The dynamics of AMPA receptors underlies the efficacy of ketamine in treatment resistant patients with depression
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, [<sup>11</sup>C]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.
Authors
- Shariful A. Syed (ORCID: https://orcid.org/0000-0002-8636-8089)
- Yuuki Takada
- Sadamitsu Ichijo (ORCID: https://orcid.org/0000-0001-8135-5740)
- Hiroki Abe (ORCID: https://orcid.org/0000-0001-7441-6664)
- Waki Nakajima (ORCID: https://orcid.org/0000-0002-2396-3112)
- Yu Fujimoto (ORCID: https://orcid.org/0000-0001-8475-0535)
- Mai Hatano
- Tetsu Arisawa (ORCID: https://orcid.org/0000-0001-7694-8728)
- Keisuke Kusudo
- Takashige Yamada (ORCID: https://orcid.org/0000-0002-1152-9853)
- Sotaro Moriyama
- Shiori Honda (ORCID: https://orcid.org/0000-0002-3756-0584)
- Shohei Tsuchimoto (ORCID: https://orcid.org/0000-0001-6545-5549)
- Yu Iwabuchi (ORCID: https://orcid.org/0000-0002-9259-6651)
- Tsuyoshi Eiro
- Akane Sano (ORCID: https://orcid.org/0000-0001-7381-031X)
- Nobuhiro Nagai (ORCID: https://orcid.org/0000-0002-2284-1287)
- Kimito Kimura
- Sota Tomiyama
- Masahiro Jinzaki
- Sakiko Tsugawa
- Kengo Yonezawa
- Kie Nomoto-Takahashi
- Hideaki Tani
- Shinichiro Nakajima
- Takuya Takahashi
- Kimio Yoshimura
- Yohei Ohtani
- Taisuke Yatomi
- Kotaro Nakano
- Hiroyuki Uchida
Institutions
- Keio University (JP)
- Stony Brook School (US)
- Sapporo Minami Hospital (JP)
- National Institute for Physiological Sciences (JP)
- Stony Brook University (US)
- The University of Tokyo (JP)
- Yokohama City University (JP)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2026-03-05
- DOI
- https://doi.org/10.1038/s41380-026-03510-w
- Primary Topic
- Treatment of Major Depression
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Research Foundation for Clinical Pharmacology
- Japan Agency for Medical Research and Development
- Keio University
- Ministry of Education, Culture, Sports, Science and Technology
- University of Miyazaki
- SENSHIN Medical Research Foundation
- Japan Society for the Promotion of Science