Treatment-resistant depression affects a large proportion of people with major depressive disorder, and while ketamine provides rapid symptom relief, its antidepressant effects wear off within a few weeks. Now, Japanese researchers have identified the enzyme NOX-1 as a key molecular target for sustaining ketamine’s antidepressant effects. Their findings shed light on important molecular and brain circuit mechanisms and point to new research directions for developing long-lasting treatments for depression.
Of the millions of people living with major depressive disorder, approximately 30% do not respond adequately to standard treatments. This condition, known as treatment-resistant depression (TRD), leaves patients with very limited treatment options and long-term suffering. Fortunately, ketamine, which has been used as an anesthetic for many years, has emerged as a true breakthrough drug for TRD patients. Unlike traditional antidepressants, which take weeks to take effect, ketamine can improve depression symptoms within hours, even in patients who have not responded to multiple previous treatments with other drugs.
Although the potential of ketamine is undeniable, the main drawback of ketamine is that its effects are not long-lasting. For most patients, the relief of symptoms disappears within days to weeks after a single dose. Although repeated dosing is effective, it also comes with practical challenges, including cost, clinic access, and long-term safety concerns. Various strategies have been tested to prolong the effects of ketamine, but none have been proven to be reliably effective. Furthermore, the biological reasons why ketamine’s antidepressant effects wear off so quickly remain poorly understood.
Against this background, a research team led by Professor Takuya Takahashi of the Department of Physiology, Graduate School of Medicine, Yokohama City University, together with Dr. Kazuaki Nakajima of the same university, investigated the molecular mechanisms in the brain that influence the antidepressant effects and duration of ketamine. Their research will be published online and molecular psychiatry The journal, March 23, 2026, identified a specific molecular target that could significantly extend the therapeutic effects of ketamine.
The research team focused on the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR), a protein in brain cells that mediates excitatory transmission between neurons and is known to play a role in the psychoactive effects of ketamine. They first developed a novel compound called K-4, a positive allosteric modulator of AMPAR. This means that it enhances AMPAR-mediated postsynaptic transmission. Next, they conducted experiments in Wistar Kyoto rats, a well-established animal model of TRD.
Remarkably, K-4 produced rapid antidepressant-like effects that persisted for at least 2 weeks after discontinuing the drug. This far exceeds what was seen with ketamine and other AMPAR-enhancing drugs. To understand why, 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 had lower levels of NADPH oxidase-1 (NOX-1), an enzyme involved in the production of reactive oxygen species that can excessively damage cells and disrupt brain circuit function.
This important finding pointed to NOX-1 as a potential regulator of the duration of antidepressant effects. To directly test this theory, the researchers combined ketamine with a pharmacological NOX-1 inhibitor and found that the combination significantly prolonged ketamine’s antidepressant-like effects compared to ketamine alone. They also selectively reduced NOX-1 expression in the mPFC by genetic engineering and achieved the same result.
At the circuit level, combining both K-4 and ketamine with NOX-1 inhibition reduced abnormal burst firing in the lateral habenula, a brain structure strongly associated with negative mood states. Moreover, these interventions restored the balance between excitatory and inhibitory neural circuits in the mPFC, a key mechanism underlying sustained antidepressant effects. ”Our findings shed light on new molecular and circuit-level mechanisms and provide insight into potential strategies to maintain antidepressant efficacy.” says Professor Takahashi.
Taken together, the results point to two specific directions for future development in this field. One is to combine ketamine with NOX-1 inhibitors as a strategy to prolong clinical efficacy, and the other is to advance K-4 or similar AMPAR modulators as a new class of long-acting antidepressants. ”This research has the potential to accelerate innovation in the pharmaceutical industry, particularly in the development of glutamate-based antidepressants and precision treatment strategies for TRD.” concluded Professor Takahashi.
For many patients who do not respond to current treatments for depression, this type of research is a meaningful step toward more permanent depression relief.
sauce:
Yokohama City University
Reference magazines:
Nakajima, W., others. (2026). Inhibition of NADPH oxidase 1 prolongs the antidepressant-like effects of ketamine. Molecular psychiatry. DOI: 10.1038/s41380-026-03527-1. https://www.nature.com/articles/s41380-026-03527-1
