The dynamics of AMPA receptors underlies the efficacy of ketamine in treatment resistant patients with depression
Waki Nakajima, Mai Hatano, Yohei Ohtani, Hideaki Tani, Taisuke Yatomi, Shohei Tsuchimoto, Yu Fujimoto, Tsuyoshi Eiro, Sadamitsu Ichijo, Kotaro Nakano, Tetsu Arisawa, Yuuki Takada, Kimito Kimura, Hiroki Abe, Akane Sano, Kie Nomoto-Takahashi, Kengo Yonezawa, Sota Tomiyama, Nobuhiro Nagai, Keisuke Kusudo, Shiori Honda, Sotaro Moriyama, Shinichiro Nakajima, Takashige Yamada, Yu Iwabuchi, Masahiro Jinzaki, Kimio Yoshimura, Shariful A. Syed, Sakiko Tsugawa, Hiroyuki Uchida, Takuya Takahashi
Molecular Psychiatry March 5, 2026 DOI: 10.1038/s41380-026-03510-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort with intervention Peer reviewed |
|---|---|
| Population | Patients with treatment-resistant depression and healthy participants |
| Intervention | Ketamine |
| Topics | Depression Esketamine Ketamine |
| Citations | 1 |
| Key findings | AMPAR density changes in specific brain areas correlate with ketamine's antidepressant effect in treatment-resistant depression. |
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.