Clinical data
Routes of
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Pharmacokinetic data
MetabolismLiver (CYP2D6)[2]
Elimination half-life10 hours[1]
  • (S)-1,2,3,4,10,14b-hexahydro-2-methylpyrazino(2,1-a)pyrido(2,3-c)(2)benzazepine
CAS Number
PubChem CID
ECHA InfoCard100.056.994 Edit this at Wikidata
Chemical and physical data
Molar mass265.360 g·mol−1
3D model (JSmol)
Melting point114 to 116 °C (237 to 241 °F)
Solubility in waterSoluble in methanol and chloroform 
  • CN1CCN2c3c(cccn3)Cc4ccccc4[C@H]2C1
  • InChI=1S/C17H19N3/c1-19-9-10-20-16(12-19)15-7-3-2-5-13(15)11-14-6-4-8-18-17(14)20/h2-8,16H,9-12H2,1H3/t16-/m1/s1 checkY
 ☒NcheckY (what is this?)  (verify)

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.[3][4][5][6] 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.[3][7]

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.[1] 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.[8][1] 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).[9]

In March 2010, Merck terminated its internal clinical development program for esmirtazapine for hot flashes and insomnia, "for strategic reasons".[10]

See also


  1. ^ a b c Ruwe F, IJzerman-Boon P, Roth T, Zammit G, Ivgy-May N (October 2016). "A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia". Journal of Clinical Psychopharmacology. 36 (5): 457–464. doi:10.1097/JCP.0000000000000546. PMID 27482970. S2CID 25639396.
  2. ^ Lillin-de Vries O, Kerbusch T, de Kam PJ, Ivgy-May N, Bursi R. "A population analysis on the effects of the CYP2D6 deficiency on pharmacokinetics and exposure of esmirtazapine in healthy volunteers" (PDF). Oss, The Netherlands: Schering-Plough Corporation.
  3. ^ a b "Future Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD".
  4. ^ Clinical trial number NCT00561574 for "A Long-Term Safety Study of Org 50081 in Elderly Outpatients With Chronic Primary Insomnia (176005)" at
  5. ^ Teegarden BR, Al Shamma H, Xiong Y (2008). "5-HT(2A) inverse-agonists for the treatment of insomnia". Current Topics in Medicinal Chemistry. 8 (11): 969–976. doi:10.2174/156802608784936700. PMID 18673166.
  6. ^ Lewis V (November 2009). "Undertreatment of menopausal symptoms and novel options for comprehensive management". Current Medical Research and Opinion. 25 (11): 2689–2698. doi:10.1185/03007990903240519. PMID 19775194. S2CID 206964530.
  7. ^ Stahl SM (2008). "Antidepresents". Depression and bipolar disorder: Stahl's essential psychopharmacology (3rd ed.). Cambridge, UK: Cambridge University Press. ISBN 978-0-521-88663-5.
  8. ^ Ivgy-May N, Ruwe F, Krystal A, Roth T (July 2015). "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. doi:10.1016/j.sleep.2015.04.001. PMID 26047892.
  9. ^ Ivgy-May N, Hajak G, van Osta G, Braat S, Chang Q, Roth T (September 2020). "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. doi:10.5664/jcsm.8526. PMC 7970588. PMID 32351205.
  10. ^ "Form 10-K" (PDF). Merck & Co., Inc. Archived from the original (PDF) on 2011-08-05. Retrieved 2011-05-03.