A Robust and Reproducible Connectome Fingerprint of Ketamine is Highly Associated with the Connectomic Signature of Antidepressants
Chadi G. Abdallah, Kyung-Heup Ahn, Lynnette A. Averill, Samaneh Nemati, Christopher L. Averill, Samar Fouda, Mohini Ranganathan, Peter T. Morgan, Deepak C. D’Souza, Daniel H. Mathalon, John H. Krystal, Naomi R. Driesen
medRxiv Preprint Server April 10, 2020 preprint DOI: 10.1101/2020.04.10.20061085 via medRxiv
Summary
AI-generated from the abstractA robust and reproducible brain connectivity fingerprint (CFP) was identified during ketamine infusion in healthy participants, characterized by reduced connectivity within primary cortices and the executive network, but increased connectivity between the executive network and the rest of the brain. This same CFP measured one week after treatment in major depressive disorder patients predicted response to eight weeks of sertraline, but not placebo. The findings suggest a brain network biomarker that links ketamine's acute effects to the mechanisms of conventional antidepressants.
Study at a glance
| Characteristics | Longitudinal functional magnetic resonance imaging study Randomized |
|---|---|
| Sample size | 265 |
| Population | Healthy participants and major depressive disorder patients |
| Interventions | Ketamine Normal saline Sertraline Placebo |
| Dose | subanesthetic dose |
| Duration | 8-week intervention, 1-week post treatment |
| Topics | Ketamine |
| Keywords | Dissociative anesthetic Rapid-acting antidepressant Brain connectivity Brain networks |
| Citations | 1 |
| Key finding | A ketamine-induced brain connectivity fingerprint, reproducible across three healthy cohorts, predicted later response to sertraline in depressed patients. |
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.