ± SD DG volumes in the ESK group were 555 ± 91 mm³ (left) and 550 ± 72 mm³ (right) at V1, and 553 ± 91 mm³ (left) and 557 ± 67 mm³ (right) at V2, and 566 ± 35 mm³ (left) and 575 ± 48 mm³ (right) in the HC group ( Figure 1 ). In the TRD group, linear mixed‐effects models revealed no main effect of time on DG volume (left: χ² = 0.07, P FDR = 0.79; right χ² = 0.83, P FDR = 0.36), while age and sex were significant predictors (left hemisphere, age: χ² = 11.26, P FDR = 0.001 and sex χ² = 32.19, P FDR < 0.001; right hemisphere, sex: χ² = 22.52, P FDR 0.5), although age and sex remained significant covariates (left hemisphere, sex χ² = 35.74, P FDR < 0.001; right hemisphere, age: χ² = 5.77, P FDR = 0.02; sex: χ² = 42.46, P FDR 0.5). Volumes at each time point and changes at V2 relative to baseline along with a detailed breakdown of the statistical analyses are provided in Supplementary Tables 2, 3 and 6 . DTI metrics FA decreased bilaterally in the dentate gyrus over two weeks of ESK, but the effect reached significance only on the right side (χ² = 9.38, P FDR = 0.01; Figure 2 ). On the left, the decrease did not reach significance (χ² = 3.25, P FDR = 0.19). Other DTI metrics showed no significant changes. At baseline, ESK patients exhibited higher FA in the DG of both hemispheres compared with HC (right: Cohen d = −1.13; left: Cohen d = −0.96; uncorrected p = 0.004 and 0.011, respectively), but these differences were no longer significant after FDR correction (P FDR = 0.10-0.11). Other DTI metrics in the DG of ESK patients did not differ significantly from those of HC. DTI values and changes at V2 relative to baseline, along with the detailed statistical analyses are provided in Supplementary Tables 4, 5 and 6 . NODDI metrics Time‐related changes of NODDI metrics (NDI, Fiso and ODI) in both DG are presented in Figure 2 . ODI increased in the DG on both sides following ESK, but the effect was significant only on the left (χ² = 10.65, P FDR = 0.003), while the right side showed no significant change (χ² = 2.03, P FDR = 0.45). NDI and Fiso remained stable over time. At baseline, the ESK group exhibited a moderately lower left-DG ODI than controls (Cohen’s d = 1.02, p = 0.007), but this difference was not significant after FDR correction (P FDR = 0.11). A lower left‑DG Fiso in the ESK group at V2 was also observed (Cohen d = 0.77, p = 0.044), which became non‑significant after adjustment (P FDR = 0.35). Average NODDI values, mean changes and standard deviations at V2 relative to baseline and a detailed breakdown of the statistical analyses, are provided in the Supplementary material ( Supplementary Tables 6, 7, and 8 ). Clinical Correlations Volume measures, at baseline or as change scores (Δ-volume), showed no significant association with clinical improvement. Correlational analyses of diffusion metrics were restricted to FA and ODI, the only metrics showing significant longitudinal changes. Lower FA at baseline in the left DG correlated with greater early improvement at V2 (r = –0.57, p = 0.05), with a similar nonsignificant trend on the right (r = –0.54, p = 0.09) ( Figure 3B ). The change in left-DG FA was positively correlated with clinical improvement (r = 0.74, p = 0.01, P FDR = 0.07), indicating that patients who exhibited greater FA increases - or smaller FA decreases - over two weeks experienced the largest reductions in MADRS scores. No similar relationship was observed on the right (r = 0.41, p = 0.23). None of these correlations remained significant after Benjamini–Hochberg correction ( Supplementary Table 9 ). Baseline ODI values did not predict clinical improvement (Left: r = 0.20, p = 0.53; Right: r = 0.27, p = 0.41) ( Figure 3A ), whereas the Δ‐ODI from V1 to V2 showed a negative trend (Left: r = –0.51, p = 0.05; Right: r = –0.46, p = 0.07), indicating that patients with smaller increases in ODI tended to experience larger reductions in MADRS scores ( Supplementary Table 9 ). Baseline imaging features and their changes did not correlate with symptom improvement at the later V3 time point (ΔMADRS V1–V3); therefore, these results are not shown. Hippocampal Subfield Microstructural Changes These post hoc exploratory analyses were restricted to FA and ODI, the only diffusion metrics showing significant longitudinal changes in the primary DG analysis. Beyond the DG, several hippocampal subfields exhibited early diffusion changes after two weeks of ESK treatment ( Supplementary Table 10 ). The right CA3 showed the largest FA decrease (−11.69 ± 16.32%), while the left CA3 exhibited the greatest ODI increase (14.53 ± 20.72%; mean ± SD of change) among hippocampal subfields. Figure 4 illustrates the ROI-based mapping of percentage change in FA (right hemisphere) and ODI (left hemisphere) across the ten bilateral hippocampal subfields,highlighting the spatial distribution and magnitude of early microstructural changes following ESK treatment. Discussion In this longitudinal study of patients with TRD, two weeks of ESK administration produced no measurable macroscopic changes in hippocampal volumes, in contrast to previous findings in healthy volunteers showing rapid volumetric increases following intravenous S-ketamine (20). However, advanced diffusion MRI revealed early bilateral microstructural modifications, characterized by decreased FA and increased ODI in both DG, although significance was reached only unilaterally. This pattern -reduced FA and increased ODI- is typically interpreted as reflecting enhanced dendritic density and complexity. NDI and Fiso showed nonsignificant tendencies toward increase and decrease, respectively, consistent with subtle effects that may not have been detectable given our sample size (n = 12). Moreover, patients showed higher baseline FA and lower baseline ODI in the DG than controls, differences that did not survive correction for multiple comparisons. These diffusion changes mirror those we previously observed in TRD patients receiving ECT (21), although baseline FA, GFA, and ODI were far more disrupted in the ECT cohort. Together, these findings suggest that ESK rapidly modulates DG microstructure - potentially reflecting dendritic arbor complexification (ODI increase) and altered fiber coherence (FA decrease) - consistent with preclinical evidence of rapid synaptogenesis following NMDA receptor blockade (31). Beyond the DG, supplementary analyses demonstrated that ESK induced similar microstructural dynamics in adjacent hippocampal subfields, suggesting a broader pattern of plastic remodeling within the hippocampal formation. Notably, FA in the right CA3 decreased whereas the ODI in the left CA3 increased over two weeks. These subfield-specific effects align with preclinical evidence identifying CA3 as a locus of stress-induced remodeling and rapid synaptogenesis after NMDA-receptor antagonism (15). Although longitudinal changes in DG microstructure did not significantly predict clinical outcome in this small sample, we observed a trend suggesting that lower baseline FA in the left DG was associated with greater clinical improvement - implying that patients with more preserved synaptic integrity at baseline may respond more favorably to ESK. The greatest clinical improvements were observed in patients who showed the smallest increases in ODI and the most stable (or even increased) FA in the left DG following ESK, suggesting that the hippocampal baseline status may be more critical in predicting treatment response than the magnitude of the longitudinal changes. Taken together, our results indicate that esketamine’s synaptogenic effects may be captured by diffusion-based MRI markers. Notably, these occurred in the absence of detectable volumetric changes. As previously observed following ECT (21), decreases in gray-matter FA may index reduced fiber coherence as new dendritic branches emerge, while ODI increases may reflect greater dendritic angular dispersion. Within corticolimbic circuits, such microstructural remodeling may support modulation of functional connectivity between the hippocampus and prefrontal regions - one of the proposed mechanisms underlying the antidepressant effects of NMDA receptor antagonists (32,33). Correlating these diffusion changes with neurobiological biomarkers may further validate their role as imaging proxies of rapid synaptic remodeling. In this study, the second MRI time point was scheduled close to two weeks after treatment initiation