Summary: Ketamine has been a miracle for the 30% of patients with treatment-resistant depression (TRD), lifting suicidal thoughts and heavy moods in hours rather than weeks. However, its “Achilles’ heel” is its fleeting nature—the effects usually vanish within days. A research team has finally cracked the code on why this relief fades.
The study identifies a specific enzyme, NOX-1, as the “off-switch” for ketamine’s benefits. By suppressing NOX-1 or using a new compound called K-4, researchers were able to extend the antidepressant effects from a few days to over two weeks in animal models.
Key Facts
- The NOX-1 Breakthrough: Researchers found that NOX-1 (an enzyme that produces reactive oxygen species) disrupts brain circuits and “shuts down” the antidepressant response. Inhibiting this enzyme keeps the “relief window” open longer.
- The K-4 Compound: The team developed a novel “AMPA receptor modulator” named K-4. Unlike current drugs, K-4 naturally keeps NOX-1 levels low, providing sustained relief for 14+ days after a single dose.
- Brain Circuit “Reset”: The treatment works by silencing abnormal “burst firing” in the lateral habenula (the brain’s “anti-reward” center) and restoring the balance of excitatory signals in the medial prefrontal cortex.
- Clinical Path: This discovery points to two future treatments: combining existing ketamine therapy with NOX-1 inhibitors, or developing K-4 as a brand-new class of long-lasting, glutamate-based antidepressants.
Source: Yokohama City University
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 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, published online in Molecular Psychiatry journal on March 23, 2026, identified a specific molecular target that, when suppressed, can significantly prolong ketamine’s therapeutic benefits.
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 called K-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 2 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 analyzed gene expression in 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.
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 reduced abnormal burst firing in 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,” remarks Prof. Takahashi.
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 of glutamate-based antidepressants and 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.
Funding information
This study was supported by JSPS KAKENHI Grant Numbers JP20H05922 (Takuya Takahashi), JP20H00549 (Takuya Takahashi), AMED Grant Numbers JP19dm0207072 (Takuya Takahashi), and the Takeda Science Foundation (Takuya Takahashi and T.Y.). This study was partially supported by AMED Grant Numbers (JP24wm0625304 (Takuya Takahashi) and JSPS KAKENHI Grant Numbers (JP23K10432 (Waki Nakajima), JP25K22755 (Susumu Jitsuki), JP24K02781 (Susumu Jitsuki).
Key Questions Answered:
A: Ketamine provides a rapid “reset” of brain connections, but the study found that the brain’s own chemistry—specifically the NOX-1 enzyme—creates oxidative stress that “re-breaks” those connections. By blocking NOX-1, we can essentially “lock in” the repairs ketamine makes.
A: Not exactly. K-4 is a different type of molecule (an AMPAR modulator) that enhances how brain cells communicate. The big difference is its staying power. In the study, K-4’s effects lasted at least two weeks, whereas traditional ketamine usually fades in less than seven days.
A: While the results in Wistar Kyoto rats (the gold standard for depression models) are incredibly promising, human clinical trials are the next step. Professor Takahashi believes this work will “accelerate innovation” in the pharmaceutical industry, potentially leading to new “extender” pills to take alongside ketamine within the next few years.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this psychopharmacology research news
Author: Public Relations Division
Source: Yokohama City University
Contact: Public Relations Division – Yokohama City University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“NADPH oxidase-1 suppression prolongs the antidepressant-like effect of Ketamine” by Waki Nakajima, Tetsu Arisawa, Susumu Jitsuki, Tomomi Yamanoue, Kaoru Fujikawa, Megumi Hara, Akane Sano, Yuuki Takada, Ryunosuke Iai, Kimito Kimura, Masataka Suzuki, Mai Hatano, Shariful A. Syed, Ayano Yajima, Minami Nagata, Taisuke Yatomi, Hiroki Abe & Takuya Takahashii. Molecular Psychiatry
DOI:10.1038/s41380-026-03527-1
Abstract
NADPH oxidase-1 suppression prolongs the antidepressant-like effect of Ketamine
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.
