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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Transcriptome analysis with longitudinal sampling |
|---|---|
| Sample size | 132 |
| Population | Individuals with treatment-resistant depression undergoing electroconvulsive therapy or ketamine infusions, and non-depressed controls |
| Interventions | Electroconvulsive therapy Ketamine infusions |
| Duration | Multiple follow-up time points |
| Topics | Ketamine Esketamine |
| Keywords | Electroconvulsive therapy Antidepressant Profiling computer programming Pharmacology Anesthesia Electroconvulsive shock |
| Key findings | No significant longitudinal gene expression changes were detected for either electroconvulsive therapy or ketamine treatment, but baseline differences in gene expression between remitters and non-remitters, and between patients and controls, suggest potential predictive biomarkers. |
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.
Comparable studies
Other observational and cohort studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Taming the Ketamine Tiger Volunteers from a prison population | 2010 | Observational study | n = 20 |
| Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin Humans | 2017 | Observational study | |
| Disruption of Frontal–Parietal Communication by Ketamine, Propofol, and Sevoflurane Surgical patients undergoing induction of anesthesia with intravenous ketamine | 2013 | Observational cohort | n = 30 |
| Do the dissociative side effects of ketamine mediate its antidepressant effects? Treatment-resistant inpatients with major depressive disorder or bipolar disorder | 2014 | Observational cohort | n = 108 |
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |