A small observational study has shed new light on how nasal esketamine affects the brain in people undergoing treatment for major depressive disorder. The researchers found that esketamine produced rapid changes in brainwave activity—indicating reduced top-down control and increased cortical excitation—that were closely linked to participants’ subjective experiences of feeling “high,” happier, and less tense. These neurophysiological shifts persisted for over an hour and may help explain the drug’s fast-acting antidepressant effects.
The research was recently published in Progress in Neuro-Psychopharmacology and Biological Psychiatry.
Esketamine is a drug derived from ketamine, an anesthetic that has also shown promise in treating depression. While ketamine consists of two mirror-image molecules (called enantiomers), esketamine contains only the S-enantiomer, which appears to be more potent.
It is typically administered as a nasal spray under the brand name Spravato. Unlike conventional antidepressants that affect serotonin and other monoamines, esketamine primarily influences glutamate, the brain’s main excitatory neurotransmitter. It blocks NMDA receptors on inhibitory interneurons, which can lead to increased excitatory signaling across brain networks.
This shift in the balance between excitation and inhibition is known as cortical disinhibition, and it’s thought to play a role in resetting dysfunctional brain circuits in depression. Esketamine reaches peak levels in the bloodstream within about 20 to 40 minutes of administration, and its effects unfold across multiple timescales—from immediate subjective changes to longer-term mood improvements.
Although esketamine has been shown to quickly reduce depressive symptoms, the precise brain mechanisms underlying these effects are not well understood. Prior research has often focused on intravenous ketamine in healthy participants, and few studies have used high-density electroencephalography (EEG) to track how esketamine influences brain activity over time in real-world clinical settings.
To address these gaps, senior author Tobias Schwippel and colleagues at the University of North Carolina at Chapel Hill and Michigan State University designed a study to examine how esketamine affects brain network activity and subjective experience in people with depression. They were particularly interested in how esketamine influenced both oscillatory brain rhythms (such as alpha, beta, delta, and gamma waves) and a type of background brain activity known as aperiodic signal, which may reflect the brain’s excitation-inhibition balance.
“Esketamine is increasingly used to treat depression. However, information on how brain networks react to this pharmacological intervention remains scarce,” explained Schwippel, who is currently affiliated with University Hospital Frankfurt at Goethe University. “We were especially interested in delineating how the experience of highness or detachment is reflected in change in brain waves (oscillations) which connect distant brain areas and orchestrate cognitive processes. Additionally, we investigated the hypothesis that (es)ketamine increases overall excitability in the brain.”
Eight adults with treatment-resistant major depressive disorder took part in the study during one of their routine esketamine treatment visits. Participants had previously received an average of 25 esketamine sessions. The research team recorded resting-state EEG from 128 scalp electrodes at six time points: once before and five times after nasal esketamine administration (up to 90 minutes later). During each recording, participants were asked to keep their eyes open and sit quietly.
At each time point, participants rated their current mood and drug-related experiences using visual analogue scales. These included feelings such as happiness, tension, and how “high” they felt. They also completed questionnaires assessing depression severity, anxiety, and quality of life. In addition, the researchers administered a side effects checklist to track physical and dissociative symptoms.
The EEG data were processed to separate oscillatory activity into standard frequency bands and to calculate the aperiodic exponent, which reflects how power decreases across frequencies and is thought to index cortical excitability.
Participants reported a noticeable shift in how they felt within minutes of receiving esketamine. Ratings of feeling “high” increased as early as 15 minutes post-administration, peaked at 35 minutes, and remained elevated for over an hour. Happiness also rose significantly at 15 and 35 minutes, while tension decreased at 35 minutes.
These self-reported effects were accompanied by distinct changes in brain activity. Alpha and beta waves—associated with top-down control, attention, and stability—were significantly reduced across wide areas of the scalp. Alpha power declined most strongly in parietal and frontal regions and remained suppressed throughout the 90-minute observation period. Beta power also dropped, particularly in central brain regions.
In contrast, delta and low gamma power increased. Delta waves, which are typically slow and associated with detachment or inward focus, rose in frontal midline regions. Low gamma activity, often linked to local neural excitation and information processing, increased in the left prefrontal cortex.
