Major depressive disorder (MDD) is the third-leading cause of disease burden and the most common cause of disability and premature death in the general population. While clearly effective, available anti-depressive drugs are significantly limited by time-to-response of up to 8 weeks, a latency period that increases the risk of suicide and self-harm. In parallel, 30-50% of patients display inadequate responses or suffer from remission. Moreover, their long-term use is often associated with side effects that further increase the risk profile of this fragile patient population. In particular, a one-time intravenous dose of Ketamine, a potent glutamate N-methyl-D-aspartate (NMDA) receptor blocker, elicits a rapid and sustained antidepressant response, even among treatment-resistant patients, and effectively manages suicidal ideation. Spravato, an intranasal formulation of estketamine, was recently approved by the FDA for treatment-resistant depression. Yet, its chronic use is associated with hallucination, impaired sensory perception, and risk of addiction, raising concerns regarding its extensive use, particularly in unsupervised outpatient settings. Overall, these limitations increase the risk of self-harm and suicide in MDD patients, highlighting the dire need for fast-acting agents with an acceptable safety profile.

In their pursuit of the molecular basis of the anti-depressive effect of Ketamine, the team led by Prof. Alon Chen conducted a single-cell RNA sequencing of ventral hippocampus cells of mice treated with Ketamine. The team found that in response to Ketamine, the Kcnq2 gene is upregulated in glutamatergic neurons, generating a response that is characteristic of resilience to stress. The team found that Kcnq2 knockdown in the ventral hippocampus of mice eliminated the antidepressant effects of Ketamine, as measured by immobile time in a forced swim test. Similarly, its pharmacological inhibition with a selective and potent channel antagonist abolished the anti-depressive effect of Ketamine. In contrast, the coadministration of Ketamine and retigabine, a selective KCNQ-activator, augmented the anti-depressive effect of Ketamine in mice, as demonstrated by significantly less immobile time in a forced swim test as compared to untreated mice and mice treated with Ketamine only.1 Importantly, the combined treatment of Ketamine and retigabine can induce a potent antidepressant effect with relatively low doses of Ketamine, which would have otherwise been sub-efficacious. Therefore, the combination therapy could potentially reduce the current undesired side effects of Ketamine, at least partially.

The enhanced effectiveness of Ketamine in combination with KCNQ-agonists has been demonstrated ex-vivo in extracted glutamatergic neurons and validated in ex-vivo electrophysiological recording analyses, as well as in vivo by monitoring animal behavior following combination treatment with pharmacological agonists and antagonists.