Mirtazapine

from Wikipedia, the free encyclopedia
Structural formula
Mirtazapine structural formula
( R ) -enantiomer (top) and ( S ) -enantiomer (bottom)
General
Non-proprietary name Mirtazapine
other names

( RS ) - (±) -2-methyl-1,2,3,4,10,14b-hexahydropyrazino [2,1- a ] pyrido [2,3- c ] [2] benzazepine ( IUPAC )

Molecular formula C 17 H 19 N 3
Brief description

white or almost white, slightly hygroscopic powder

External identifiers / databases
CAS number
  • 61337-67-5
  • 85650-52-8 [( RS ) -Mirtazapine]
  • 61364-37-2 [( R ) -Mirtazapine]
  • 61337-87-9 [( S ) -Mirtazapine]
EC number 288-060-6
ECHA InfoCard 100.080.027
PubChem 4205
ChemSpider 4060
DrugBank DB00370
Wikidata Q421930
Drug information
ATC code

N06 AX11

Drug class

antidepressant

Mechanism of action

α 2 adrenoceptor antagonist

properties
Molar mass 265,35 g · mol -1
Physical state

firmly

Melting point

114-116 ° C [( RS ) -Mirtazapine]

solubility

practically insoluble in water, easily soluble in absolute ethanol

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
Toxicological data

810 mg kg −1 ( LD 50 ,  mouse ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Mirtazapine is a drug from the group of noradrenergic and specifically serotonergic antidepressants ( NaSSA ). It is the pyridyl - analogue of mianserin and how this is the chemical structure according to the tetracyclic antidepressants counted. Mirtazapine was first patented by AkzoNobel ( Organon (Pharma) ) in 1976 .

pharmacology

Mirtazapine is a noradrenergic and specifically serotonergic antidepressant ( NaSSA ): It occupies specific binding sites for the messenger substances noradrenaline and serotonin in the brain and thus changes the influence of these on signal transmission in the brain. In particular, it indirectly increases the release of dopamine in the prefrontal cortex and noradrenergic transmission in cortical - limbic areas. The serotonin level is only marginally affected.

Active principle (pharmacodynamics)

In particular, mirtazapine blocks presynaptic adrenergic α 2A / C autoreceptors and serotonin receptors of the 5-HT 2A type . This causes a reduced inhibition by these autoreceptors or inhibitory heteroreceptors (5-HT 2A ) and thus presumably an increased release of noradrenaline and dopamine in parts of the brain. This could be verified in animal experiments. A relevant increase in serotonin release, however, could not be confirmed in studies and animal experiments. The substance also inhibits the serotonin receptors of the 5-HT 2C and 5-HT 3 types . Mirtazapine presumably acts as an agonist on the serotonin autoreceptors of the type 5-HT 1A and thus prevents an increase in serotonergic transmission mediated by α 2A / C blockade. Ultimately, the pronounced inhibitory effect on the H 1 receptor ensures the sedating properties of mirtazapine, especially in low doses.

There is only a weak affinity for cholinergic muscarinic synapses , which is why there are only slight anticholinergic or cardiovascular side effects. The resumption of norepinephrine, dopamine and serotonin is hardly affected due to a lack of sufficient affinity for their membrane transporters ; the affinity for β-adrenergic and dopaminergic synapses is also low. The effect of mirtazapine on opioid receptors was confirmed in a study by administering opioid antagonists. It has a high affinity for the κ 3 opioid receptor and, to a lesser extent, for the μ opioid receptor .

The receptor affinities are (specification of the dissociation constants (K i ) and the mean inhibitory concentration (IC 50 ) in nano or micro molar (nM or µM); molar = mol / liter ):

Mirtazapine has a very low affinity for the noradrenaline transporter and almost none for the serotonin and dopamine transporter and therefore does not act as a reuptake inhibitor:

  • Noradrenaline transporter (K i = 4.6 µM; IC 50 = 260 nM)
  • Serotonin transporter (K i > 10 µM)
  • Dopamine transporter (K i > 10 µM; IC 50 ≈1 µM)

The effect of mirtazapine is presumably mediated by its two enantiomers , but in a different way: While the ( S ) - ( + ) -enantiomer is responsible for the α 2 - and 5-HT 2 -receptor blockade, the ( R ) - (-) - Enantiomer the blockade of the 5-HT 3 receptor.

