Researchers have identified a molecular target that could extend the antidepressant effects of ketamine, offering a potential new strategy for treating treatment-resistant depression.

Treatment-resistant depression affects a significant proportion of patients with major depressive disorder, with around 30% failing to respond adequately to standard therapies. While ketamine has emerged as a fast-acting option, its clinical benefits are typically short-lived, often fading within days to weeks.

In a study published in Molecular Psychiatry, a research team from Yokohama City University investigated the biological mechanisms underlying this limited duration and identified NADPH oxidase-1 (NOX-1) as a key regulator of sustained antidepressant response.

The researchers focused on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, which are involved in excitatory signalling in the brain and are known to contribute to ketamine’s antidepressant effects. They developed a novel compound, K-4, designed to enhance receptor activity, and tested it in a rat model of treatment-resistant depression.

K-4 produced rapid antidepressant-like effects that persisted for at least two weeks after treatment ended, exceeding the duration typically observed with ketamine. Further analysis showed that this prolonged effect was associated with reduced levels of NOX-1 in the medial prefrontal cortex, a brain region linked to mood regulation.

To confirm the role of NOX-1, the team combined ketamine with a pharmacological inhibitor of the enzyme. This approach significantly extended the antidepressant-like effects compared with ketamine alone. Similar results were observed when NOX-1 expression was reduced using genetic techniques.

At a circuit level, both approaches reduced abnormal neuronal activity in the lateral habenula, a region associated with negative mood states, and restored balance in excitatory and inhibitory signalling in the medial prefrontal cortex.

Takuya Takahashi, professor at Yokohama City University, said: “Our findings shed light on novel molecular and circuit-level mechanisms, providing insights into potential strategies to sustain antidepressant efficacy.”

The findings point to two potential therapeutic strategies: combining ketamine with NOX-1 inhibitors to extend its clinical benefit, and developing AMPA receptor modulators such as K-4 as longer-acting antidepressants.

Interest in glutamate-based approaches to depression has grown in recent years, particularly for patients who do not respond to conventional therapies. However, maintaining durable treatment effects remains a key challenge.

The study adds to a growing body of research aimed at improving the longevity of rapid-acting antidepressants and could support future drug development efforts targeting both molecular and circuit-level mechanisms in depression.