to capture early neuroplastic changes with potential predictive value for clinical response; however, this objective was not achieved in our sample. In practice, baseline diffusion measures (such as baseline FA) may offer a more accessible and clinically relevant biomarker for guiding treatment selection in TRD than their longitudinal evolution. This study presents several limitations. First, the sample size was relatively small, which limits statistical power and may introduce sampling bias, a limitation explained by the difficulty of assembling large cohorts in longitudinal interventional imaging studies. Second, only four of the twelve ESK-treated patients met response criteria and two achieved remission, mirroring recent real-world reports (34) and leaving the study underpowered to assess clinical–imaging relationships. Third, we did not perform long-term MRI follow-up (e.g., at 3 or 6 months) to determine whether the observed diffusion changes are sustained or transient. Finally, the diffusion imaging resolution of 2 mm remains limited for precise assessment of the hippocampus subfields. Ultra-high-resolution diffusion MRI (35), combined with advanced analytical frameworks such as hippocampal unfolding (36), holds promise for improving the characterization of hippocampal plasticity in psychiatric populations. In conclusion, this study provides the first in vivo evidence that esketamine induces rapid microstructural remodeling in the human dentate gyrus in TRD - detectable by diffusion MRI - without concomitant macroscopic volumetric changes over two weeks. Patients who benefit most from this treatment exhibited the least altered DG microstructure at baseline. Integrating neurobiological biomarker correlations may further validate the specificity and mechanistic relevance of these imaging markers. Ultimately, connecting diffusion-based signatures of microstructural plasticity to clinical outcomes and treatment mechanisms could offer new perspectives on the role of neuroimaging in treatment stratification and precision psychiatry. Declarations Acknowledgements We thank the patients for their trust and commitment, which made this research possible. We acknowledge the invaluable contribution of the nursing and administrative staff, who devoted time and effort to the success of this project. We are particularly grateful to Bénédicte Launay-Saucet, clinical trial nurse coordinator, for her pivotal role throughout the study. We also extend our sincere thanks to the neuroradiology team and MRI radiographers (Anna Fayolle and Maliesse Lui) of GHU Paris Psychiatrie & Neurosciences for their dedication. This work was sponsored by the GHU Paris Psychiatrie & Neurosciences and its Delegation for Clinical Research and Innovation, with special recognition to Viviane Awassi, Kenza Sabi, Khaoussou Sylla, and Marin Chapelle for their support. Generative AI toola were used solely for language editing during manuscript preparation. All content was reviewed and verified by the authors. Financial support This work was supported by the Groupe Hospitalier Universitaire Paris Psychiatrie & Neurosciences (“Appel à projets 2017”); and the Fondation de France (“AO 2017 sur les maladies psychiatriques”). Author contributions DA, MP and CO contributed to the conception and design of the study. DA, MP, MD, CP, LM, and PG contributed to clinical data acquisition. CD, SC, ML, JB, ALB, and CO contributed to MRI data acquisition and interpretation. IU and CP provided methodological developments. ALB, IU, PP, and FR performed MRI data processing. ALB, PP, and AC carried out statistical analyses. ALB, DA, AC, CO and MP interpreted the results, with additional contributions from PP, MM and AH. DA, MP, ML, CP, CD, and SC provided administrative, technical, and material support. ALB drafted the manuscript. CO and MP supervised the study. CO, AC, DA and MP critically revised the manuscript. All authors reviewed and approved the final version of the manuscript. Conflicts of interest MP has been invited to scientific meetings, served as a speaker, and received compensation from Janssen. DA has been invited to scientific meetings, served as a speaker, and received compensation from Janssen. DA has been invited to scientific meetings by Neuraxpharm. ALB has received a research grant from Servier Institute. CO served as speaker for Canon medical and Guerbet and received compensation fees for a scientific advivisor board from Olea Medical. PG 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. LM served as a speaker and received compensation from Johnson & Johnson. MD received meals from Janssen-Cilag and Eisai SAS. The other authors declare that they have no conflicts of interest. References McIntyre RS, Alsuwaidan M, Baune BT, Berk M, Demyttenaere K, Goldberg JF, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023 Oct;22(3):394–412. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. 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Giachetti I, Padelli F, Aquino D, Garbelli R, De Santis D, Rossini L, et al. Role of NODDI in the MRI Characterization of Hippocampal Abnormalities in Temporal Lobe Epilepsy. Neurology. 2022 Apr 26;98(17):e1771–82. Haykal S, Invernizzi A, Carvalho J, Jansonius NM, Cornelissen FW. Microstructural Visual Pathway White Matter Alterations in Primary Open-Angle Glaucoma: A Neurite Orientation Dispersion and Density Imaging Study. AJNR Am J Neuroradiol. 2022 May;43(5):756–63. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382–9. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(1):56–62. Jenkinson M, Beckmann CF, Behrens TEJ, Woolrich MW, Smith SM. FSL. NeuroImage. 2012 Aug 15;62(2):782–90. Sämann PG, Iglesias JE, Gutman B, Grotegerd D, Leenings R, Flint C, et al. FreeSurfer-based segmentation of hippocampal subfields: A review of methods and applications, with a novel quality control procedure for ENIGMA studies and other collaborative efforts. Hum Brain Mapp. 2022 Jan;43(1):207–33. De Jager JE, Boesjes R, Roelandt GHJ, Koliaki I, Sommer IEC, Schoevers RA, et al. Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A Systematic Review of Animal Models of Depression. Neurosci Biobehav Rev. 2024 July 7;105796. Siegel JS, Palanca BJA, Ances BM, Kharasch ED, Schweiger JA, Yingling MD, et al. Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression. Psychopharmacology (Berl). 2021 Apr;238(4):1157–69. Alexander L, Hawkins PCT, Evans JW, Mehta MA, Zarate CA. Preliminary evidence that ketamine alters anterior cingulate resting-state functional connectivity in depressed individuals. Transl Psychiatry. 2023 Dec 1;13(1):371. Samalin L, Mekaoui L, Rothärmel M, Sauvaget A, Wicart C, Dupin J, et al. Use of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression in Routine Practice: A Real-World French Study. Depress Anxiety. 2024 July 16;2024:7262794. Lee CY, Ghorbani R, Rajabi M, Mani M. Advanced microstructure imaging at high b-values and high resolution combining ultra-high performance gradient diffusion imaging and model-based deep learning demonstrated using 3D multi-slab acquisition. Magn Reson Med. 2025 Aug 24; DeKraker J, Cabalo DG, Royer J, Ngo A, Khan AR, Karat BG, et al. HippoMaps: multiscale cartography of human hippocampal organization. Nat Methods. 2025 Oct;22(10):2211–22. Table Table 1 : Characteristics of the patient sample at three time points and the control group. Values are expressed as mean ± standard deviation unless otherwise stated. Age comparison was performed using the Wilcoxon Rank Sum Test, and gender ratio comparison was performed using Pearson's Chi-Square Test. HDRS-21: 21-item Hamilton Depression Rating Scale; MADRS: Montgomery–Asberg Depression Rating Scale; M: male; F: female. Baseline (V1) At 2 weeks into Esketamine (V2) After completing treatment (V3) Healthy controls p-value b Number of patients (n) 12 12 12 24 Sex (M / F) 5 / 7 - - 10 / 14 1 Age 43 ± 14 - - 49 ± 21 0.38 Unipolar / Bipolar disorder 10 / 2 - - NA Age at first depressive episode 28 ± 9 - - NA Current episode duration (months) 26 ± 21 - - NA Lifetime depression duration (months) 65 ± 48 - - NA Number of intranasal esketamine sessions (mean ± SD, [range]) NA 5 ± 0.3 [4-5] 13 ± 6 [5-27] NA MADRS 31 ± 9 21 ± 10 20 ± 8 NA HDRS-21 24 ± 7 17 ± 7 15 ± 5 NA Response rate (n, %) 3/12 (25%) 4/12 (33%) NA Remission rate (n, %) 3/12 (25%) 2/12 (17%) NA Additional Declarations The authors declare potential competing interests as follows: MP has been invited to scientific meetings, served as a speaker, and received compensation from Janssen. DA has been invited to scientific meetings, served as a speaker, and received compensation from Janssen. DA has been invited to scientific meetings by Neuraxpharm. ALB has received a research grant from Servier Institute. CO served as speaker for Canon medical and Guerbet and received compensation fees for a scientific advivisor board from Olea Medical. PG 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. LM served as a speaker and received compensation from Johnson & Johnson. MD received meals from Janssen-Cilag and Eisai SAS. The other authors declare that they have no conflicts of interest. 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08:18:25","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":217653,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8196324/v1/b3e957faee9db60344fabb95.html"},{"id":97125420,"identity":"e9bf5a61-7b49-45f1-91c3-549a1cc7a267","added_by":"auto","created_at":"2025-12-01 08:18:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":99797,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLongitudinal changes in dentate gyrus and whole-hippocampus volumes in TRD patients and healthy controls.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX-axis denotes group and time-points (V1 = baseline; V2 = 2 weeks of intranasal esketamine; HC = healthy controls); Y-axis shows volume (mm³). Data were analyzed using linear mixed-effects ANOVA; no significant volume changes were observed over time.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8196324/v1/af556e278e317a6facaa31b6.png"},{"id":97125423,"identity":"23968cc2-a994-4cc5-ae22-6802a4973967","added_by":"auto","created_at":"2025-12-01 08:18:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":141484,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLongitudinal changes in dentate gyrus diffusion metrics in TRD patients and healthy controls.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe X-axis denotes group and time-points (V1 = baseline; V2 = 2 weeks of intranasal esketamine; HC = healthy controls); the Y-axis shows diffusion metrics values. Data are modeled with linear mixed-effects ANOVA; significant longitudinal changes after FDR correction are indicated by brackets (* p \u0026lt; 0.05; ** p \u0026lt; 0.01; *** p \u0026lt; 0.001). FA = fractional anisotropy; NDI = neurite density index; ODI = orientation dispersion index; Fiso = isotropic fraction.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8196324/v1/a44affefe70002e9cb9c6846.png"},{"id":97125424,"identity":"0cfabbb6-49c2-47ae-9d77-5b6fd06e3075","added_by":"auto","created_at":"2025-12-01 08:18:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":67821,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelations between baseline dentate gyrus microstructure and early clinical response to intranasal esketamine.\u003c/strong\u003e Scatterplots show Pearson correlations of (A) baseline ODI and (B) baseline FA (x-axes) versus proportional MADRS reduction from V1 to V2 (ΔMADRS; y-axes) in the left (red) and right (blue) dentate gyrus of TRD patients (n = 12).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8196324/v1/c68133832dc03b930ec81478.png"},{"id":97141465,"identity":"b9c6a6fd-e1b8-4a29-82e7-55e2c8bebb13","added_by":"auto","created_at":"2025-12-01 10:06:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":241926,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROI-based heat map of esketamine-induced microstructural change in hippocampal subfields.\u003cbr\u003e\n \u003c/strong\u003eAverage FA and ODI changes were mapped back onto hippocampal anatomy with a color‑coded scale according to the direction and magnitude of the mean change and overlaid on a representative patient’s 3D T1‑weighted image. Panels A–C show percentage change in fractional anisotropy (%ΔFA) in the right hippocampus at V2 versus V1 (coronal, sagittal, axial views). Panels D–F show percentage change in orientation dispersion index (%ΔODI) in the left hippocampus (coronal, sagittal, axial). Panel G presents an anatomical schematic of the hippocampal subfields (FreeSurfer v7.0.0 segmentation) - parasubiculum, presubiculum, subiculum, Cornu Ammonis 1 (CA1), CA3 (including CA2), CA4/dentate gyrus (DG), hippocampus–amygdala transition area (HATA), fimbria, hippocampal tail, and the hippocampal fissure - in coronal, sagittal, and axial views.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8196324/v1/6df550a66f258641b7ffdf5e.png"},{"id":97248350,"identity":"3e4e5f7a-36ae-4e84-ab58-1b534ac1ca83","added_by":"auto","created_at":"2025-12-02 12:54:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1529109,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8196324/v1/de842cd9-df07-458c-a376-ccd376d762ab.pdf"},{"id":97142022,"identity":"978efc3f-5d55-4197-a1a6-0f1337701ce1","added_by":"auto","created_at":"2025-12-01 10:07:17","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":50262,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8196324/v1/3ac1ce355704ac8ecaa7f4af.docx"}],"financialInterests":"The authors declare potential competing interests as follows: MP has been invited to scientific meetings, served as a speaker, and received compensation from Janssen. DA has been invited to scientific meetings, served as a speaker, and received compensation from Janssen. DA has been invited to scientific meetings by Neuraxpharm. ALB has received a research grant from Servier Institute. CO served as speaker for Canon medical and Guerbet and received compensation fees for a scientific advivisor board from Olea Medical. PG received during the last 5 years fees for presentations at congresses or participation in scientific boards from Biogen, Johnson \u0026 Johnson, Lundbeck, MindMed, MS Pharma, Newron, Otsuka, Richter and Viatris. LM served as a speaker and received compensation from Johnson \u0026 Johnson. MD received meals from Janssen-Cilag and Eisai SAS. The other authors declare that they have no conflicts of interest.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEsketamine-induced dentate gyrus plasticity in treatment resistant depression: First-in-human evidence\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTreatment-resistant depression (TRD) represents a major clinical challenge due to its multifactorial etiology, heterogeneous treatment approaches, and public-health impact (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The high prevalence of TRD - affecting 30\u0026ndash;55% of individuals with major depressive disorder (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) - underscores both the limitations of conventional antidepressant treatments and the complexity of its underlying pathophysiology. TRD reflects intricate interactions among multiple neurotransmitter systems, genetic vulnerabilities, environmental factors and impaired neuroplasticity (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Specifically, TRD is increasingly viewed as a disorder of synaptic plasticity - the brain\u0026rsquo;s ability to form, strengthen, and prune connections. Consistent with this view, chronic stress-induced atrophy of glutamatergic synapses in hippocampal and prefrontal regions is thought to disrupt mood regulation and cognitive function (\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTraditional monoaminergic antidepressants rescue synaptic plasticity slowly - requiring weeks of treatment to increase BDNF expression, adult neurogenesis, and dendritic spine formation (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). This delay highlights the need for fast-acting interventions that directly target neuroplasticity. Intranasal esketamine (ESK) has emerged as such a therapy for TRD, producing rapid antidepressant effects, reducing suicidal ideation and relapse risk (\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), with a favorable tolerability profile (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). As an NMDA-receptor antagonist, ESK disinhibits glutamatergic transmission, activates mTORC1-dependent protein synthesis, elevates BDNF levels, and induces robust synaptic potentiation and spine growth in the prefrontal cortex and hippocampus in mouse models (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). These microstructural changes - spine enlargement, new spine formation, and dendritic branching - occur preferentially within the dentate gyrus (DG) and CA1\u0026ndash;3 subfields of the murine hippocampus (\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eValidating this mechanistic model in humans requires in-vivo markers of microstructural plasticity. In heathy volunteers, an MRI performed 65 minutes after the start of an IV S-ketamine infusion detected rapid and significant increases in hippocampal subfield volumes - most notably a trend toward left CA1 enlargement (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). However, volumetric MRI cannot directly assess the underlying microstructural changes. We previously showed that neurite orientation dispersion and density imaging (NODDI) detects increases in dendritic density and complexity in the hippocampus of TRD patients after electroconvulsive therapy (ECT) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Because the orientation dispersion index (ODI) and the neurite density index (NDI) reflect, respectively, neurite fanning and volume fraction (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), they provide complementary indices of dendritic spine proliferation and maturation.