Metabolism (pharmacokinetics)

Mirtazapine is rapidly absorbed after oral administration , but is partially metabolized in the intestinal wall and in the liver before it enters the body's circulation (presystemic ). The highest plasma concentrations are reached after two hours at the latest; the bioavailability is about 50%. The metabolism, especially through N - demethylation , N - oxidation and 8 - hydroxylation , takes place primarily via the cytochrome P450 isoenzymes CYP2D6 and CYP3A4. When administered once a day, steady state is achieved within four to six days . The plasma half-life in adults is 20 to 40 hours. The main metabolite, demethyl-mirtazapine, has little pharmacological activity. The formation of other active metabolites is insignificant in terms of quantity.

The pharmacokinetic properties of mirtazapine are not identical for both enantiomers of the substance. The ( R ) - (-) - enantiomer has a longer plasma half-life than the ( S ) - (+) - enantiomer (approx. 18 vs. approx. 10 hours). A genetic CYP2D6 polymorphism also affects the two enantiomers differently. During the metabolism of ( R ) - (-) - enantiomer thereof is unaffected, has in so-called poor metabolisers (Engl. Poor metabolizers) with a much longer half-life for the ( S ) - enantiomer be expected - (+).

Clinical information

Application areas (indications)

Mirtazapine is approved in Germany and Switzerland only for the treatment of depressive illnesses .

Outside of the approved areas of application ( off-label use ), it is also used to treat generalized anxiety disorder (GAS), social phobia , panic disorder , winter depression (SAD) and sleep disorders . Mirtazapine is also used off-label in adjuvant pain therapy , with the available study data speaking in favor of the much better tested tricyclics such as amitriptyline . Mirtazapine can also be used off-label for the treatment of post-traumatic stress disorder . In severe cases, it may be more symptomatic than SSRIs .

Dosage forms

Mirtazapine exists as a commercial preparation in the form of film-coated tablets and orodispersible tablets as well as an oral solution. A parenteral application is possible with concentrate for preparation of infusion solution.

effectiveness

According to a benefit assessment by the Institute for Quality and Efficiency in Health Care (IQWiG), a benefit of mirtazapine compared to placebo for the antidepressant effect (response) in short-term acute therapy has been proven. There is no evidence of an additional benefit of mirtazapine in comparison with other antidepressants for the outcomes remission, response and mean change in depressive symptoms in short-term or long-term acute therapy, partly due to a lack of studies. There is also no proof of an added benefit of mirtazapine with regard to the social functioning level or health-related quality of life. In general, hardly any advantages or disadvantages were found in terms of reducing the degree of depression compared to other antidepressants that were recognized as effective, but in terms of improving sleep, mirtazapine was superior (due to its strong sedative effect).

unwanted effects

Particularly at the beginning of treatment, but also for the entire duration of use, it can lead to very severe tiredness and sluggishness, as mirtazapine has a sedative effect. Often (10%) weight gain due to increased appetite and edema is observed. Antidepressants can cause Restless Legs Syndrome (RLS), with up to a quarter of patients developing RLS after taking mirtazapine. An increase in cholesterol has also been reported. If the patient is stopped suddenly, symptoms (slight restlessness, temporary sleep disturbances, slight sweating) may occur.

Interactions

Mirtazapine may increase the depressant effects of alcohol, many benzodiazepines, and other sedative drugs on the central nervous system . Carbamazepine and phenytoin increase mirtazapine clearance two-fold, causing plasma mirtazapine concentrations to decrease by 45–60%. The dose of mirtazapine may need to be adjusted. Drug interactions can occur due to a slight inhibition of cytochrome P450 2D6 .

Use during pregnancy and breastfeeding

Sufficient data on the use of mirtazapine in pregnant women are not available, which has to be taken into account in the risk-benefit assessment. Animal studies have shown risks to the fetuses. Although only negligible amounts of mirtazapine passed into breast milk in animal experiments, the use of mirtazapine should be avoided during breastfeeding due to the lack of human studies.

