Transcriptional profiling of antidepressant ketamine and electroconvulsive therapy treatment

Treatment-resistant depression affects 30-50% of people with major depressive disorder. Electroconvulsive therapy and ketamine can relieve it, but how they work is unclear. This transcriptome analysis of peripheral blood from 37 people receiving electroconvulsive therapy, 60 receiving ketamine, and 35 non-depressed controls found no longitudinal changes in gene expression for either treatment after correcting for multiple comparisons. In the ketamine group, one gene (IGKV1-9) differed between remitters and non-remitters at baseline. In the electroconvulsive therapy group, six co-regulated gene modules differed at baseline between patients and controls. Pre-treatment gene expression differences may have predictive value, but larger studies are needed.

Study at a glance

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.