\u003c/p\u003e\u003cp\u003eThe primary objective of this study was to assess longitudinal changes in hippocampal volume and microstructure using anatomical T1, diffusion tensor imaging (DTI) and NODDI in patients with TRD treated with ESK, with healthy controls serving as a baseline reference. We focused specifically on the DG - a region critically involved in adult neurogenesis and synaptic remodeling, and consistently reported as reduced in volume in depressed patients compared to controls (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). We hypothesized that ESK would induce rapid macro- and microstructural modifications in the human DG, reflecting spine growth and dendritic remodeling consistent with its proposed synaptogenic effects. We also examined, post hoc, whether baseline and early changes in DG MRI metrics predicted clinical improvement after ESK treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eParticipant recruitment and study framework\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdults (\u0026ge; 18 years) were consecutively enrolled at Sainte-Anne Hospital (GHU‑Paris Psychiatry \u0026amp; Neurosciences, Paris, France) between February 2022 and February 2024.\u0026nbsp;The inclusion criteria were (i) a DSM-5 diagnosis of a major depressive episode (unipolar or bipolar disorder) and (ii) a clinical indication for ESK treatment, as determined by the treating psychiatric team.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExclusion criteria comprised any comorbid psychiatric condition (e.g., schizophrenia, pervasive developmental disorders), any substance‑use disorders other than nicotine, any neurological condition (e.g. Parkinson disease, dementia), ECT within the preceding six months, contraindication to brain MRI, compulsory psychiatric care, protected adults, people under legal protection, and pregnant or breastfeeding women.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinical and MRI assessments were conducted at baseline (V1) and after two weeks of treatment (corresponding to four to five ESK administrations) (V2), with a final clinical evaluation conducted at the end of the treatment course (V3). Each patient underwent two MRI scans, at V1 and V2. An age- and sex-matched healthy control (HC) group, free of psychiatric and neurological illness, was scanned for reference in the neuroimaging analyses. Healthy control participants were part of a previously published dataset (21). The sample size was based on prior cross‑sectional and longitudinal NODDI studies that detected microstructural changes with comparable group sizes\u0026nbsp;(25,26) .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Comit\u0026eacute; de Protection des Personnes Sud‑M\u0026eacute;diterran\u0026eacute;e (ID-RCB number: 2017-A01812-51) and registered at ClinicalTrials.gov (NCT06661616).\u0026nbsp;All participants provide written informed consent prior to inclusion. All procedures were conducted in accordance with the Declaration of Helsinki and relevant national regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEsketamine treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEsketamine was administered intranasally twice weekly, either during daytime outpatient visits or inpatient hospitalization.\u0026nbsp;Treatment was continued until sustained remission - defined as a Montgomery\u0026ndash;\u0026Aring;sberg Depression Rating Scale (MADRS)\u0026nbsp;(27)\u0026nbsp;score \u0026le;10 for at least two consecutive weeks - or discontinued at the treating psychiatrist\u0026rsquo;s discretion if no further benefit was observed. Concomitant medications were made by the clinical team, and detailed medication data for each visit are provided in \u003cstrong\u003eSupplementary Table 10\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical assessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepressive symptom severity and treatment response were evaluated using the MADRS and the 21‑item Hamilton Depression Rating Scale (HDRS‑21)\u0026nbsp;(28)\u0026nbsp;at V1, V2, and V3. Response was defined as a \u0026ge;50 % reduction in MADRS, and remission as a MADRS \u0026le;10.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRI data acquisition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll imaging was performed on a 3-Tesla General Electric MR750 scanner fitted with a 16‑channel head coil. Each participant underwent the same protocol at V1 and V2. High‑resolution structural images were acquired using a 3D T1‑weighted spoiled gradient‑echo sequence incorporating inversion recovery (isotropic resolution = 1 mm, TE/TR/TI = 3.2/8.2/400 ms, flip angle = 11\u0026deg;). Diffusion-weighted images were acquired with a multi‑shell echo‑planar sequence optimized for NODDI: three b‑value shells (200, 1500, and 2500 s mm⁻\u0026sup2;) were sampled with 30, 45, and 60 diffusion‑encoding directions, respectively along with three b = 0 s mm⁻\u0026sup2; images for reference (isotropic resolution = 2 mm, TE/TR = 80/4400 ms). To correct for susceptibility-induced distortions, a scan with reversed phase‑encoding (b = 2500 s mm⁻\u0026sup2;, 6 directions) was also collected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImage processing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStructural and diffusion datasets were processed with the Ginkgo Toolbox (CEA; https://framagit.org/cpoupon/gkg). First, susceptibility artefacts were removed by pairing the forward and reverse phase‑encoded images in FSL (29), after which all shells were concatenated. Outlier detection, eddy‑current correction, and rigid‑body motion correction were then applied in a unified Ginkgo framework. The T1‑weighted volume was skull‑stripped, rigidly aligned to the averaged b = 0 s mm⁻\u0026sup2; image, and used to generate an accurate brain mask. NODDI parameter maps - neurite density index (NDI), isotropic volume fraction (Fiso), and orientation dispersion index (ODI) - were estimated with the intrinsic and isotropic diffusivities fixed at 1.7 \u0026times; 10⁻\u0026sup3; mm\u0026sup2; s⁻\u0026sup1; and 3 \u0026times; 10⁻\u0026sup3; mm\u0026sup2; s⁻\u0026sup1;, respectively. Conventional diffusion‑tensor metrics (fractional anisotropy, axial, radial, and mean diffusivities) were also computed, and a Q‑ball reconstruction (spherical‑harmonics order 8, regularization \u0026lambda; = 0.006) yielded generalized FA maps.