Weaning problem

Suddenly stopping mirtazapine can lead to withdrawal symptoms . The severity of this withdrawal syndrome depends on both the duration of the previous treatment and the level of the daily dose. Mirtazapine is gradually withdrawn to reduce symptoms such as nausea, headache, anxiety, sleep disorders and restlessness .

Chemistry and stereoisomerism

Mirtazapine has a stereocenter on the benzylic carbon atom, so there are two stereoisomers : the ( R ) form and the mirror image ( S ) form. The finished medicinal products all contain the racemate [1: 1 mixture of the ( R ) form and the ( S ) form].

Trade names

Monopreparations : Remergil (Soltab) (D), Mirtazapin Aurobindo (Aurobindo Pharma GmbH) (D), Mirtabene, Mirtel (A), Remeron (CH), various generics

Web links

Individual evidence

  1. ↑ a b Data sheet MIRTAZAPINE CRS (PDF) at EDQM , accessed on January 22, 2009.
  2. ↑ a b c Entry on mirtazapine. In: Römpp Online . Georg Thieme Verlag, accessed on October 1, 2014.
  3. ↑ Mirtazapine data sheet from Sigma-Aldrich , accessed on April 10, 2011 ( PDF ).
  4. ↑ a b M. J. Millan et al .: Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of α 2 -adrenergic and serotonin 2C receptors: a comparison with citalopram . In: Eur. J. Neurosci. . 12, No. 3, March 2000, pp. 1079-1095. doi : 10.1046 / j.1460-9568.2000.00982.x . PMID 10762339 .
  5. ↑ a b Gillman, PK. (2006): A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. Hum Psychopharmacol. 21 (2): 117-25; PMID 16342227 .
  6. ↑ a b c d [1] - Mirtazapine - role in the treatment of depression (371 KB)
  7. ↑ a b K. Fukuyama et al .: Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study. . In: Psychopharmacology . 229, No. 4, 2013, pp. 617-626. doi : 10.1007 / s00213-013-3122-9 . PMID 23657423 .
  8. ↑ Shaul Schreiber, Avi Bleich and Chaim G. Pick: Venlafaxine and mirtazapine - Different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects — A possible opioid involvement in severe depression? . In: Journal of Molecular Neuroscience . 18, 2002, pp. 143-149. doi : 10.1385 / JMN: 18: 1-2: 143 .
  9. ↑ NIMH Psychoactive Drug Screening Program (PDSP): PDSP K i Database - Mirtazepine 5-HT 1A ( Memento from March 31, 2014 in the Internet Archive )
  10. ↑ A. Orjales et al .: Syntheses and binding studies of new [(aryl) (aryloxy) methyl] piperidine derivatives and related compounds as potential antidepressant drugs with high affinity for serotonin (5-HT) and norepinephrine (NE) transporters. . In: J Med Chem . 46, No. 25, 2003, pp. 5512-5532. doi : 10.1021 / jm0309349 . PMID 14640559 .
  11. ↑ HV Wikström et al .: Synthesis and pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo [c, f] pyrazino [1,2-a] azepine and its enantiomers in comparison with the two antidepressants mianserin and mirtazapine. . In: J Med Chem . 45, No. 15, 2002, pp. 3280-3285. PMID 12109911 .
  12. ^ T De Boer: The pharmacologic profile of mirtazapine . In: Journal of Clinical Psychiatry . 57 Suppl 4, 1996, pp. 19-25. PMID 8636062 .
  13. ↑ Kooyman AR, Zwart R, Vanderheijden PM, Van Hooft JA, Vijverberg HP: Interaction between enantiomers of mianserin and ORG3770 at 5-HT3 receptors in cultured mouse neuroblastoma cells . In: Neuropharmacology . 33, No. 3-4, 1994, pp. 501-7. doi : 10.1016 / 0028-3908 (94) 90081-7 . PMID 7984289 .
  14. ↑ a b c HV. Wikström, MM. Mensonides-Harsema, TI. Cremers, EK. Moltzen, J. Arnt: Synthesis and pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo [c, f] pyrazino [1,2-a] azepine and its enantiomers in comparison with the two antidepressants mianserin and mirtazapine. . In: J Med Chem . 45, No. 15, July 2002, pp. 3280-3285. PMID 12109911 .
