2. Academic Validation
  3. NADPH oxidase-1 suppression prolongs the antidepressant-like effect of ketamine

NADPH oxidase-1 suppression prolongs the antidepressant-like effect of ketamine

  • Mol Psychiatry. 2026 Mar 23. doi: 10.1038/s41380-026-03527-1.
Waki Nakajima 1,  Tetsu Arisawa 2,  Susumu Jitsuki 3,  Tomomi Yamanoue 1,  Kaoru Fujikawa 1,  Megumi Hara 1,  Akane Sano 1,  Yuuki Takada 1,  Ryunosuke Iai 1,  Kimito Kimura 1,  Masataka Suzuki 4,  Mai Hatano 1,  Shariful A Syed 1,  Ayano Yajima 1,  Minami Nagata 1,  Taisuke Yatomi 1,  Hiroki Abe 1,  Takuya Takahashi 5 6
Affiliations

Affiliations

  • 1 Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
  • 2 Radioisotope Research Center, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
  • 3 Department of Biochemistry, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan.
  • 4 Department of Microbiology, Harvard Medical School, Division of Infectious Diseases, Brigham & Women's Hospital, Boston, MA, 02115, USA.
  • 5 Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan. takahast@yokohama-cu.ac.jp.
  • 6 The International Research Center for Neurointelligence, Institutes for Advanced Study, University of Tokyo, Tokyo, 113-8654, Japan. takahast@yokohama-cu.ac.jp.
PMID: 41872515 DOI: 10.1038/s41380-026-03527-1
Abstract

Subanesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, produce rapid and robust antidepressant effects in patients with treatment-resistant depression (TRD). However, after a single administration, the therapeutic benefit is short-lived, and strategies to maintain its efficacy remain unclear. This study focused on the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), whose activation is known to be a key effector for the action of ketamine. Thus, we developed a novel positive allosteric modulator of AMPAR (K-4) with potential antidepressant-like effects. In Wistar Kyoto rats, a model of TRD, K-4 produced a more sustained antidepressant-like effect than ketamine. Bulk RNA Sequencing analysis revealed that K-4-treated rats showed lower expression of NADPH-oxidase-1 (NOX-1) in the medial prefrontal cortex (mPFC) than in ketamine-treated rats. Furthermore, simultaneous administration of a NOX-1 inhibitor with ketamine prolonged the antidepressant-like effect and reduced burst firing in the lateral habenula (LHb). Similarly, short hairpin RNA knockdown of NOX-1 in the mPFC sustained the antidepressant-like effects of ketamine and suppressed LHb bursting activity. These results indicate that NOX-1 suppression prolongs the antidepressant-like effect of ketamine and represents a promising target for maintenance strategies in TRD.

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