Mirtazapine: Difference between revisions

Mirtazapine was developed in the Netherlands and introduced in the United States in 1996.<ref> "REMERON (mirtazapine) tablet, film coated [Organon Pharmaceuticals USA]". DailyMed. Organon Pharmaceuticals USA. October 2012. Retrieved 24 October 2013.</ref> Its patent expired in 2004 and generic versions have been widely available since.<ref name="Schatzberg">{{cite book | vauthors=((Schatzberg, A. F.)), ((Cole, J. O.)), ((DeBattista, C.)) | date= 2010 | title=Manual of clinical psychopharmacology | publisher=American Psychiatric Pub | volume=3 | edition=7th ed | isbn=9781585623778}}</ref> It is used primarily in the treatment of major depressive disorder and other mood disorders.<ref>{{cite journal | vauthors=((Gorman, J. M.)) | journal=The Journal of Clinical Psychiatry | title=Mirtazapine: clinical overview | volume=60 Suppl 17 | pages=9–13; discussion 46-48 | date= 1999 | issn=0160-6689}}</ref><ref>{{cite journal | journal=Expert Opinion on Pharmacotherapy | title=Review of the use of mirtazapine in the treatment of depression | url=https://informahealthcare.com/doi/abs/10.1517/14656566.2011.585459}}</ref> It has also been prescribed off-label for the treatment of  

