Transcriptional profiling of antidepressant ketamine and electroconvulsive therapy treatment

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.