Researchers at the Texas A&M University Naresh K. Vashisht College of Medicine have identified time-specific patterns of brain activity following ketamine treatment in older adults with treatment-resistant depression.
The findings, published in Translational Psychiatry, could help researchers identify potential biological markers associated with ketamine’s antidepressant effects and better understand why patients respond differently to treatment.
Ketamine is increasingly used as a rapid-acting treatment for treatment-resistant depression, but its use in older adults has not been widely adopted due to concerns about safety and efficacy associated with aging pathology. To address these questions, the Experimental Psychopharmacology of Mood and Anxiety Disorders Lab (EPMAD Lab) at Texas A&M, led by Dr. Sanjay Mathew, professor and head of Psychiatry, has been studying how the brain responds to ketamine in U.S. veterans over 55 years old.
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Dr. Nicholas Murphy, research associate professor in the Department of Psychiatry and Behavioral Sciences at Texas A&M, coordinates the neuroscience-informed treatments wing of the EPMAD Lab. He compares ketamine’s effects to opening a floodgate: the drug allows communication to flow through the brain, leading to enhanced flexibility. Murphy suggested patients’ clinical response to ketamine is tied more closely to the malleability of the brain than how large of an initial response it has.
“Let’s say you had a map of rivers in the desert,” he said. “You release the dam, and now all the tributaries are being flooded with water. We now have these connections between places, and that’s what ketamine does; it helps to create a more flexible and densely connected environment. But this isn’t the end of the story. For it to be useful, we need to understand how that water is flowing, and that’s where our current analysis comes in. It tells us how the surging of glutamate released by ketamine needs to flow to get a clinical response.”
The new study focused on the next questions: how is information organized across the brain after ketamine use in older adults, and how does that organization change over time?
The Texas A&M team collaborated with researchers at Baylor College of Medicine and the University of the Balearic Islands to examine brain activity over the hours and days following a single ketamine infusion.
Krisha Shah, research associate in the Department of Psychiatry and Behavioral Sciences, said the team’s goal was to understand how ketamine reorganizes communication across the brain over time and how those changes could impact patients’ clinical responses.
“Often, EEG research looks at individual brain signals or communication between pairs of signals, but the brain doesn’t operate in pairs. It’s a highly interconnected system,” she said. “Ketamine is unusual because the drug exposure is brief, but antidepressant effects have the potential to extend well beyond that experience.”
To capture that complexity, the researchers used high-order interactions, an information-theory approach that examines how information is organized across multiple EEG signals at once rather than only looking at signals individually or in pairs.
The researchers found that ketamine did not produce a single, stable pattern of brain activity. Instead, the organization of information changed substantially over time, with different patterns emerging one hour, 24 hours and seven days after treatment. Greater increases in one measure of brain-wide information sharing at 24 hours were also associated with greater improvement in depressive symptoms at Day 7.
The research builds on two previous publications by the group, which found that intravenous ketamine is both feasible and effective in older adults. By mapping out patterns of brain connectivity over time after a ketamine infusion, the researchers identified brain-signal changes that could serve as potential biomarkers of ketamine’s antidepressant effects in late-life demographics. The new study also replicates and extends earlier higher-order interaction research in healthy volunteers.
“Most drug studies end at age 65, leaving relatively little research on how ketamine affects the aging brain,” Murphy said. “Although older adults make up more than one-third of the nation’s population, they remain underrepresented in clinical research.”
“Ketamine has come a long way from its humble beginnings as an anesthetic,” Murphy said. “However, it still has a strong abuse potential. The goal of the work that my team has been doing is to identify these key points in that physiological roadmap so it can be acted upon via another mechanism that doesn’t have the psychedelic or medical side effects of ketamine.”
Other collaborators in the study were Rahul Balakrishnan and Baylor College of Medicine professors Dr. Alan C. Swann and Dr. Brittany O’Brien.
