by YCU Advanced Medical Research Center

A major drawback of ketamine when used as an antidepressant is that depressive symptoms often reappear within a few weeks. In this study, researchers found that NOX-1 inhibition could extend the antidepressant effects of ketamine. Moreover, a newly developed compound, called K-4, exhibited sustained antidepressant effects by acting as a positive modulator of AMPA receptors. Credit: Professor Takuya Takahashi, Yokohama City University Graduate School of Medicine, Japan

Treatment-resistant depression affects a large proportion of people with major depressive disorder, and while ketamine offers rapid relief, its antidepressant effects fade within a few weeks. Now, researchers from Japan have identified the enzyme NOX-1 as a key molecular target to prolong ketamine's antidepressant effects.

Their findings,publishedin the journalMolecular Psychiatry, shed light on key molecular and brain circuit mechanisms and point to new research directions for developing longer-lasting treatments for depression.

Among the millions of people living with major depressive disorder, nearly 30% of them do not respond adequately to standard treatments. This condition, known as treatment-resistant depression (TRD), leaves patients with very limited therapeutic options, facing prolonged suffering.

Fortunately, ketamine, a drug long used as an anesthetic, has emerged as a genuine breakthrough for people with TRD. Unlike conventional antidepressants that can take weeks to produce results, ketamine can lift depressive symptoms within hours, even in patients who did not respond to multiple prior treatments with other drugs.

Despite its undeniable potential, the main drawback of ketamine is that its benefits are short-lived. For most patients, relief fades within days to a couple of weeks after a single dose. While repeated dosing can help, this comes with its own set of practical challenges, such as cost, access to clinics, and concerns about long-term safety.

Various strategies have been tested to extend ketamine's effects, but none have proven reliably effective. Moreover, the biological reasons why ketamine's antidepressant effects wear off so quickly remain poorly understood.

Against this backdrop, a research team led by Professor Takuya Takahashi from the Department of Physiology, Yokohama City University Graduate School of Medicine, Japan, along with Dr. Waki Nakajima from the same university, investigated the molecular mechanisms in the brain that influence ketamine's antidepressant effects and duration.

Their study identified a specific molecular target that, when suppressed, can significantly prolong ketamine's therapeutic benefits.

How a new AMPAR drug behaves

The team focused on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs)—proteins in brain cells that mediate excitatory communication between neurons and are known to play a role in ketamine's psychoactive effects.

They first developed a novel compound calledK-4, a positive allosteric modulator of AMPARs, meaning that it enhances the AMPARs-mediated postsynaptic transmission. Then, they conducted experiments in Wistar Kyoto rats, a well-established animal model of TRD.

Notably, K-4 produced rapid antidepressant-like effects that persisted for at least two weeks after the drug was discontinued, which is well beyond what was seen with ketamine or other AMPAR-boosting drugs. To understand why, the researchers analyzedgene expressionin the medial prefrontal cortex (mPFC), a brain region central to mood regulation.

They found that rats treated with K-4 exhibited lower levels of NADPH oxidase-1 (NOX-1), an enzyme involved in the production of reactive oxygen species that, in excess, can damage cells and disrupt brain circuit function.

Zeroing in on NOX-1's role

This key finding pointed to NOX-1 as a potential regulator of the duration of antidepressant effects. To test this theory directly, the team combined ketamine with a pharmacological NOX-1 inhibitor and found that this combination significantly extended ketamine's antidepressant-like effects compared to ketamine alone. They also selectively reduced NOX-1 expression in the mPFC via genetic engineering, achieving the same result.

At the circuit level, both K-4 and ketamine combined with NOX-1 inhibition reducedabnormal burst firingin the lateral habenula, a brain structure strongly linked to negative mood states. Additionally, these interventions restored the balance of excitatory and inhibitory neural circuits in the mPFC, a key mechanism underlying the sustained antidepressant effects.

"Our findings shed light on novel molecular and circuit-level mechanisms, providing insights into potential strategies to sustain antidepressant efficacy," said Prof. Takahashi.

What this could mean for patients

Taken together, the results point to two concrete directions for future development in this field: combining ketamine with NOX-1 inhibitors as a strategy to prolong its clinical benefits, and advancing K-4 or similar AMPAR modulators as a new class of longer-lasting antidepressants.

"This work may accelerate innovation in the pharmaceutical industry, particularly in the development ofglutamate-based antidepressantsand precision treatment strategies for TRD," concludes Prof. Takahashi.

For the many patients for whom current treatments for depression fall short, this type of research represents a meaningful step toward more durable relief.

Publication details Waki Nakajima et al, NADPH oxidase-1 suppression prolongs the antidepressant-like effect of ketamine, Molecular Psychiatry (2026). DOI: 10.1038/s41380-026-03527-1 Journal information: Molecular Psychiatry