Esmirtazapine (DB06678): A Comprehensive Monograph on an Investigational Tetracyclic Compound

1.0 Executive Summary

Esmirtazapine, identified by DrugBank ID DB06678 and developmental codes such as ORG-50,081 and SCH 900265, is the purified (S)-(+)-enantiomer of the well-established tetracyclic antidepressant mirtazapine.[1] Developed initially by Organon and later by Merck & Co., the compound was investigated as a novel therapeutic agent for primary insomnia and vasomotor symptoms (VMS) associated with menopause.[1] The central rationale for its development was based on a classic "chiral switch" strategy, aiming to leverage the distinct pharmacokinetic profile of the (S)-enantiomer. Esmirtazapine possesses a significantly shorter elimination half-life of approximately 10 hours compared to the 20-40 hours of its parent racemic mixture, a property hypothesized to reduce the incidence of next-day residual sedation, a common limiting side effect of sedative-hypnotics.[3]

Pharmacologically, Esmirtazapine shares the core mechanism of mirtazapine, acting as a potent antagonist at histamine H1 and serotonin 5-HT2 receptors and as an antagonist at presynaptic α2-adrenergic receptors.[3] This dual blockade of H1 and 5-HT2A receptors forms the basis of its strong sleep-promoting effects.[7]

The extensive Phase III clinical development program yielded a bifurcated efficacy profile. For the treatment of primary insomnia, Esmirtazapine demonstrated robust, consistent, and clinically meaningful efficacy, significantly improving objective and patient-reported measures of sleep onset, maintenance, and duration.[9] In contrast, its efficacy in reducing the frequency and severity of menopausal VMS was statistically significant but clinically modest, requiring higher doses to achieve limited benefit.[11]