Esmirtazapine (ORG-50,081) is a tetracyclic antidepressant drug that was under development by Organon for the treatment of insomnia, and for vasomotor symptoms associated with menopause (such as hot flashes) . Esmirtazapine is the (S)-(+)-enantiomer of mirtazapine; it has similar overall pharmacology as mirtazapine, including inverse agonist actions at H1 and 5-HT2 receptors, and antagonist actions at α2-adrenergic receptors.
Notably, esmirtazapine has a shorter half life )around 10 hours), compared to R-mirtazapine and racemic mixture, which has a half-life of 18–40 hours. Merck has run several studies on low dose (3–4.5 mg) esmirtazapine for the treatment of insomnia. It is attractive for treating insomnia since it is a potent H1-inhibitor and a 5-HT2A antagonist. Unlike low-dose mirtazapine, the half life (10 hours) is short enough that next-day sedation may be manageable, however, for people with CYP2D6 polymorphisms, which constitute a sizable fraction of the population, the half-life is expected to be quite a bit longer. Merck researchers claimed that the incidence of next-day sedation was not a problem in one of their studies, but this claim has been challenged (15% of patients complained of daytime sleepiness vs 3.5% in the placebo group).
Merck terminated its internal clinical development program In March 2010 for esmirtazapine "for strategic reasons".
See also List of investigational insomnia drugs Cidoxepin
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