Intranasal esketamine expands key frontal and hippocampal regions and reduces serum neurofilament levels in patients with major depressive disorder

Introduction: we investigated the effects of intranasal esketamine (ESK-IN) on brain structural volumes and serum neurofilament light chain (sNfL) levels over a six-month period in patients with treatment-resistant depression (TRD).

Methods: This study was designed as a 6-month prospective, open-label trial involving patients diagnosed with major depressive disorder (MDD) who met the criteria for TRD. 25 patients with TRD received ESK-IN in addition to ongoing oral antidepressant therapy. Clinical follow-up was assessed at baseline, 1, 3, and 6 months using the following scales: 1) the Montgomery–Åsberg Depression Rating Scale (MADRS), 2) the Columbia-Suicide Severity Rating Scale (C-SSRS), 3) the Patient Health Questionnaire-9 (PHQ-9), 4) the SAD persons (SAD-p) Scale, 5) the Disability Assessment Instrument (DAI), and 6) the Zarit Burden Interview (Zarit) Scale. Structural brain MRI and blood sampling were conducted at baseline and at the six-month follow-up. MRI data from 50 matched healthy controls were also analyzed to enable comparisons of basal brain volume measures. Brain volumetric analyses were performed using VolBrain2 and DSI Studio software. Blood samples were collected from participants at baseline and after 6 months of treatment to measure sNfL levels using the Lumipulse G1200 automated system with the Lumipulse G NfL blood kit (Ref: 81215, Fujirebio Inc., Tokyo) according to the manufacturer’s instructions. Data were analyzed using appropriate statistical methods to compare case–control, baseline, and post-treatment measures. The Friedman test was used to analyze clinical tests. Case–control analyses (brain volume) were performed using the Mann–Whitney U test, while pre- and post-treatment analyses (brain volume, tractography, sNfL levels) were performed using the Wilcoxon signed-rank test. Multiple comparisons were controlled using the Benjamini–Hochberg false discovery rate (FDR) procedure, with a significance threshold set at q<0.05.

Results: at baseline, TRD patients showed significantly reduced volumes compared to healthy controls in the insula (152± 6,8 vs.143±7.1 p=0.0125), frontal cortex (910±21 vs. 818±24, p=0.0006), superior parietal cortex (101± 8.1 vs. 88.3± 6.9, p=0.0047), and both superior (120±9.0 vs. 105±8.2, p=0.0069) and inferior (70±6.8 vs. 63±7.1, p=0.0270) temporal cortices. Reduced volumes were also observed in subcortical structures, such as the nucleus accumbens (3.4± vs. 3.1± , p=0.01), thalamus (62±2.4 vs. 55±1.7, p=0.001), and hippocampus (26±0.8 vs. 21±0.9, p=0.001). Following six months of ESK-IN treatment, significant volumetric increases were detected in the frontal cortex (20.4±6.8, p=0.0001), superior frontal gyrus (4.9± 0.8, p=0.0002), medial frontal gyrus (7.5±0.6, p=0.0352), frontal operculum (1.4± 0.3, p=0.004), and anterior cingulate cortex (2.8±0.4, p=0.001), as well as in the hippocampus (1.4± 0.2, p=0.001). Additionally, increases were observed in the volume and integrity of white-matter tracts involved in emotional regulation and cognitive control, including the frontoparahippocampal (574.1±102.5, p=0.001 and 47±4.8, p=0.001), frontoparietal (290.4±38.7, p=0.001 and 1500±476.8, p=0.002), and frontal aslant (3902.8± 353±2, p=0.002 and 248±26.7, p=0.001) tracts. Concomitantly, sNfL concentrations (15.7±1.6 vs.10.1±0.8, p=0.004) decreased after treatment, suggesting a reduction in ongoing neuronal damage.

Conclusions: altogether, these findings indicate that ESK-IN may induce neuroplastic structural changes in brain regions critical for mood regulation and suicidal ideation balance while exerting potential neuroprotective effects in patients with TRD.

References

Rodríguez Lorente A, Campos-Navarro MP, Gil Montoya Á, Marín Pérez C, Maso Navarro ML, Orgaz Morales T, López Ramirez N, García-Carmona JA. Rebuilding the atrophied brain: 6-month nasal esketamine therapy expands key frontal and hippocampal regions and reduces serum neurofilament levels in patients with major depressive disorder. A proof-of-concept study of the depTesk (DEPression treatment with ESKetamine) study. CNS Spectr. 2025 Oct 21;30(1):e83. doi: 10.1017/S1092852925100631. PMID: 41117366; PMCID: PMC13064687.