A Robust and Reproducible Connectome Fingerprint of Ketamine is Highly Associated with the Connectomic Signature of Antidepressants
medRxiv Preprint Server – April 10, 2020
Source: medRxiv
Summary
A new discovery reveals how ketamine impacts brain networks, offering insights into depression treatment. Researchers identified a unique 'connectome fingerprint' for ketamine, showing it robustly alters brain connectivity. This signature, characterized by increased connections between the executive network and other brain regions, was consistently found. Remarkably, these ketamine-induced brain changes predicted how well patients with depression responded to a common antidepressant, sertraline. This work successfully identifies a reliable brain biomarker for ketamine, strongly linking its effects to the mechanisms of existing antidepressants, highlighting a promising avenue for understanding and treating mental health conditions.
Abstract
Over the past decade, various N-Methyl-D-Aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In this longitudinal functional magnetic resonance imaging study of data from 265 participants, we used a validated predictive model approach that allows the full assessment of brain functional connectivity, without the need for seed selection or connectivity summaries. First, we identified a connectome fingerprint (CFP) in healthy participants (Cohort A, n=25) during intravenous infusion of a subanesthetic dose of ketamine, compared to normal saline. We then demonstrated the robustness and reproducibility of the discovered Ketamine CFP in two separate healthy samples (Cohort B, n=22; Cohort C, n=18). Finally, we investigated the Ketamine CFP connectivity at 1-week post treatment in major depressive disorder patients randomized to 8 weeks of sertraline or placebo (Cohort D, n=200). We found a significant, robust, and reproducible Ketamine CFP, consistent with reduced connectivity within the primary cortices and within the executive network, but increased connectivity between the executive network and the rest of the brain. Compared to placebo, the Ketamine CFP connectivity changes at 1-week predicted response to sertraline at 8-weeks. In each of Cohort A-C, ketamine significantly increased connectivity in a previously identified Antidepressant CFP. Investigating the brain connectivity networks, we successfully identified a robust and reproducible ketamine biomarker that is related to the mechanisms of antidepressants.