\u003c/p\u003e\n\u003cp\u003eFreeSurfer 7.0.0 was used to segment the T1 images, delineated the hippocampi, and compute subfield parcellations. In line with earlier work\u0026nbsp;(21,30), the DG was defined by aggregating its thin internal labels within the \u0026lsquo;CA\u0026rsquo; segmentation, mitigating boundary inaccuracies at 2 mm resolution. All segmentations and inter‑modality registrations were visually inspected by a neuroradiologist (ALB). Bilateral DG volumes and mean diffusion metrics were extracted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were conducted in R 3.4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOutlier removal\u003c/em\u003e\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Diffusion metrics outliers within the DG were removed using a mean absolute deviation (MAD) approach. The median and MAD were computed for each hemisphere (left/right), diffusion metric, study group (ESK vs. HC), and - within the ESK group - visit (V1, V2). Exclusion thresholds were set at \u0026plusmn;2.5 MAD from the median, and values exceeding these limits were replaced with \u0026apos;not available\u0026rsquo;. This procedure eliminated 63 outliers from 768 total observations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eLongitudinal effects and group comparisons\u003c/em\u003e\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;To assess treatment-related DG changes over time, separate univariate linear mixed-effects models were fitted for DG volume and each microstructural metric (DTI and NODDI) in each hemisphere. Models included fixed effects of time (V1 vs V2), age, and sex, with participants modeled as random intercepts. Wald \u0026chi;\u0026sup2; tests were used to evaluate the significance of fixed effects in the mixed models. At each visit, ESK patients were compared to age- and sex-matched healthy controls: normally distributed metrics were tested via independent t-tests, while skewed variables (e.g. GFA, volumes) used Mann\u0026ndash;Whitney U tests. All p-values were adjusted for multiple comparisons using the Benjamini\u0026ndash;Hochberg false discovery rate (FDR) procedure, with FDR-corrected two-tailed p \u0026lt; 0.05 considered significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical correlation\u003c/em\u003e\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;This post-hoc analysis focused on the DG volume and diffusion metrics that show significant time effects in the linear mixed-effects model to examine their association with clinical response. For each participant and each selected metric, we extracted the baseline value (V1) and calculated its proportional change from V1 to V2:\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003c/p\u003e\n\u003cp\u003eOnly subjects with both V1 and V2 data were included in this analysis. We then assessed Pearson correlations separately for (1) baseline V1 metrics versus \u0026Delta;MADRS and (2) \u0026Delta;metrics versus \u0026Delta;MADRS, in left and right DG. For each correlation test we report the correlation coefficient (\u003cem\u003er\u003c/em\u003e), the two-tailed \u003cem\u003ep\u003c/em\u003e-value, and the 95% confidence interval. To control for 12 total comparisons (3 metrics \u0026times; 2 timepoints \u0026times; 2 hemispheres), we applied Benjamini\u0026ndash;Hochberg FDR correction; uncorrected \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05 were noted as significant or trend-level, with FDR-adjusted values presented alongside.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe correlation analysis was also extended to test whether early MRI changes (\u0026Delta;V1 \u0026rarr; V2) were associated with longer-term clinical improvement (\u0026Delta;MADRS V1 \u0026rarr; V3).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePost‑hoc metric‑change mapping\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFinally, we conducted an exploratory, ROI-based mapping of microstructural change. As in the previous step, the analysis was confined to the metrics that showed significant longitudinal effects under ESK. For each of the ten bilateral hippocampal subfields provided by the \u0026lsquo;CA\u0026rsquo;‑version FreeSurfer segmentation (CA1, CA2/3, CA4 -including the dentate gyrus-, subiculum, presubiculum, parasubiculum, fimbria, hippocampal tail, hippocampal fissure and the hippocampal‑amygdalar transition area), we extracted the subject‑level mean metrics at baseline (V1) and week 2 (V2). Percentage change was then calculated as\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003c/p\u003e\n\u003cp\u003eFor each subfield, we computed the mean \u0026plusmn; SD of %\u0026Delta;metric and mapped these average changes onto the hippocampal anatomy using a color-coded scale reflecting the direction and magnitude of the mean change. No statistical tests were applied in this exploratory analysis.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwelve patients with TRD treated with ESK were included, along with 24 age- and sex-matched HC. In the ESK group, the median interval between the baseline MRI (V1) and post-ESK MRI scan (V2) was 20.5 days (range: 11–42),\u0026nbsp;and the mean ± SD number of ESK sessions was 5 ± 0.3. At V2, three patients (25%) were both responders and remitters. The median interval between V1 and the final clinical evaluation (V3) was 56 days (range: 14–82). At V3, four patients (33%) were responders and 2 (17%) were remitters. Demographic and clinical characteristics of the ESK and HC groups are summarized in \u003cstrong\u003eTable 1\u003c/strong\u003e. Pharmacological regimens at V1, V2, and V3 during ESK treatment are provided in \u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLongitudinal effects and group comparisons\u003c/strong\u003e\u003c/p\u003e\n\u003ch4\u003e\u003cem\u003eVolume change\u003c/em\u003e\u003c/h4\u003e\n\u003cp\u003eMean ± SD DG volumes in the ESK group were 555 ± 91 mm³ (left) and 550 ± 72 mm³ (right) at V1, and 553 ± 91 mm³ (left) and 557 ± 67 mm³ (right) at V2, and 566 ± 35 mm³ (left) and 575 ± 48 mm³ (right) in the HC group (\u003cstrong\u003eFigure 1\u003c/strong\u003e). In the TRD group, linear mixed‐effects models revealed no main effect of time on DG volume (left: χ² = 0.07, P\u003csub\u003eFDR\u003c/sub\u003e = 0.79; right χ² = 0.83, P\u003csub\u003eFDR\u003c/sub\u003e = 0.36), while age and sex were significant predictors (left hemisphere, age: χ² = 11.26, P\u003csub\u003eFDR\u003c/sub\u003e = 0.001 and sex χ² = 32.19, P\u003csub\u003eFDR\u003c/sub\u003e \u0026lt; 0.001; right hemisphere, sex: χ² = 22.52, P\u003csub\u003eFDR\u003c/sub\u003e \u0026lt; 0.001). \u0026nbsp;Similarly, whole-hippocampus volumes did not change significantly over time (all P\u003csub\u003eFDR\u003c/sub\u003e \u0026gt; 0.5), although age and sex remained significant covariates (left hemisphere, sex χ² = 35.74, P\u003csub\u003eFDR\u003c/sub\u003e \u0026lt; 0.001; right hemisphere, age: χ² = 5.77, P\u003csub\u003eFDR\u003c/sub\u003e = 0.02; sex: χ² = 42.46, P\u003csub\u003eFDR\u003c/sub\u003e \u0026lt; 0.001). All comparisons between patients and healthy controls were non-significant (all P\u003csub\u003eFDR\u003c/sub\u003e \u0026gt; 0.5).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVolumes at each time point and changes at V2 relative to baseline along with a detailed breakdown of the statistical analyses are provided in \u003cstrong\u003eSupplementary Tables 2, 3 and 6\u003c/strong\u003e.\u003c/p\u003e\n\u003ch4\u003e\u003cem\u003eDTI metrics\u003c/em\u003e\u003c/h4\u003e\n\u003cp\u003eFA decreased bilaterally in the dentate gyrus over two weeks of ESK, but the effect reached significance only on the right side (χ² = 9.38, P\u003csub\u003eFDR\u003c/sub\u003e = 0.01; \u003cstrong\u003eFigure 2\u003c/strong\u003e). On the left, the decrease did not reach significance (χ² = 3.25, P\u003csub\u003eFDR\u003c/sub\u003e = 0.19). Other DTI metrics showed no significant changes.\u003c/p\u003e\n\u003cp\u003eAt baseline, ESK patients exhibited higher FA in the DG of both hemispheres compared with HC (right: Cohen \u003cem\u003ed\u0026nbsp;\u003c/em\u003e= −1.13; left: Cohen \u003cem\u003ed\u003c/em\u003e = −0.96; uncorrected p = 0.004 and 0.011, respectively), but these differences were no longer significant after FDR correction (P\u003csub\u003eFDR\u003c/sub\u003e = 0.10-0.11). Other DTI metrics in the DG of ESK patients did not differ significantly from those of HC. DTI values and changes at V2 relative to baseline, along with the detailed statistical analyses are provided in \u003cstrong\u003eSupplementary Tables 4, 5 and\u003c/strong\u003e \u003cstrong\u003e6\u003c/strong\u003e.\u003c/p\u003e\n\u003ch4\u003e\u003cem\u003eNODDI metrics\u003c/em\u003e\u003c/h4\u003e\n\u003cp\u003eTime‐related changes of NODDI metrics (NDI, Fiso and ODI) in both DG are presented in \u003cstrong\u003eFigure 2\u003c/strong\u003e. ODI increased in the DG on both sides following ESK, but the effect was significant only on the left (χ² = 10.65, P\u003csub\u003eFDR\u003c/sub\u003e = 0.003), while the right side showed no significant change (χ² = 2.03, P\u003csub\u003eFDR\u003c/sub\u003e = 0.45). NDI and Fiso remained stable over time.