generalized anxiety disorder,<ref name="Anttila2006">{{cite journal | vauthors=((Anttila, S. A. K.)), ((Leinonen, E. V. J.)) | journal=CNS Drug Reviews | title=A Review of the Pharmacological and Clinical Profile of Mirtazapine | volume=7 | issue=3 | pages=249–264 | date=7 June 2006 | url=https://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2001.tb00198.x | issn=1080563X | doi=10.1111/j.1527-3458.2001.tb00198.x}}</ref> social anxiety disorder,<ref name="Croom2009">{{cite journal | vauthors=((Croom, K. F.)), ((Perry, C. M.)), ((Plosker, G. L.)) | journal=CNS Drugs | title=Mirtazapine | volume=23 | issue=5 | pages=427–452 | date=1 May 2009 | url=https://doi.org/10.2165/00023210-200923050-00006 | issn=1179-1934 | doi=10.2165/00023210-200923050-00006}}</ref><ref>{{cite journal | vauthors=((Muehlbacher, M.)), ((Nickel, M. K.)), ((Nickel, C.)), ((Kettler, C.)), ((Lahmann, C.)), ((Gil, F. P.)), ((Leiberich, P. K.)), ((Rother, N.)), ((Bachler, E.)), ((Fartacek, R.)), ((Kaplan, P.)), ((Tritt, K.)), ((Mitterlehner, F.)), ((Anvar, J.)), ((Rother, W. K.)), ((Loew, T. H.)), ((Egger, C.)) | journal=Journal of Clinical Psychopharmacology | title=Mirtazapine Treatment of Social Phobia in Women: A Randomized, Double-Blind, Placebo-Controlled Study | volume=25 | issue=6 | pages=580–583 | date= December 2005 | url=http://journals.lww.com/00004714-200512000-00015 | issn=0271-0749 | doi=10.1097/01.jcp.0000186871.04984.8d}}</ref> obsessive-compulsive disorder,<ref name="Croom2009"/><ref>Mirtazapine Treatment of Obsessive-Compulsive Disorder | http://journals.lww.com/psychopharmacology/Citation/2001/10000/Mirtazapine_Treatment_of_Obsessive_Compulsive.16.aspx</ref> panic disorder,<ref name="Croom2009"/><ref name="Carpenter1999">{{cite journal | vauthors=((Carpenter, L.)), ((Leon, Z.)), ((Yasmin, S.)), ((Price, L.)) | journal=Annals of Clinical Psychiatry | title=Clinical Experience with Mirtazapine in the Treatment of Panic Disorder | volume=11 | issue=2 | pages=81–86 | date=1 June 1999 | issn=1040-1237 | doi=10.3109/10401239909147053}}</ref> post-traumatic stress disorder,<ref name="Croom2009"/> low appetite,<ref>{{cite journal | vauthors=((Landowski, J.)) | journal=Psychiatria Polska | title=[Mirtazapine--an antidepressant] | volume=36 | issue=6 Suppl | pages=125–130 | date= December 2002 | issn=0033-2674}}</ref><ref>{{cite journal | vauthors=((Chinuck, R. S.)), ((Fortnum, H.)), ((Baldwin, D. R.)) | journal=Journal of Human Nutrition and Dietetics | title=Appetite stimulants in cystic fibrosis: a systematic review | volume=20 | issue=6 | pages=526–537 | date= December 2007 | url=https://onlinelibrary.wiley.com/doi/10.1111/j.1365-277X.2007.00824.x | issn=0952-3871 | doi=10.1111/j.1365-277X.2007.00824.x}}</ref><ref>{{cite journal | journal=Expert Review of Anticancer Therapy | title=Management of symptons associated with advanced cancer: olanzapine and mirtazapine | url=https://informahealthcare.com/doi/abs/10.1586/14737140.2.4.365}}</ref> insomnia,<ref>{{cite journal | vauthors=((Hartmann, P. M.)) | journal=American Family Physician | title=Mirtazapine: a newer antidepressant | volume=59 | issue=1 | pages=159–161 | date=1 January 1999 | issn=0002-838X}}</ref><ref>{{cite journal | vauthors=((Jindal, R. D.)) | journal=CNS Drugs | title=Insomnia in Patients with Depression | volume=23 | issue=4 | pages=309–329 | date=1 April 2009 | url=https://doi.org/10.2165/00023210-200923040-00004 | issn=1179-1934 | doi=10.2165/00023210-200923040-00004}}</ref> nausea/vomiting,<ref>{{cite journal | vauthors=((Nutt, D. J.)) | journal=Human Psychopharmacology: Clinical and Experimental | title=Tolerability and safety aspects of mirtazapine | volume=17 | issue=S1 | pages=S37–S41 | date= June 2002 | url=https://onlinelibrary.wiley.com/doi/10.1002/hup.388 | issn=0885-6222 | doi=10.1002/hup.388}}</ref><ref name="Li2011">{{cite journal | vauthors=((Li, T.-C.)), ((Shiah, I.-S.)), ((Sun, C.-J.)), ((Tzang, R.-F.)), ((Huang, K.-C.)), ((Lee, W.-K.)) | journal=The Journal of ECT | title=Mirtazapine Relieves Post-Electroconvulsive Therapy Headaches and Nausea: A Case Series and Review of the Literature | volume=27 | issue=2 | pages=165–167 | date= June 2011 | url=https://journals.lww.com/00124509-201106000-00016 | issn=1095-0680 | doi=10.1097/YCT.0b013e3181e63346}}</ref><ref>{{cite journal | vauthors=((Kast, R. E.)), ((Foley, K. F.)) | journal=European Journal of Cancer Care | title=Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects | volume=16 | issue=4 | pages=351–354 | date= July 2007 | url=https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2354.2006.00760.x | issn=0961-5423 | doi=10.1111/j.1365-2354.2006.00760.x}}</ref>  

itching,<ref>{{cite journal | vauthors=((Twycross, R.)) | journal=QJM | title=Itch: scratching more than the surface | volume=96 | issue=1 | pages=7–26 | date=1 January 2003 | url=https://academic.oup.com/qjmed/article-lookup/doi/10.1093/qjmed/hcg002 | issn=14602393 | doi=10.1093/qjmed/hcg002}}</ref><ref>{{cite journal | vauthors=((Greaves, M. W.)) | journal=Dermatologic Therapy | title=Itch in systemic disease: therapeutic options: Itch in systemic disease | volume=18 | issue=4 | pages=323–327 | date=17 November 2005 | url=https://onlinelibrary.wiley.com/doi/10.1111/j.1529-8019.2005.00036.x | issn=13960296 | doi=10.1111/j.1529-8019.2005.00036.x}}</ref> and headaches and migraines.<ref name="Li2011"/><ref>{{cite journal | vauthors=((Colombo, B.)), ((Annovazzi, P. O. L.)), ((Comi, G.)) | journal=Neurological Sciences | title=Therapy of primary headaches: the role of antidepressants | volume=25 | issue=3 | pages=s171–s175 | date=1 October 2004 | url=https://doi.org/10.1007/s10072-004-0280-x | issn=1590-3478 | doi=10.1007/s10072-004-0280-x}}</ref><ref>{{cite journal | vauthors=((Tajti, J.)), ((Almási, J.)) | journal=Neuropsychopharmacologia Hungarica: A Magyar Pszichofarmakologiai Egyesulet Lapja = Official Journal of the Hungarian Association of Psychopharmacology | title=[Effects of mirtazapine in patients with chronic tension-type headache. Literature review] | volume=8 | issue=2 | pages=67–72 | date= June 2006 | issn=1419-8711}}</ref>

