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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| 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 Esketamine |
| Keywords | Dissociative anesthetic Rapid-acting antidepressant Brain connectivity Brain networks Neural networks Brain alterations Brain changes Neural connectivity Depression treatment Mental health treatment Antidepressant therapy Sertraline Therapeutic response Biomarkers Brain biomarker Predictive marker Connectome fingerprint Neural signature |
| Citations | 1 |
| Key findings | 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.
Comparable studies
Other observational and cohort studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Taming the Ketamine Tiger Volunteers from a prison population | 2010 | Observational study | n = 20 |
| Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin Humans | 2017 | Observational study | |
| Disruption of Frontal–Parietal Communication by Ketamine, Propofol, and Sevoflurane Surgical patients undergoing induction of anesthesia with intravenous ketamine | 2013 | Observational cohort | n = 30 |
| Do the dissociative side effects of ketamine mediate its antidepressant effects? Treatment-resistant inpatients with major depressive disorder or bipolar disorder | 2014 | Observational cohort | n = 108 |
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
Citations in the library
Cites 15
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics Annual Review of Medicine October 23, 2014
- NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia Proceedings of the National Academy of Sciences September 25, 2012
and 10 more in the library