Ketamine and electroconvulsive therapy can produce substantial improvement in people with treatment-resistant depression, but researchers are still working to understand why some patients respond while others do not. New interventional psychiatry research suggests that part of the answer may eventually be found in patterns of gene activity detectable in the blood.
Published in Translational Psychiatry, the study examined whether peripheral blood gene expression could provide a practical window into the biological processes associated with ketamine and electroconvulsive therapy, or ECT. Rather than identifying dramatic molecular changes after treatment, the findings point toward a subtler possibility: biological differences present before treatment may prove more informative than changes measured afterward.
Searching For Biological Signals Behind Rapid Antidepressant Treatment
Treatment-resistant depression remains one of the most difficult forms of major depressive disorder to manage. When conventional antidepressant strategies do not provide adequate relief, interventions such as serial ketamine infusions and ECT can become important treatment options.
Both approaches can produce clinically meaningful antidepressant effects, yet clinicians still lack reliable biomarkers that can determine in advance which treatment is most likely to benefit an individual patient.
Blood-based biomarkers would be particularly attractive because blood collection is relatively accessible compared with brain imaging or other intensive biological assessments. The researchers therefore investigated whether RNA sequencing could reveal patterns of gene activity associated with treatment, diagnosis, or eventual clinical response.
How Researchers Studied Ketamine Gene Expression In Treatment-Resistant Depression
The analysis included 60 participants with treatment-resistant depression receiving serial ketamine infusions, 37 receiving ECT, and 35 non-depressed control participants. Blood samples were collected before treatment and at multiple follow-up points.
Researchers examined both individual genes and networks of genes that appeared to behave together. They used differential gene expression analysis alongside Weighted Gene Co-Expression Network Analysis, an approach designed to identify groups of co-regulated genes that may reflect broader biological processes.
This combination allowed the investigators to ask two related questions: Does successful treatment produce measurable changes in peripheral gene activity, and are molecular differences already present before treatment associated with who ultimately improves?
Large Treatment-Related Gene Expression Changes Were Not Detected
One of the study’s most important findings was also a cautionary one.
Despite clinical improvement associated with ketamine and ECT, researchers did not identify significant longitudinal changes in individual genes or gene networks after correcting for multiple statistical comparisons.
That result suggests that the antidepressant effects of these treatments may not produce a large, easily detectable transcriptional signature in peripheral blood, at least within the sample sizes and measurement strategy used in this study.
It also highlights an important distinction. Clinical improvement does not necessarily mean that a corresponding molecular change will be readily measurable in blood.
Pretreatment Biology May Hold More Information
The baseline findings were more intriguing.
Among participants receiving ketamine, researchers found evidence that immune-related biological functions differed between patients who later achieved remission and those who did not. One gene, IGKV1-9, showed a statistically significant baseline difference between these groups.
In the ECT cohort, researchers also identified several co-regulated gene modules that differed between patients and non-depressed controls before treatment.
These observations do not establish a clinically usable biomarker. Instead, they raise the possibility that a patient’s biological state before treatment could contain information relevant to subsequent antidepressant outcomes.
Previous research has reached related conclusions. A 2022 Translational Psychiatry study analyzing whole-blood RNA sequencing found baseline transcriptional differences involving interferon signaling in treatment-resistant depression and reported that genes involved in glutamate signaling differed between eventual ketamine responders and nonresponders.
Why Peripheral Blood May Tell Only Part Of The Story
Ketamine’s antidepressant effects are thought to involve complex changes across glutamatergic signaling, synaptic plasticity, neural circuitry, and potentially immune pathways. ECT similarly produces widespread neurobiological effects that cannot be reduced to a single mechanism.
Peripheral blood RNA therefore represents only one biological layer.
The absence of large longitudinal transcriptional changes does not imply that ketamine or ECT lacks molecular effects. Instead, some of the most relevant changes may occur within the brain, involve proteins rather than RNA, appear only temporarily, or differ substantially between individuals.
A Step Toward More Personalized Interventional Psychiatry
What distinguishes this study is its direct comparison of longitudinal transcriptional profiles across two established interventions for treatment-resistant depression while also examining pretreatment differences associated with outcome.
The findings shift attention toward prediction rather than simply measuring what changes after treatment.
If future larger studies identify reproducible pretreatment molecular signatures, blood-based information could potentially become one component of a broader precision psychiatry framework incorporating clinical characteristics, neuroimaging, electrophysiology, genetics, and other biomarkers.
For now, the results remain exploratory. They do not provide a blood test capable of selecting ketamine or ECT for an individual patient. They do, however, reinforce an increasingly important direction for the field: understanding the biology patients bring into treatment may ultimately be as valuable as measuring what changes afterward.
Citations
- Zavaliangos-Petropulu A, Ghang G, Boltz T, et al. “Transcriptional profiling of antidepressant ketamine and electroconvulsive therapy treatment.” Translational Psychiatry. Published August 5, 2026. DOI: 10.1038/s41398-026-04196-y. https://www.nature.com/articles/s41398-026-04196-y
- Cathomas F, Bevilacqua L, Ramakrishnan A, et al. “Whole blood transcriptional signatures associated with rapid antidepressant response to ketamine in patients with treatment resistant depression.” Translational Psychiatry. 2022;12:12. DOI: 10.1038/s41398-021-01712-0. https://www.nature.com/articles/s41398-021-01712-0
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