The dynamics of AMPA receptors underlies the efficacy of ketamine in treatment resistant patients with depression
Molecular Psychiatry – March 05, 2026
Source: OpenAlex
Summary
Approximately 30% of patients with depression experience treatment-resistant depression (TRD), but ketamine offers hope. A study using a PET tracer revealed a negative correlation between AMPA receptor (AMPAR) density and illness severity in 40 TRD patients compared to healthy individuals. Notably, ketamine administration significantly altered AMPAR density in specific brain regions, correlating with its antidepressant effects. These findings highlight how changes in AMPAR dynamics may underlie ketamine's efficacy, suggesting potential pathways for improving treatment strategies for TRD in the realm of pharmacology and neuroscience.
Abstract
Approximately 30% of patients with depression suffer from treatment-resistant depression (TRD). Ketamine has shown antidepressant efficacy for TRD. While glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) has been demonstrated to play crucial roles in the process of pharmacological action of ketamine in experimental animals, it remains elusive how ketamine exhibits its efficacy through changes in AMPAR dynamics in patients with TRD. In this study, using a positron emission tomography (PET) tracer, [11C]K-2, which depicts AMPAR density in the living human brain, we detected a negative correlation between AMPAR density and illness severity and differences in AMPAR distribution between patients with TRD and healthy participants. Furthermore, we detected brain areas where ketamine administration altered AMPAR density in significant correlations with ketamine-induced antidepressant effect in patients with TRD. AMPAR density alteration in these regions partially rescued AMPAR phenotype in the affected areas. Thus, AMPAR dynamics underlies the antidepressant effect of ketamine in patients with TRD.