Mirtazapine enhances central adrenergic and serotonergic transmission, possibly by acting as an antagonist at central presynaptic alpha 2 adrenergic inhibitory autoreceptors and heteroreceptors. This agent is a potent antagonist of 5-hydroxytryptamine type 2 (5-HT2), 5-HT3, and histamine 1 (H1) receptors, and a moderate antagonist of peripheral alpha 1 adrenergic and muscarinic receptors.<ref>{{Citation | title=NCI Thesaurus - Mirtazapine (Code C29265) | url=https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C29265}}</ref>  

Mirtazapine acts as an [[antagonist]]/inverse agonist upon the following receptors:<ref name="Fernandez2005">{{cite journal | vauthors=((Fernández, J.)), ((Alonso, J. M.)), ((Andrés, J. I.)), ((Cid, J. M.)), ((Díaz, A.)), ((Iturrino, L.)), ((Gil, P.)), ((Megens, A.)), ((Sipido, V. K.)), ((Trabanco, A. A.)) | journal=Journal of Medicinal Chemistry | title=Discovery of New Tetracyclic Tetrahydrofuran Derivatives as Potential Broad-Spectrum Psychotropic Agents | volume=48 | issue=6 | pages=1709–1712 | date=1 March 2005 | url=https://pubs.acs.org/doi/10.1021/jm049632c | issn=0022-2623 | doi=10.1021/jm049632c}}</ref><ref>{{cite journal | vauthors=((Boer, Th. de)), ((Maura, G.)), ((Raiteri, M.)), ((Vos, C. J. de)), ((Wieringa, J.)), ((Pinder, R. M.)) | journal=Neuropharmacology | title=Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, org 3770 and its enantiomers | volume=27 | issue=4 | pages=399–408 | date=1 April 1988 | url=https://www.sciencedirect.com/science/article/pii/0028390888901499 | issn=0028-3908 | doi=10.1016/0028-3908(88)90149-9}}</ref>

*[[serotonin|5-HT_2A receptor]]<ref name="Fernandez2005"/>

*5-HT_2B receptor<ref>{{cite journal | vauthors=((Boer, T. de)) | journal=The Journal of Clinical Psychiatry | title=The pharmacologic profile of mirtazapine | volume=57 Suppl 4 | pages=19–25 | date= 1996 | issn=0160-6689}}</ref>

*5-HT_2C receptor<ref name="Fernandez2005"/>

*[[adrenaline|α₁-adrenergic receptor]]<ref name="Goodman2011">{{cite book | veditors=((Goodman, L. S.)), ((Brunton, L. L.)), ((Chabner, B.)), ((Knollmann, B. C.)) | date= 2011 | title=Goodman & Gilman’s pharmacological basis of therapeutics | publisher=McGraw-Hill | edition=12th ed | isbn=9780071624428}}</ref>

*α_2A-adrenergic receptor<ref name="TGAeBS">{{Citation | title=TGA eBS - Product and Consumer Medicine Information Licence | url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05345-3}}</ref>

*α_2B-adrenergic receptor<ref>{{cite journal | vauthors=((Kennis, L. E.)), ((Bischoff, F. P.)), ((Mertens, C. J.)), ((Love, C. J.)), ((Van den Keybus, F. A.)), ((Pieters, S.)), ((Braeken, M.)), ((Megens, A. A.)), ((Leysen, J. E.)) | journal=Bioorganic & Medicinal Chemistry Letters | title=New 2-substituted 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine having highly active and potent central alpha 2-antagonistic activity as potential antidepressants | volume=10 | issue=1 | pages=71–74 | date=3 January 2000 | issn=0960-894X | doi=10.1016/s0960-894x(99)00591-0}}</ref>

