Originally discovered through collaboration with
SAN2465 was rigorously tested in the chronic mild stress model of depression in the laboratory of Professor
The rapid antidepressant effect of esketamine is believed to stem from fast onset neuroplastic changes in molecular signaling cascades in relevant brain regions [4,5]. Similar changes have been observed through pharmacological negative allosteric modulation of the GABAA α5 receptors in rodent studies [5,6] suggesting that this mechanism could have a comparable rapid antidepressant effect in humans. Importantly, unlike NMDA receptor blockade with esketamine, negative modulation of GABAA α5 receptors is not anticipated to lead to significant adverse effects, as the expression of these receptors is more localized and mainly restricted to limbic areas [7,8]. Use of esketamine is restricted by a Risk Evaluation and Mitigation Strategy (REMS) Program.
Thomas Feldthus, CEO of
More about Major Depressive Disorder
Depressive disorders affect 280 million people globally and stand as the leading cause of disability [10]. Current conventional treatment relies on modulation of the monoaminergic system such as selective serotonin reuptake inhibitors, monoamine oxidase inhibitors and tricyclic antidepressants. However, existing conventional therapies exhibit delayed clinical responses, low remission rates, and a substantial portion of patients (more than 30%) do not respond adequately, leading to treatment-resistant depression [11]. In 2019, the FDA approved esketamine (Spravato™), the first prescription NMDA-antagonist-based fast-acting antidepressant. However, esketamine is associated with significant risks, including sedation, dissociation, respiratory depression, and abuse and misuse. Therefore, SPRAVATO® is only available through a restricted program called the SPRAVATO® Risk Evaluation and Mitigation Strategy (REMS) Program. Because of the risk associated with esketamine, there is a significant medical need for improved safe treatment options with rapid-onset and clinical response devoid of the use limitations associated with esketamine, in the large population of treatment-resistant patients.
1 Willner P, Neurobiol. Stress, 2017
2 Ionescu D.F et al., Int. J. Neuropsychopharmacol., 2021
3 Zarate C.A et al., Arch. Gen. Psychiat., 2006
4 Zanos P et al., eNeuro, 2017
5 Fischell J. Et al., Neuropsychopharmacol., 2016
6 Zanos P et al., J. Neurosci., 2023
7 Sur C et al.,
8 Atack J, Pharmacol. Therapeutics, 2010
9 https://www.spravato.com/
10
11 Zhdanava M et al., JclinPsychiat., 2021
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