\u003c/p\u003e\n\u003cp\u003eAt baseline, the ESK group exhibited a moderately lower left-DG ODI than controls (Cohen’s d = 1.02, p = 0.007), but this difference was not significant after FDR correction (P\u003csub\u003eFDR\u003c/sub\u003e = 0.11). A lower left‑DG Fiso in the ESK group at V2 was also observed (Cohen \u003cem\u003ed\u003c/em\u003e = 0.77, p = 0.044), which became non‑significant after adjustment (P\u003csub\u003eFDR\u003c/sub\u003e = 0.35). Average NODDI values, mean changes and standard deviations at V2 relative to baseline and a detailed breakdown of the statistical analyses, are provided in the Supplementary material (\u003cstrong\u003eSupplementary Tables 6, 7, and 8\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Correlations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVolume measures, at baseline or as change scores (Δ-volume), showed no significant association with clinical improvement.\u003c/p\u003e\n\u003cp\u003eCorrelational analyses of diffusion metrics were restricted to FA and ODI, the only metrics showing significant longitudinal changes. Lower FA at baseline in the left DG correlated with greater early improvement at V2 (r = –0.57, p = 0.05), with a similar nonsignificant trend on the right (r = –0.54, p = 0.09) (\u003cstrong\u003eFigure 3B\u003c/strong\u003e). The change in left-DG FA was positively correlated with clinical improvement (r = 0.74, p = 0.01, P\u003csub\u003eFDR\u003c/sub\u003e = 0.07), indicating that patients who exhibited greater FA increases - or smaller FA decreases - over two weeks experienced the largest reductions in MADRS scores. No similar relationship was observed on the right (r = 0.41, p = 0.23). None of these correlations remained significant after Benjamini–Hochberg correction (\u003cstrong\u003eSupplementary Table 9\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eBaseline ODI values did not predict clinical improvement (Left: \u003cem\u003er\u003c/em\u003e = 0.20, \u003cem\u003ep\u003c/em\u003e = 0.53; Right: \u003cem\u003er\u003c/em\u003e = 0.27, p = 0.41) (\u003cstrong\u003eFigure 3A\u003c/strong\u003e), whereas the Δ‐ODI from V1 to V2 showed a negative trend (Left: \u003cem\u003er\u003c/em\u003e = –0.51, p = 0.05; Right: \u003cem\u003er\u003c/em\u003e = –0.46, p = 0.07), indicating that patients with smaller increases in ODI tended to experience larger reductions in MADRS scores (\u003cstrong\u003eSupplementary Table 9\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eBaseline imaging features and their changes did not correlate with symptom improvement at the later V3 time point (ΔMADRS V1–V3); therefore, these results are not shown.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHippocampal Subfield Microstructural Changes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese post hoc exploratory analyses were restricted to FA and ODI, the only diffusion metrics showing significant longitudinal changes in the primary DG analysis.\u0026nbsp;Beyond the DG, several hippocampal subfields exhibited early diffusion changes after two weeks of ESK treatment (\u003cstrong\u003eSupplementary Table 10\u003c/strong\u003e). The right CA3 showed the largest FA decrease (−11.69 ± 16.32%), while the left CA3 exhibited the greatest ODI increase (14.53 ± 20.72%; mean ± SD of change) among hippocampal subfields. \u003cstrong\u003eFigure 4\u0026nbsp;\u003c/strong\u003eillustrates the ROI-based mapping of percentage change in FA (right hemisphere) and ODI (left hemisphere) across the ten bilateral hippocampal subfields,highlighting the spatial distribution and magnitude of early microstructural changes following ESK treatment.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this longitudinal study of patients with TRD, two weeks of ESK administration produced no measurable macroscopic changes in hippocampal volumes, in contrast to previous findings in healthy volunteers showing rapid volumetric increases following intravenous S-ketamine (20). However, advanced diffusion MRI revealed early bilateral microstructural modifications, characterized by decreased FA and increased ODI in both DG, although significance was reached only unilaterally. This pattern -reduced FA and increased ODI- is typically interpreted as reflecting enhanced dendritic density and complexity. NDI and Fiso showed nonsignificant tendencies toward increase and decrease, respectively, consistent with subtle effects that may not have been detectable given our sample size (n = 12).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMoreover, patients showed higher baseline FA and lower baseline ODI in the DG than controls, differences that did not survive correction for multiple comparisons. These diffusion changes mirror those we previously observed in TRD patients receiving ECT (21), although baseline FA, GFA, and ODI were far more disrupted in the ECT cohort. Together, these findings suggest that ESK rapidly modulates DG microstructure - potentially reflecting dendritic arbor complexification (ODI increase) and altered fiber coherence (FA decrease) - consistent with preclinical evidence of rapid synaptogenesis following NMDA receptor blockade (31).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBeyond the DG, supplementary analyses demonstrated that ESK induced similar microstructural dynamics in adjacent hippocampal subfields, suggesting a broader pattern of plastic remodeling within the hippocampal formation. Notably, FA in the right CA3 decreased whereas the ODI in the left CA3 increased over two weeks. These subfield-specific effects align with preclinical evidence identifying CA3 as a locus of stress-induced remodeling and rapid synaptogenesis after NMDA-receptor antagonism (15).\u003c/p\u003e\n\u003cp\u003eAlthough longitudinal changes in DG microstructure did not significantly predict clinical outcome in this small sample, we observed a trend suggesting that lower baseline FA in the left DG was associated with greater clinical improvement - implying that patients with more preserved synaptic integrity at baseline may respond more favorably to ESK. The greatest clinical improvements were observed in patients who showed the smallest increases in ODI and the most stable (or even increased) FA in the left DG following ESK, suggesting that the hippocampal baseline status may be more critical in predicting treatment response than the magnitude of the longitudinal changes.\u003c/p\u003e\n\u003cp\u003eTaken together, our results indicate that esketamine’s synaptogenic effects may be captured by diffusion-based MRI markers. Notably, these occurred in the absence of detectable volumetric changes. As previously observed following ECT (21), decreases in gray-matter FA may index reduced fiber coherence as new dendritic branches emerge, while ODI increases may reflect greater dendritic angular dispersion. Within corticolimbic circuits, such microstructural remodeling may support modulation of functional connectivity between the hippocampus and prefrontal regions - one of the proposed mechanisms underlying the antidepressant effects of NMDA receptor antagonists (32,33). Correlating these diffusion changes with neurobiological biomarkers may further validate their role as imaging proxies of rapid synaptic remodeling.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this study, the second MRI time point was scheduled close to two weeks after treatment initiation to capture early neuroplastic changes with potential predictive value for clinical response; however, this objective was not achieved in our sample. In practice, baseline diffusion measures (such as baseline FA) may offer a more accessible and clinically relevant biomarker for guiding treatment selection in TRD than their longitudinal evolution.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study presents several limitations. First, the sample size was relatively small, which limits statistical power and may introduce sampling bias, a limitation explained by the difficulty of assembling large cohorts in longitudinal interventional imaging studies. Second, only four of the twelve ESK-treated patients met response criteria and two achieved remission, mirroring recent real-world reports (34) and leaving the study underpowered to assess clinical–imaging relationships. Third, we did not perform long-term MRI follow-up (e.g., at 3 or 6 months) to determine whether the observed diffusion changes are sustained or transient. Finally, the diffusion imaging resolution of 2 mm remains limited for precise assessment of the hippocampus subfields. Ultra-high-resolution diffusion MRI (35), combined with advanced analytical frameworks such as hippocampal unfolding (36), holds promise for improving the characterization of hippocampal plasticity in psychiatric populations.