Transcriptional profiling of antidepressant ketamine and electroconvulsive therapy treatment
Artemis Zavaliangos‐petropulu, Ginny Ghang, Toni Boltz, Paloma Pfeiffer, Lingyu Zhan, Eliza Congdon, Randall Espinoza, Katherine L. Narr, Roel A. Ophoff
medRxiv July 29, 2025 preprint DOI: 10.1101/2025.07.29.25332162 via OpenAlex
Summary
Electroconvulsive therapy (ECT) and ketamine treatment can alleviate treatment-resistant depression (TRD), but this study found limited longitudinal gene expression changes in peripheral blood samples from patients. While no significant transcriptional changes were detected over time for either treatment, differences in baseline gene expression profiles suggest potential predictive value, particularly in the ketamine group where one gene (IGKV1-9) was significantly differentially expressed. Further research with larger samples is needed to better understand molecular signatures of antidepressant response.
Study at a glance
| Design | observational cohort |
|---|---|
| Sample size | 132 |
| Population | individuals with treatment-resistant depression undergoing ECT or ketamine treatment, and non-depressed controls |
| Key finding | Limited longitudinal gene expression changes were detected for either ECT or ketamine treatment, though baseline differences in gene expression profiles may have predictive value. |
Abstract
Background: Treatment-resistant depression (TRD) affects 30-50% of patients with major depressive disorder (MDD). Electroconvulsive therapy (ECT) and sub-anesthetic ketamine treatment can relieve TRD, yet their antidepressant mechanisms remain unclear. Peripheral blood gene expression offers a non-invasive proxy to examine potential treatment-response biomarkers. Methods: We conducted a transcriptome analysis on peripheral blood samples from individuals with TRD undergoing ECT (N=37) or serial ketamine infusions (N=60), and non-depressed controls (N=35). Samples were collected at baseline and at multiple follow-up time points. Differential gene expression (DGE) at the single gene and network level identified transcriptional changes and co-regulated gene modules associated with diagnosis, treatment, and remission status using Weighted Gene Co-Expression Network Analysis (WGCNA), including correction for multiple comparisons. Results: Longitudinal transcriptional changes were not detected for either treatment for individual genes or networks (FDR corrected or |logFC|>0.05). When comparing remitters and non-remitters at baseline in the ketamine group, we observed evidence of enrichment for immune-related functions overall with one gene significantly differentially expressed (i.e., IGKV1-9) (p=2.5E-05, logFC=-0.51). In the ECT sample, when considering gene networks, we observed significant interaction effects between time and diagnosis. At least six co-regulated gene modules yielded significant differences at baseline between ECT patients and controls. Conclusion: Despite the robust clinical improvements associated with ECT and ketamine, peripheral blood RNA-seq revealed limited detectable longitudinal gene expression changes. However, pre-treatment differences in gene expression profiles suggest some potential predictive value. Larger samples are warranted to clarify peripheral molecular signatures of rapid-acting antidepressant response.