Esmirtazapine Explained

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.^{[1] [2] [3]} Esmirtazapine is the (S)-(+)-enantiomer of mirtazapine and possesses similar overall pharmacology, including inverse agonist actions at H₁ and 5-HT₂ receptors and antagonist actions at α₂-adrenergic receptors.^{[1] [4]}

Notably, esmirtazapine has a shorter half life of 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-HT_2A antagonist.^[5] 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).^[6]

In March 2010, Merck terminated its internal clinical development program for esmirtazapine for hot flashes and insomnia, "for strategic reasons".^[7]

See also

• Cidoxepin

Notes and References

1. Web site: Future Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD . Neurotransmitter.net .
2. Teegarden BR, Al Shamma H, Xiong Y . 5-HT(2A) inverse-agonists for the treatment of insomnia . Current Topics in Medicinal Chemistry . 8 . 11 . 969–976 . 2008 . 18673166 . 10.2174/156802608784936700 .
3. Lewis V . Undertreatment of menopausal symptoms and novel options for comprehensive management . Current Medical Research and Opinion . 25 . 11 . 2689–2698 . November 2009 . 19775194 . 10.1185/03007990903240519 . 206964530 .
4. Book: Stahl SM . Antidepresents . Depression and bipolar disorder: Stahl's essential psychopharmacology . 3rd . Cambridge University Press . Cambridge, UK . 2008 . 978-0-521-88663-5 . https://books.google.com/books?id=zqvVZOea2JAC&q=esmirtazapine&pg=PA112.
5. Ivgy-May N, Ruwe F, Krystal A, Roth T . Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a randomized, 6-week sleep laboratory trial . Sleep Medicine . 16 . 7 . 838–844 . July 2015 . 26047892 . 10.1016/j.sleep.2015.04.001 .
6. Ivgy-May N, Hajak G, van Osta G, Braat S, Chang Q, Roth T . Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension . Journal of Clinical Sleep Medicine . 16 . 9 . 1455–1467 . September 2020 . 32351205 . 7970588 . 10.5664/jcsm.8526 .
7. Web site: Form 10-K . Merck & Co., Inc. . 2011-05-03 . 2011-08-05 . https://web.archive.org/web/20110805215529/http://www.merck.com/investors/financials/form-10-K-2009-final.pdf . dead .