Aperiodic activity also shifted in a consistent way. The slope of the aperiodic signal became flatter—indicating a move toward increased excitation—starting 15 minutes after administration. This pattern lasted through the entire 90-minute window and was most prominent in frontal and central brain areas.
Importantly, the changes in EEG patterns were significantly related to how participants said they felt. Increased gamma and delta power—and decreased alpha, beta, and aperiodic exponent—were all linked to stronger reports of feeling high. Decreases in beta and increases in gamma also predicted lower tension. Changes in alpha, delta, and gamma activity were associated with increases in happiness.
“Our study shows that nasal esketamine rapidly affects brain activity and behavior in people with depression, with effects lasting up to 90 minutes,” Schwippel told PsyPost. “We observed increases in fast brain waves (gamma) and decreases in slower ones (alpha/beta), suggesting that the brain becomes more locally excitable while reducing the influence of top-down control mechanisms.
“Additionally, changes in background brain activity pointed to a shift in the balance between excitation and inhibition toward greater neural excitability. These brain changes were linked to how each person experienced the drug, supporting the idea that esketamine disrupts overly rigid brain networks, which may help alleviate depressive symptoms.”
Side effects peaked at 50 minutes, with participants reporting some dissociation, but these effects had mostly faded by the end of the 90-minute session.
“Our findings provide real-time evidence in humans that esketamine does more than just alter mood,” Schwippel said. “It rapidly and strongly reshapes brain network dynamics. The changes we observed align with the disinhibition hypothesis, suggesting that esketamine reduces the impact of the brain’s usual filtering and control systems. What’s particularly striking is that besides the observed changes in brain waves, the brain’s background excitability changed in a way that matches theories based on animal studies but had not been clearly shown in people until now.”
While the study provides insight into how esketamine shapes brain activity and subjective experience in people with depression, the findings should be interpreted with caution. The sample size was small, with only eight participants, and there was no placebo or control group. Participants also varied widely in their depression severity and treatment history, which could influence the results.
Despite these limitations, the study offers a unique look at the moment-by-moment neural dynamics of esketamine in a clinical population. The researchers suggest that future work could expand on these findings by including larger samples, examining cross-frequency coupling, and using more advanced analytical tools to explore network connectivity and complexity.
These results also raise the possibility that EEG markers—such as changes in alpha or gamma power, or shifts in the aperiodic exponent—could serve as biomarkers to track or predict individual responses to esketamine. Ultimately, such insights could help refine personalized treatments for depression and enhance our understanding of how brain stimulation and pharmacological interventions work at the network level.
“We want to explore how mental illnesses manifest through changes in the brain’s networks, which connect and coordinate activity across regions,” Schwippel explained. “These networks coordinate brain activity to produce stable patterns of function that underlie our thoughts and feelings. When network dynamics become disrupted, the brain can shift into dysfunctional patterns associated with symptoms of mental disorders.
“Different treatments affect these networks in distinct ways, leading to changes that help the brain move away from dysfunctional patterns or states. By comparing these effects, we aim to identify the mechanisms that support recovery at the network level. This approach opens the door to customizing therapies based on an individual’s unique brain network patterns and symptom profiles. For instance, our lab recently conducted a study in which brain stimulation was tailored in real-time to the ongoing brain activity of participants with depression.”
“This study was conducted under the guidance of Flavio Frohlich, PhD, at the Carolina Center for Neurostimulation at the University of North Carolina at Chapel Hill and represents the culmination of an undergraduate honors thesis by Verina Guirguis,” Schwippel added. “What makes it particularly special is that it reflects the collaborative effort of an undergraduate research team, highlighting the impact that dedicated students can have in contributing to scientific discoveries.”
The study, “Esketamine disinhibits brain networks in depression: Evidence from oscillatory and aperiodic activity,” Verina Guirguis, Sanvi Korsapathy, Francesca Pupillo, Robert K. McClure, David Zarzar, Mengsen Zhang, Flavio Frohlich, and Tobias Schwippel.
