Yokohama City University Researchers Identify NOX-1 Enzyme as Key to Extending Ketamine’s Antidepressant Effects

Researchers identify the NOX-1 enzyme as the key to making ketamine's antidepressant effects last longer, offering hope for treatment-resistant depression.

By: AXL Media

Published: Mar 30, 2026, 6:59 AM EDT

Source: Information for this report was sourced from Yokohama City University via EurekAlert!

Addressing the Limitations of Rapid-Acting Antidepressants

While ketamine has revolutionized the treatment of treatment-resistant depression by providing relief within hours, its clinical utility is hampered by a significant lack of durability. Most patients experience a return of depressive symptoms within days or weeks of a single dose, necessitating frequent and costly retreatments. Researchers at the Yokohama City University Graduate School of Medicine have now identified the molecular reasons for this "fading effect," pinpointing specific brain enzymes that regulate how long the drug remains effective.

The Role of NOX-1 in Mood Regulation

The study, led by Professor Takuya Takahashi and published in Molecular Psychiatry, identified NADPH oxidase-1 (NOX-1) as a primary culprit in the premature cessation of ketamine’s benefits. NOX-1 is an enzyme involved in producing reactive oxygen species which, when present in excess, can disrupt neural circuit functions. By using pharmacological inhibitors or genetic engineering to suppress NOX-1 in the medial prefrontal cortex, the team was able to significantly prolong the antidepressant-like effects of ketamine in laboratory models.

Development of the Novel K-4 Compound

A central element of the research involved the creation of K-4, a positive allosteric modulator designed to enhance the function of AMPA receptors. These receptors are critical for excitatory communication between neurons and are a known pathway for ketamine’s therapeutic action. Unlike existing treatments, K-4 demonstrated sustained antidepressant effects that lasted for at least two weeks after the final dose. This suggests that targeting AMPA receptors with more precision could lead to a new class of glutamate-based antidepressants that do not require frequent administration.