  15. ↑ Unknown whether this is agonist or antagonist activity see - PMID = 15771415
  16. ↑ J. Fernández, JM Alonso, JI Andrés, JM Cid, A. Díaz, L. Iturrino, P. Gil, A. Megens, VK Sipido, AA Trabanco: Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents. In: Journal of medicinal chemistry. Volume 48, Number 6, March 2005, pp. 1709-1712, doi: 10.1021 / jm049632c . PMID 15771415 .
  17. ↑ NIMH Psychoactive Drug Screening Program (PDSP): PDSP K i Database - Mirtazepine Norepinephrine transporter
  18. ↑ NN. Bogolepov, TV. Vorob'eva, GS. Burd, NI. Pavlovskaia: [Changes in the mitochondria of human cerebral cortex nerve cells as the result of strokes]. . In: Zh Nevropatol Psikhiatr Im SS Korsakova . 75, No. 7, 1975, pp. 980-986. PMID 1210991 .
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  21. ↑ A. Orjales, R. Mosquera, A. Toledo, MC. Pumar, N. García, L. Cortizo, L. Labeaga, A. Innerárity: Syntheses and binding studies of new [(aryl) (aryloxy) methyl] piperidine derivatives and related compounds as potential antidepressant drugs with high affinity for serotonin (5- HT) and norepinephrine (NE) transporters. . In: J Med Chem . 46, No. 25, December 2003, pp. 5512-5532. doi : 10.1021 / jm0309349 . PMID 14640559 .
  22. ↑ Specialist information on mirtazapine: ( page no longer available , search in web archives: summary of the product characteristics ).@1@ 2Template: Dead Link / www.gl-pharma.at
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    • Boshuisen ML, Slaap BR, Vester-Blokland ED, den Boer JA: The effect of mirtazapine in panic disorder: an open label pilot study with a single-blind placebo run-in period . In: International Clinical Psychopharmacology . 16, No. 6, November 2001, pp. 363-368. doi : 10.1097 / 00004850-200111000-00008 . PMID 11712626 .
    • Carpenter LL, Leon Z, Yasmin S, Price LH: Clinical experience with mirtazapine in the treatment of panic disorder . In: Annals of Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists . 11, No. 2, June 1999, pp. 81-86. PMID 10440525 .
    • Carli V, Sarchiapone M, Camardese G, Romano L, DeRisio S: Mirtazapine in the treatment of panic disorder . In: Archives of General Psychiatry . 59, No. 7, July 2002, pp. 661-662. doi : 10.1001 / archpsyc.59.7.661 . PMID 12090820 .
    • Ribeiro L, Busnello JV, Kauer-Sant'Anna M, et al. : Mirtazapine versus fluoxetine in the treatment of panic disorder . In: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Médicas E Biológicas / Sociedade Brasileira De Biofísica… [et al.] . 34, No. 10, October 2001, pp. 1303-1307. PMID 11593305 .
  27. ↑ B. Hesselmann, A. Habeler, N. Praschak-Rieder, M. Willeit, A. Neumeister, S. Kasper: Mirtazapine in seasonal affective disorder (SAD): a preliminary report. In: Human Psychopharmacology: Clinical and Experimental. 14, 1999, p. 59, doi : 10.1002 / (SICI) 1099-1077 (199901) 14: 1% 3C59 :: AID-HUP67% 3E3.0.CO; 2-6 .
  28. ↑ Winokur A, DeMartinis NA, McNally DP, Gary EM, Cormier JL, Gary KA: Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia . In: The Journal of Clinical Psychiatry . 64, No. 10, October 2003, pp. 1224-1229. PMID 14658972 .
    • Kim SW, Shin IS, Kim JM, et al. : Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression . In: Psychiatry and Clinical Neurosciences . 62, No. 1, February 2008, pp. 75-83. doi : 10.1111 / j.1440-1819.2007.01778.x . PMID 18289144 .