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this study provides the first \u003cem\u003ein vivo\u003c/em\u003e evidence that esketamine induces rapid microstructural remodeling in the human dentate gyrus in TRD - detectable by diffusion MRI - without concomitant macroscopic volumetric changes over two weeks. Patients who benefit most from this treatment exhibited the least altered DG microstructure at baseline. Integrating neurobiological biomarker correlations may further validate the specificity and mechanistic relevance of these imaging markers. Ultimately, connecting diffusion-based signatures of microstructural plasticity to clinical outcomes and treatment mechanisms could offer new perspectives on the role of neuroimaging in treatment stratification and precision psychiatry.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patients for their trust and commitment, which made this research possible. We acknowledge the invaluable contribution of the nursing and administrative staff, who devoted time and effort to the success of this project. We are particularly grateful to Bénédicte Launay-Saucet, clinical trial nurse coordinator, for her pivotal role throughout the study.\u003c/p\u003e\n\u003cp\u003eWe also extend our sincere thanks to the neuroradiology team and MRI radiographers (Anna Fayolle and Maliesse Lui) of GHU Paris Psychiatrie \u0026amp; Neurosciences for their dedication. This work was sponsored by the GHU Paris Psychiatrie \u0026amp; Neurosciences and its Delegation for Clinical Research and Innovation, with special recognition to Viviane Awassi, Kenza Sabi, Khaoussou Sylla, and Marin Chapelle for their support.\u003c/p\u003e\n\u003cp\u003eGenerative AI toola were used solely for language editing during manuscript preparation. All content was reviewed and verified by the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial support\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Groupe Hospitalier Universitaire Paris Psychiatrie \u0026amp; Neurosciences (“Appel à projets 2017”); and the Fondation de France (“AO 2017 sur les maladies psychiatriques”).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDA, MP and CO contributed to the conception and design of the study. DA, MP, MD, CP, LM, and PG contributed to clinical data acquisition. CD, SC, ML, JB, ALB, and CO contributed to MRI data acquisition and interpretation. IU and CP provided methodological developments. ALB, IU, PP, and FR performed MRI data processing. ALB, PP, and AC carried out statistical analyses. ALB, DA, AC, CO and MP interpreted the results, with additional contributions from PP, MM and AH. DA, MP, ML, CP, CD, and SC provided administrative, technical, and material support. ALB drafted the manuscript. CO and MP supervised the study. CO, AC, DA and MP critically revised the manuscript. All authors reviewed and approved the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMP has been invited to scientific meetings, served as a speaker, and received compensation from Janssen. DA has been invited to scientific meetings, served as a speaker, and received compensation from Janssen. DA has been invited to scientific meetings by Neuraxpharm. ALB has received a research grant from Servier Institute. CO served as speaker for Canon medical and Guerbet and received compensation fees for a scientific advivisor board from Olea Medical. PG\u0026nbsp;received during the last 5 years fees for presentations at congresses or participation in scientific boards from Biogen, Johnson \u0026amp; Johnson, Lundbeck, MindMed, MS Pharma, Newron, Otsuka, Richter and Viatris.\u0026nbsp;LM served as a speaker and received compensation from\u0026nbsp;Johnson \u0026amp; Johnson.\u0026nbsp;MD received meals\u0026nbsp;from Janssen-Cilag and Eisai SAS. The other authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMcIntyre RS, Alsuwaidan M, Baune BT, Berk M, Demyttenaere K, Goldberg JF, et al. 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Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012 Sept;18(9):1413\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eDuman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016 Mar;22(3):238\u0026ndash;49. \u003c/li\u003e\n\u003cli\u003eDuman RS, Sanacora G, Krystal JH. Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments. Neuron. 2019 Apr 3;102(1):75\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eKim J, Kim TE, Lee SH, Koo JW. The Role of Glutamate Underlying Treatment-resistant Depression. Clin Psychopharmacol Neurosci. 2023 Aug 31;21(3):429\u0026ndash;46. \u003c/li\u003e\n\u003cli\u003eRong Y, Yan W, Gao Z, Yang Y, Xu C, Zhang C. NRXN3-NLGN1 complex influences the development of depression induced by maternal separation in rats. Brain Res. 2025 Apr 24;1858:149659. \u003c/li\u003e\n\u003cli\u003eJanik A, Qiu X, Lane R, Popova V, Drevets WC, Canuso CM, et al. Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2025 Sept 1;82(9):877\u0026ndash;87. \u003c/li\u003e\n\u003cli\u003eCanuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. AJP. 2018 July;175(7):620\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eDaly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Feb 1;75(2):139\u0026ndash;48. \u003c/li\u003e\n\u003cli\u003eZaki N, Chen LN, Lane R, Doherty T, Drevets WC, Morrison RL, et al. Safety and Efficacy with Esketamine in Treatment-Resistant Depression: Long-Term Extension Study. Int J Neuropsychopharmacol. 2025 May 4;pyaf027. \u003c/li\u003e\n\u003cli\u003eKosik-Gonzalez C, Fu DJ, Chen LN, Lane R, Bloch MH, DelBello M, et al. Effect of Esketamine on Depressive Symptoms in Adolescents With Major Depressive Disorder at Imminent Suicide Risk: A Randomized Psychoactive-Controlled Study. J Am Acad Child Adolesc Psychiatry. 2025 Mar 7;S0890-8567(25)00122-4. \u003c/li\u003e\n\u003cli\u003eMa ZZ, Guzikowski NJ, Kim JW, Kavalali ET, Monteggia LM. Enhanced ERK activity extends ketamine\u0026rsquo;s antidepressant effects by augmenting synaptic plasticity. Science. 2025 May 8;388(6747):646\u0026ndash;55. \u003c/li\u003e\n\u003cli\u003e\u0026Ouml;zler C, \u0026Ouml;zkan E, Shomalizadeh N, Kesibi J, Sapancı S, Salman FA, et al. Role of CaMKII/CREB pathway in rapid-antidepressant-like effect: comparison of ketamine with rapastinel. Exp Brain Res. 2025 May 4;243(6):138. \u003c/li\u003e\n\u003cli\u003eBulthuis NE, McGowan JC, Ladner LR, LaGamma CT, Lim SC, Shubeck CX, et al. GluN2B on Adult-Born Granule Cells Modulates (R,S)-Ketamine\u0026rsquo;s Rapid-Acting Effects in Mice. Int J Neuropsychopharmacol. 2024 Sept 6;27(10):pyae036. \u003c/li\u003e\n\u003cli\u003eMcGowan JC, Ladner LR, Shubeck CX, Tapia J, LaGamma CT, Anqueira-Gonz\u0026aacute;lez A, et al. Traumatic Brain Injury-Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine. Biol Psychiatry. 2024 Jan 1;95(1):15\u0026ndash;26. \u003c/li\u003e\n\u003cli\u003eXu M, Wang J, Shi J, Wu X, Zhao Q, Shen H, et al. Esketamine mitigates endotoxin-induced hippocampal injury by regulating calcium transient and synaptic plasticity via the NF-\u0026alpha;1/CREB pathway. Neuropharmacology. 2025 May 15;269:110362. \u003c/li\u003e\n\u003cli\u003eH\u0026ouml;flich A, Kraus C, Pfeiffer RM, Seiger R, Rujescu D, Zarate CA, et al. Translating the immediate effects of S-Ketamine using hippocampal subfield analysis in healthy subjects-results of a randomized controlled trial. Transl Psychiatry. 2021 Apr 1;11(1):200. \u003c/li\u003e\n\u003cli\u003eLe Berre A, Attali D, Uszynski I, Debacker C, Lui M, Charron S, et al. Hippocampal microstructural changes following electroconvulsive therapy in severe depression. Mol Psychiatry. 2025 Apr 8; \u003c/li\u003e\n\u003cli\u003eZhang H, Schneider T, Wheeler-Kingshott CA, Alexander DC. NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. Neuroimage. 2012 July 16;61(4):1000\u0026ndash;16. \u003c/li\u003e\n\u003cli\u003eNuninga JO, Mandl RCW, Boks MP, Bakker S, Somers M, Heringa SM, et al. Volume increase in the dentate gyrus after electroconvulsive therapy in depressed patients as measured with 7T. Mol Psychiatry. 