Esmirtazapine (ORG-50,081) is a tetracyclic antidepressant drug that was under development by Organon for the treatment of insomnia and vasomotor symptoms (e.g., hot flashes) associated with menopause. Esmirtazapine is the (S)-(+)-enantiomer of mirtazapine and possesses similar overall pharmacology, including inverse agonist actions at H<sub>1</sub> and 5-HT<sub>2</sub> receptors and antagonist actions at ñ<sub>2</sub>-adrenergic receptors.
Notably, esmirtazapine has a shorter half life of around 10 hours, compared to R-mirtazapine and racemic mixture, which has a half-life of 18âÂÂ40 hours. Merck has run several studies on low dose (3âÂÂ4.5 mg) esmirtazapine for the treatment of insomnia. It is attractive for treating insomnia since it is a potent H<sub>1</sub>-inhibitor and a 5-HT<sub>2A</sub> 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).
In March 2010, Merck terminated its internal clinical development program for esmirtazapine for hot flashes and insomnia, "for strategic reasons".