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

  • Mol Psychiatry. 2026 Jul;31(7):4192-4204. 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
  • 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. [email protected].
  • 6. The International Research Center for Neurointelligence, Institutes for Advanced Study, University of Tokyo, Tokyo, 113-8654, Japan. [email protected].
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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