A research team from Yokohama City University Graduate School of Medicine has used positron emission tomography (PET) imaging to investigate how ketamine acts as a rapid-acting antidepressant in people with treatment-resistant depression (TRD). The study, led by Professor Takuya Takahashi, was published on March 5, 2026, in the journal Molecular Psychiatry.
Major depressive disorder is a leading cause of disability worldwide. About 30% of patients do not respond well to standard antidepressant treatments and are considered to have TRD. Ketamine has shown effectiveness for these individuals, but its exact mechanism in the human brain had remained unclear until now.
"Although ketamine has shown rapid antidepressant effects in patients with treatment-resistant depression, its molecular mechanism in the human brain has remained unclear," said Prof. Takahashi.
The researchers employed an innovative PET tracer called [¹¹C]K-2 to visualize cell-surface AMPAR proteins in living human brains. AMPAR is involved in synaptic plasticity and glutamatergic signaling—processes linked to mood regulation. Previous animal studies suggested that ketamine’s antidepressant effects were tied to AMPAR activity, but this study is the first to directly show such changes in humans.
The investigation included data from three clinical trials conducted in Japan. It involved 34 patients with TRD and 49 healthy controls. Participants received either intravenous ketamine or a placebo over two weeks. PET scans were performed before and after the treatment period.
Findings revealed that people with TRD had significant abnormalities in AMPAR density across different brain regions compared with healthy participants. Ketamine treatment did not produce uniform changes throughout the brain; instead, improvements correlated with dynamic, region-specific shifts in AMPAR levels. Increases were seen in several cortical areas while decreases appeared notably within reward-related regions like the habenula. These specific changes aligned closely with reductions in depressive symptoms among participants.
"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."
The study suggests that PET imaging of AMPAR could serve as a biomarker for evaluating and predicting patient response to ketamine therapy—a development that could help address unmet needs for those who do not benefit from conventional treatments.
By visualizing molecular changes directly within living subjects, this work connects earlier preclinical findings from animal models to clinical outcomes observed during psychiatric care for depression resistant to standard therapies.
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