Cell-free DNA as a biomarker of electroconvulsive therapy in treatment-resistant depression

Major depression impacts >350 million lives worldwide and contributes to 1 million suicides each year. Although depression is treatable, approximately one-third of patients are classified as having treatment-resistant depression (TRD) due to inadequate response to first-line pharmacotherapies, despite appropriate dosing and duration. Among the alternative treatment options, the FDA-approved neuromodulation therapy of electroconvulsive therapy (ECT), is widely regarded as the most effective acute intervention. ECT is a safe, fast- acting and highly effective treatment for TRD though stigma and risk of short-term cognitive side effects can dissuade eligible patients from treatment. Furthermore, whether mechanisms accounting for ECT’s antidepressant and adverse cognitive effects engage different physiological pathways remain unclear Understanding the therapeutic mechanisms of ECT thus remains a priority for guiding maximally effective ECT treatment with minimal cognitive risks. Existing evidence indicates that the physiological effects of ECT include an initial inflammatory response and at the same time, ECT is shown to induce neurotrophic processes in animal models that appear consistent with findings of neuro-structural and functional changes in human imaging studies of ECT. To address this more specifically, we propose a high-risk/high-reward R21 proposal, in which we will examine the dynamics of circulating cell-free DNA (cfDNA) in the context of ECT in TRD using the infrastructure of an ongoing longitudinal NIMH funded study of ECT in subjects with TRD. cfDNA are short fragments of DNA that are released into the bloodstream from cells throughout the body. These DNA fragments originate from normal cell turnover and can also come from diseased cells. There is evidence that cfDNA can pass the blood- brain barrier which provides opportunity to also examine brain-specific cellular events. DNA methylation patterns of cfDNA are used to identify their tissue and cell-type origins. cfDNA’s ability to provide real-time insights into the dynamics of molecular/cellular processes occurring with ECT holds substantial promise for understanding the temporal mechanisms underlying its therapeutic and cognitive risk effects. Together with biomarkers of inflammatory response collected from blood samples longitudinally at the same time points, and MRI measures of structural and functional connectivity allow empirical evaluation of the disrupt, potentiate and rewire hypothesis, which has been proposed for the mechanism underlying ECT. cfDNA profiling may elucidate whether ECT-induced changes occur at the cellular level and relate to observed patterns of inflammatory response and/or the reorganization of neural networks, all measured in-vivo. This approach has the potential to significantly advance our understanding of ECT's mechanisms and guide improved personalized treatment. Project Number: 1R21MH143206-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Roel Ophoff (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $433,125 | Activity Code: R21 | Study Section: Pathophysiological Basis of Mental Disorders and Addictions Study Section[PMDA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11289221