2020 July;25(7):1559\u0026ndash;68. \u003c/li\u003e\n\u003cli\u003eWu C, Jia L, Mu Q, Fang Z, Hamoudi HJAS, Huang M, et al. Altered hippocampal subfield volumes in major depressive disorder with and without anhedonia. BMC Psychiatry. 2023 July 25;23(1):540. \u003c/li\u003e\n\u003cli\u003eGiachetti I, Padelli F, Aquino D, Garbelli R, De Santis D, Rossini L, et al. Role of NODDI in the MRI Characterization of Hippocampal Abnormalities in Temporal Lobe Epilepsy. Neurology. 2022 Apr 26;98(17):e1771\u0026ndash;82. \u003c/li\u003e\n\u003cli\u003eHaykal S, Invernizzi A, Carvalho J, Jansonius NM, Cornelissen FW. Microstructural Visual Pathway White Matter Alterations in Primary Open-Angle Glaucoma: A Neurite Orientation Dispersion and Density Imaging Study. AJNR Am J Neuroradiol. 2022 May;43(5):756\u0026ndash;63. \u003c/li\u003e\n\u003cli\u003eMontgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eHamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(1):56\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eJenkinson M, Beckmann CF, Behrens TEJ, Woolrich MW, Smith SM. FSL. NeuroImage. 2012 Aug 15;62(2):782\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eS\u0026auml;mann PG, Iglesias JE, Gutman B, Grotegerd D, Leenings R, Flint C, et al. FreeSurfer-based segmentation of hippocampal subfields: A review of methods and applications, with a novel quality control procedure for ENIGMA studies and other collaborative efforts. Hum Brain Mapp. 2022 Jan;43(1):207\u0026ndash;33. \u003c/li\u003e\n\u003cli\u003eDe Jager JE, Boesjes R, Roelandt GHJ, Koliaki I, Sommer IEC, Schoevers RA, et al. Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A Systematic Review of Animal Models of Depression. Neurosci Biobehav Rev. 2024 July 7;105796. \u003c/li\u003e\n\u003cli\u003eSiegel JS, Palanca BJA, Ances BM, Kharasch ED, Schweiger JA, Yingling MD, et al. Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression. Psychopharmacology (Berl). 2021 Apr;238(4):1157\u0026ndash;69. \u003c/li\u003e\n\u003cli\u003eAlexander L, Hawkins PCT, Evans JW, Mehta MA, Zarate CA. Preliminary evidence that ketamine alters anterior cingulate resting-state functional connectivity in depressed individuals. Transl Psychiatry. 2023 Dec 1;13(1):371. \u003c/li\u003e\n\u003cli\u003eSamalin L, Mekaoui L, Roth\u0026auml;rmel M, Sauvaget A, Wicart C, Dupin J, et al. Use of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression in Routine Practice: A Real-World French Study. Depress Anxiety. 2024 July 16;2024:7262794. \u003c/li\u003e\n\u003cli\u003eLee CY, Ghorbani R, Rajabi M, Mani M. Advanced microstructure imaging at high b-values and high resolution combining ultra-high performance gradient diffusion imaging and model-based deep learning demonstrated using 3D multi-slab acquisition. Magn Reson Med. 2025 Aug 24; \u003c/li\u003e\n\u003cli\u003eDeKraker J, Cabalo DG, Royer J, Ngo A, Khan AR, Karat BG, et al. HippoMaps: multiscale cartography of human hippocampal organization. Nat Methods. 2025 Oct;22(10):2211\u0026ndash;22. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e \u003cstrong\u003eCharacteristics of the patient sample at three time points and the control group.\u0026nbsp;\u003c/strong\u003eValues are expressed as mean \u0026plusmn; standard deviation unless otherwise stated. Age comparison was performed using the Wilcoxon Rank Sum Test, and gender ratio comparison was performed using Pearson\u0026apos;s Chi-Square Test. HDRS-21: 21-item Hamilton Depression Rating Scale; MADRS: Montgomery\u0026ndash;Asberg Depression Rating Scale; M: male; F: female.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"939\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.159%;\"\u003e\u003cbr\u003e\u0026nbsp;\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline (V1)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAt 2 weeks into Esketamine (V2)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter completing treatment (V3)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHealthy controls\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value \u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eNumber of patients (n)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eSex (M / F)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e5 / 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003e10 / 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e43 \u0026plusmn; 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003e49 \u0026plusmn; 21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eUnipolar / Bipolar disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e10 / 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eAge at first depressive episode\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e28 \u0026plusmn; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eCurrent episode duration (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e26 \u0026plusmn; 21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eLifetime depression duration (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e65 \u0026plusmn; 48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eNumber of intranasal esketamine sessions (mean \u0026plusmn; SD, [range])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e5 \u0026plusmn; 0.3 [4-5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e13 \u0026plusmn; 6 [5-27]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eMADRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e31 \u0026plusmn; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e21 \u0026plusmn; 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e20\u0026nbsp;\u0026plusmn; 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eHDRS-21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e24 \u0026plusmn; 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e17 \u0026plusmn; 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e15 \u0026plusmn; 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eResponse rate (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e3/12 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e4/12 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23.159%;\"\u003e\n \u003cp\u003eRemission rate (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.7673%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.02775%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.2337%;\"\u003e\n \u003cp\u003e3/12 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.13447%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4077%;\"\u003e\n \u003cp\u003e2/12 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 1.8143%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8741%;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5539%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"GHU Paris Psychiatrie \u0026 Neurosciences","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"depression, imaging, esketamine, neuroplasticity, hippocampus, treatment-resistance","lastPublishedDoi":"10.21203/rs.3.rs-8196324/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8196324/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u0026nbsp;\u003c/strong\u003eTreatment-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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u0026nbsp;\u003c/strong\u003eTwelve 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u0026nbsp;\u003c/strong\u003eDG volumes were stable from V1 to V2. Right-DG fractional anisotropy (FA) decreased (χ²=9.38, P\u003csub\u003eFDR\u003c/sub\u003e=0.01) and left-DG orientation dispersion index (ODI) increased (χ²=10.65, P\u003csub\u003eFDR\u003c/sub\u003e=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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u0026nbsp;\u003c/strong\u003eESK 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.\u003c/p\u003e","manuscriptTitle":"Esketamine-induced dentate gyrus plasticity in treatment resistant depression: First-in-human evidence","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 08:18:20","doi":"10.21203/rs.3.rs-8196324/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"438b6e6c-4f2f-4296-82ba-d2c22b6f2991","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-01T08:18:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 08:18:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8196324","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8196324","identity":"rs-8196324","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}