    • Cankurtaran ES, Ozalp E, Soygur H, Akbiyik DI, Turhan L, Alkis N: Mirtazapine improves sleep and lower anxiety and depression in cancer patients: superiority over imipramine . In: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer . 16, No. 11, November 2008, pp. 1291-1298. doi : 10.1007 / s00520-008-0425-1 . PMID 18299900 .
  29. ↑ Korean J Psychopharmacol., December 2002; 13 (4): pp. 254-261. Korean.
    • Chung, MY. et al. (2004): Efficacy and tolerability of mirtazapine and sertraline in Korean veterans with posttraumatic stress disorder: a randomized open label trial. Hum. Psychopharmacol. 19 (7), pp. 489-494; PMID 15378676 .
    • Zohar, J. et al. (2002): Double-blind placebo-controlled pilot study of sertraline in military veterans with posttraumatic stress disorder. J. Clin. Psychopharmacol. 22 (2): 190-195; PMID 11910265 .
    • Davidson JR, Weisler RH, Butterfield MI, et al. : Mirtazapine vs. placebo in posttraumatic stress disorder: a pilot trial . In: Biological Psychiatry . 53, No. 2, January 2003, pp. 188-191. doi : 10.1016 / S0006-3223 (02) 01411-7 . PMID 12547477 .
    • Kim W, Pae CU, Chae JH, Jun TY, Bahk WM: The effectiveness of mirtazapine in the treatment of post-traumatic stress disorder: a 24-week continuation therapy . In: Psychiatry and Clinical Neurosciences . 59, No. 6, December 2005, pp. 743-747. doi : 10.1111 / j.1440-1819.2005.01447.x . PMID 16401254 .
    • Bahk WM, Pae CU, Tsoh J, et al. : Effects of mirtazapine in patients with post-traumatic stress disorder in Korea: a pilot study . In: Human Psychopharmacology . 17, No. 7, October 2002, pp. 341-344. doi : 10.1002 / hup.426 . PMID 12415552 .
    • Chung MY, Min KH, Jun YJ, Kim SS, Kim WC, Jun EM: Efficacy and tolerability of mirtazapine and sertraline in Korean veterans with posttraumatic stress disorder: a randomized open label trial . In: Human Psychopharmacology . 19, No. 7, October 2004, pp. 489-494. doi : 10.1002 / hup.615 . PMID 15378676 .
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  30. ↑ IQWiG: Final report A05-20C Bupropion, mirtazapine and reboxetine in the treatment of depression (version 1.1). Abstract of the final report A05-20C version 1.1
  31. ↑ Antidepressants: The benefit of reboxetine has not been proven. However, people with depression can benefit from bupropion XL and mirtazapine. Nov 24, 2009.
  32. ↑ T. Gallwitz, Restless Legs Syndrome as a side effect of "modern" antidepressants (PDF; 299 kB), dissertation, 2007
  33. ^ S. Perez-Lloret, MV Rey, E. Bondon-Guitton, O. Rascol, AJ Montastruc: Drugs associated with restless legs syndrome: a case / noncase study in the French pharmacovigilance database. In: Journal of clinical psychopharmacology. Volume 32, Number 6, December 2012, pp. 824-827, doi: 10.1097 / JCP.0b013e318272cdd8 . PMID 23131889 .
  34. ↑ Mitchell D. Feldman & John F. Christensen (Eds.): Behavioral Medicine: A Guide for Clinical Practice: A Practical Guide. Mcgraw Hill Medical; 3rd edition, 2007, p. 219.
  35. ^ Alan F. Schatzberg, u. a. (Ed.): Manual of Clinical Psychopharmacology. 6th edition, Amer Psychiatric Pub Inc 2007, p. 94.
  36. ^ Specialist information of the Swiss Medicines Compendium: Remeron®; Information as of December 2007.
  37. ↑ Package leaflet: mirtazapin-biomo 15 mg film-coated tablets; Status: 02/2008.
  38. ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 509.
  39. ↑ Swiss specialist information Remeron; Status: August 2006.