Novel Combination Therapy For Improved Management of Depression

Background and Unmet Need

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 selfharm. In parallel, 30-50% of patients display inadequate responses or suffer from remission. Moreover, their longterm 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.

The Solution

Ketamine-based combination treatment to amplify the anti-depressive effect of Ketamine while minimizing side
effects

Technology Essence

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 KCNQactivator, 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.

Applications and Advantages

Combination therapy for ketamine-based antidepressants
Improved efficacy of ketamine-based antidepressant regimes, especially for treatment-resistant depression
Improved safety profile of ketamine-based antidepressant regimes

Development Status

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.

References

Lopez JP, Lücken MD, Brivio E, et al. Ketamine exerts its sustained antidepressant effects via cell-type-specific
regulation of Kcnq2. Neuron. Published online May 2022:S0896627322004093. doi:10.1016/j.neuron.2022.05.001
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