Metabolic Burden and Response to Repeated Intranasal Esketamine in Treatment-Resistant Depression: A Longitudinal Multidomain Biomarker Study
Jennifer L Phillips, Ifeoluwa Olaoluwa, Areebah Ahmed, Suzannah Wojcik, Edward Horn, Jessica Clausen, Richard Kohl, Pierre Blier, Jess G. Fiedorowicz, Kelly Mascioli, Robyn McQuaid, Stefan Trivunovic, Jeanne Talbot
Research Square September 7, 2026 preprint DOI: 10.21203/rs.3.rs-10923483/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Longitudinal |
|---|---|
| Sample size | 30 |
| Population | Individuals with treatment-resistant depression receiving esketamine in a real-world clinical setting |
| Intervention | Esketamine |
| Duration | Eight intranasal esketamine treatments |
| Measures | Montgomery Åsberg Depression Rating Scale |
| Topics | Depression Esketamine Ketamine |
| Key findings | Esketamine treatment was associated with a mean 7.7-point reduction in Montgomery Åsberg Depression Rating Scale scores, and greater baseline metabolic burden predicted greater symptom improvement. Fasting glucose fell by 1.58 mmol/L without weight change. Baseline inflammatory and neurotrophic composites were not associated with symptom change, and no inflammatory or neurotrophic biomarkers changed significantly; in sensitivity analyses excluding diabetes or glucose-altering medications, higher baseline VEGF predicted greater symptom reduction. |
Abstract
Abstract Metabolic, inflammatory, and neurotrophic measures may provide complementary insight into biological heterogeneity underlying treatment-resistant depression and response to ketamine-based treatments. However, biomarker studies of ketamine treatment have focused on individual markers or biological domains, most commonly inflammatory or neurotrophic, while metabolic measures remain comparatively understudied. All three domains were examined in 30 individuals with treatment-resistant depression receiving eight intranasal esketamine treatments in a real-world clinical setting. Depressive symptoms, metabolic, inflammatory, and neurotrophic biomarkers were assessed before and after treatment. Esketamine treatment was associated with a reduction in Montgomery Åsberg Depression Rating Scale scores (mean decrease 7.7 points, p < 0.001; Cohen’s d = -0.90). Greater metabolic burden, quantified using a composite based on metabolic syndrome criteria and comprising waist circumference, triglycerides, HDL cholesterol, blood pressure, and fasting glucose, was associated with greater reductions in depressive symptoms following treatment, after adjustment for baseline depressive symptom severity (p = 0.032). Fasting glucose decreased following esketamine treatment (mean decrease 1.58 mmol/L, pFDR < 0.001; Cohen’s d = −1.61), without significant changes in body weight. In contrast, baseline inflammatory and neurotrophic composites were not associated with changes in depressive symptoms, and no inflammatory or neurotrophic biomarkers showed significant longitudinal changes. In sensitivity analyses excluding participants with diabetes or prescribed glucose-altering medications, higher baseline serum vascular endothelial growth factor (VEGF) was associated with greater reductions in depressive symptoms (pFDR = 0.043). These findings highlight the value of a multidomain approach and identify metabolic measures as an important domain for understanding heterogeneity in response to esketamine.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.