The rapid antidepressant effects of intranasal esketamine have changed expectations around how quickly severe depressive symptoms can respond to treatment. New interventional psychiatry research now suggests that some of these early clinical improvements may be accompanied by detectable changes in the brain’s electrical activity within just 24 hours.
Published in the Journal of Affective Disorders, the prospective study examined patients hospitalized with major depressive disorder and suicidal ideation or behavior. Rather than focusing only on symptom improvement, researchers used resting-state electroencephalography, or EEG, to investigate what might be changing in the brain during the earliest stage of treatment.
Why Rapid Response Needs Better Biological Measures
Major depressive disorder accompanied by suicidal ideation represents an especially urgent clinical challenge. Conventional oral antidepressants may require days or weeks to produce substantial improvement, leaving clinicians with a critical need for interventions capable of acting more quickly.
Intranasal esketamine has emerged as one rapid-acting option. Previous controlled studies have shown that adding esketamine to comprehensive standard care can produce greater improvement in depressive symptoms within hours or by the following day, although its specific effects on suicidality are more complex and have not been consistently separated from the effects of intensive standard care.
The next question is increasingly important: can clinicians identify objective brain-based signals that accompany this rapid clinical response?
Esketamine EEG Microstates Capture A Different Kind Of Brain Signal
The researchers enrolled 31 hospitalized patients between ages 18 and 64 with major depressive disorder and suicidal ideation or behavior. Participants received intranasal esketamine alongside standard clinical care. Clinical assessments and resting-state EEG recordings were collected before the first treatment and again 24 hours later.
The investigators compared two ways of analyzing EEG activity.
One was power spectral density, or PSD, which measures electrical activity across frequency bands including delta, theta, alpha, beta, and gamma. The other examined EEG microstates, brief periods in which the brain’s electrical activity forms relatively stable spatial configurations.
Microstates may offer a different window into brain function because they capture rapid transitions between large-scale neural states rather than simply measuring the strength of activity within particular frequency ranges.
Clinical Improvement Emerged Within One Day
The clinical findings were notable. Depressive symptoms improved significantly within 24 hours, with HAMD scores decreasing from 25.32 to 20.55 among paired complete cases.
At the same time, conventional whole-brain PSD measures did not show statistically significant changes after correction across the major frequency bands. EEG microstates told a different story.
Researchers detected early alterations in microstate organization, with microstate D showing particularly clear changes in occurrence and coverage. Transition patterns among several microstate classes also shifted after treatment.
This distinction matters because it suggests that some forms of EEG analysis may be more sensitive than others to the rapid neural changes associated with esketamine treatment.
From Symptom Scores To Network Reorganization
EEG microstates are often described as short-lived representations of coordinated whole-brain activity. Instead of treating the EEG signal as one continuous stream, microstate analysis divides it into recurring configurations that remain relatively stable for milliseconds before transitioning into another state.
Changes in their duration, frequency, coverage, or transitions may therefore provide information about how large-scale brain networks are reorganizing.
In this study, microstate measures detected changes when conventional spectral measures did not. The findings raise the possibility that rapid antidepressant response involves shifts in the temporal organization of distributed neural networks that may not be visible through standard frequency-based EEG measures alone.
A Candidate Biomarker, Not Yet A Clinical Test
The study is particularly interesting because it directly compared conventional EEG spectral analysis with a more dynamic microstate approach. Rather than assuming that a single EEG method would capture treatment effects, the researchers examined whether different analytical frameworks varied in sensitivity.
However, the results should remain preliminary. The study was conducted at a single center, the effective sample became smaller after EEG quality control and incomplete follow-up data, and there was no control group. As the authors note, these factors prevent the observed brain changes from being attributed specifically to esketamine.
The work therefore does not establish EEG microstates as a validated biomarker for treatment response.
Toward Faster Feedback In Interventional Psychiatry
The broader opportunity is the development of objective tools capable of tracking how the brain responds during rapid-acting psychiatric treatment.
If future controlled studies replicate these findings in larger populations, EEG microstates could potentially contribute to a more measurement-driven approach to esketamine treatment. Researchers could investigate whether early microstate changes predict later response, identify patients most likely to benefit, or distinguish transient neural effects from clinically meaningful network changes.
For now, the study provides an important proof of concept. Intranasal esketamine was associated with significant clinical improvement within 24 hours, while EEG microstate analysis detected neural changes that conventional spectral measures did not.
The next step is determining whether those signals can move from an intriguing research finding to a reproducible and clinically useful measure of rapid antidepressant response.
Citations
- Gu T, Zhang J, Wang R, et al. Rapid clinical and EEG microstate changes 24 h after intranasal esketamine in major depressive disorder with suicidal ideation: a prospective paired study. Journal of Affective Disorders. 2026. DOI: 10.1016/j.jad.2026.122307.https://pubmed.ncbi.nlm.nih.gov/42492692/
- Ionescu DF, Fu DJ, Qiu X, et al. Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II). International Journal of Neuropsychopharmacology. 2021;24(1):22-31. https://pubmed.ncbi.nlm.nih.gov/32861217/
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