Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and approximately 30% of patients develop treatment-resistant depression (TRD), a condition that does not respond adequately to conventional antidepressant therapies. Although ketamine has emerged as a rapid-acting antidepressant for individuals with TRD, its underlying biological mechanism in the human brain has remained poorly understood, limiting efforts to optimize and personalize treatment.
In a new study published in the journal Molecular Psychiatry on March 05, 2026, a research team led by Professor Takuya Takahashi from the Department of Physiology, Yokohama City University Graduate School of Medicine, Japan, employed an innovative positron emission tomography (PET) imaging approach to directly examine changes in glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR), a key protein involved in synaptic plasticity and glutamatergic signaling, in patients receiving ketamine. Prof. Takahashi noted, “Although ketamine has shown rapid antidepressant effects in patients with treatment-resistant depression, its molecular mechanism in the human brain has remained unclear.”
This advance was made possible by the team’s previously developed PET tracer, [¹¹C]K-2, which enables visualization of cell-surface AMPAR in the living human brain. While preclinical studies have long suggested that ketamine’s antidepressant effects depend on AMPAR activity, this study provides the first direct evidence supporting this mechanism in humans.
The study integrated data from three registered clinical trials conducted in Japan and included 34 patients with TRD and 49 healthy control participants. Patients received intravenous ketamine or a placebo over a two-week period, with PET imaging performed before treatment initiation and after the final infusion.
Results revealed that individuals with TRD exhibited widespread, region-specific abnormalities in AMPAR density compared with healthy participants. Notably, ketamine did not induce uniform changes across the brain. Instead, clinical improvement was associated with dynamic, region-specific modulation of AMPAR. Increases in receptor density were observed in several cortical regions, while decreases were detected in reward-related areas, particularly the habenula. These region-specific changes were strongly correlated with reductions in depressive symptoms.
“Ketamine’s antidepressant effect in patients with TRD is mediated by dynamic changes in AMPAR in the living human brain,” Prof. Takahashi explained. “Using a novel PET tracer, [¹¹C]K-2, we were able to visualize how ketamine alters AMPAR distribution across specific brain regions and how these changes correlate with improvements in depressive symptoms.” These findings provide direct human evidence linking molecular mechanisms previously identified in animal models to clinical antidepressant effects.
Beyond advancing mechanistic understanding, the findings have important clinical implications. AMPAR PET imaging may represent a valuable biomarker for evaluating and predicting individual response to ketamine treatment in TRD. Given the substantial proportion of patients who do not benefit from standard antidepressants, the identification of such biomarkers addresses a critical unmet need in mental healthcare.
By directly visualizing AMPAR dynamics in the living human brain, this study bridges a longstanding gap between preclinical research and clinical psychiatry. The results establish AMPAR modulation as a central molecular mechanism underlying ketamine’s rapid antidepressant effects and highlight AMPAR PET imaging as a promising tool for guiding personalized treatment strategies. Ultimately, this work may accelerate the development of more precise, targeted therapies for individuals with treatment-resistant depression.
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Reference
DOI: 10.0.4.14/s41380-026-03510-w
About Yokohama City University
Located in the international city of Yokohama, Yokohama City University has 4 campuses, 5 schools, 6 graduate schools, 2 affiliated research centers, and 2 affiliated hospitals that serve as the bases for education, research, and medical care. Research emerging from Yokohama City University contributes to state-of-the-art technology with a global outlook. Aiming to contribute to the advancement of science and the global community, Yokohama City University also provides support to an array of global standard research programs.
About Professor Takuya Takahashi from Yokohama City University Graduate School of Medicine, Japan
Dr. Takuya Takahashi is a Professor at the Yokohama City University Graduate School of Medicine, Japan. His research group primarily studies AMPA receptors, plasticity, synapses, stress hormones, and the comprehensive brain networks. He has over 120 publications to his credit and received several research awards, including the Yokohama City University’s Chairman Award, National Alliance for Research’s Young Investigator Award, Tsukahara Nakaakira Memorial Award, and the Commendation for Science and Technology by the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Prof. Takahashi is a highly cited researcher, with work published in reputed journals such as Science, Cell, Scientific Reports, and Nature Medicine.
Funding information
This work was supported by the Ministry of Education, Culture, Sports, Science and Technology (Special Coordination Funds for Promoting Science and Technology); the Japan Agency for Medical Research and Development (AMED) (grant numbers: JP18dm0207023, JP19dm0207072, JP24wm0625304, JP25gm7010019, and JP20dm0107124); the Japan Society for the Promotion of Science KAKENHI (grant numbers: 22H03001, 20H00549, 20H05922, 23K10432, 19H03587, 20K20603, 22K15793, and 21K07508); the Takeda Science Foundation; the Keio Next-Generation Research Project Program; the SENSHIN Medical Research Foundation; and the Japan Research Foundation for Clinical Pharmacology.
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