*α_2C-adrenergic receptor<ref name="TGAeBS"/>

*H₁ receptor<ref>{{cite journal | vauthors=((Wikström, H. V.)), ((Mensonides-Harsema, M. M.)), ((Cremers, T. I. F. H.)), ((Moltzen, E. K.)), ((Arnt, J.)) | journal=Journal of Medicinal Chemistry | title=Synthesis and Pharmacological Testing of 1,2,3,4,10,14b-Hexahydro-6-methoxy-2-methyldibenzo[ c , f ]pyrazino[1,2- a ]azepin and Its Enantiomers in Comparison with the Two Antidepressants Mianserin and Mirtazapine | volume=45 | issue=15 | pages=3280–3285 | date=1 July 2002 | url=https://pubs.acs.org/doi/10.1021/jm010566d | issn=0022-2623 | doi=10.1021/jm010566d}}</ref>

*[[acetylcholine|mACH receptors]]<ref name="Goodman2011"/>

While mirtazapine has some affinity for the 5-HT_2A receptor, it acts as an [[antagonist]]<ref name="Anttila2006"/> thus it is unlikely that this mechanism is responsible for its [[psychedelic]] and [[deliriant]] effects.

*[[Opioid]] receptor κ₃<ref>{{cite journal | vauthors=((Schreiber, S.)), ((Rigai, T.)), ((Katz, Y.)), ((Pick, C. G.)) | journal=Brain Research Bulletin | title=The antinociceptive effect of mirtazapine in mice is mediated through serotonergic, noradrenergic and opioid mechanisms | volume=58 | issue=6 | pages=601–605 | date= September 2002 | url=https://linkinghub.elsevier.com/retrieve/pii/S0361923002008250 | issn=03619230 | doi=10.1016/S0361-9230(02)00825-0}}</ref>

Mirtazapine has also been found to modulate the κ₃ opioid receptor, supporting the claim that mirtazapine causes pain relief<ref>{{cite journal | vauthors=((Dapoigny, M.)), ((Abitbol, J. L.)), ((Fraitag, B.)) | journal=Digestive Diseases and Sciences | title=Efficacy of peripheral kappa agonist fedotozine versus placebo in treatment of irritable bowel syndrome. A multicenter dose-response study | volume=40 | issue=10 | pages=2244–2249 | date= October 1995 | issn=0163-2116 | doi=10.1007/BF02209014}}</ref> and adds to the [[sedative]] and [[hallucinogenic]] effects of mirtazapine<ref>{{cite journal | vauthors=((Pande, A. C.)), ((Pyke, R. E.)), ((Greiner, M.)), ((Wideman, G. L.)), ((Benjamin, R.)), ((Pierce, M. W.)) | journal=Clinical Neuropharmacology | title=Analgesic efficacy of enadoline versus placebo or morphine in postsurgical pain | volume=19 | issue=5 | pages=451–456 | date= October 1996 | issn=0362-5664 | doi=10.1097/00002826-199619050-00009}}</ref><ref>{{cite journal | vauthors=((Rimoy, G. H.)), ((Wright, D. M.)), ((Bhaskar, N. K.)), ((Rubin, P. C.)) | journal=European Journal of Clinical Pharmacology | title=The cardiovascular and central nervous system effects in the human of U-62066E. A selective opioid receptor agonist | volume=46 | issue=3 | pages=203–207 | date= 1994 | issn=0031-6970 | doi=10.1007/BF00192549}}</ref>. This even may explain mirtazapine's withdrawal/discontinuation effects as well as its promotion of diuresis and a possible increase in food intake (usually resulting in weight gain).

The oral bioavailability of mirtazapine is about 50%. It is found mostly bound to plasma proteins, about 85%. It is metabolized primarily in the liver by demethylation and hydroxylation via cytochrome P450 enzymes, CYP1A2, CYP2D6, CYP3A4.<ref name="Anttila2006"/> One of its major metabolites is desmethylmirtazapine. The overall elimination half-life is 20–40 hours. It is conjugated in the kidney for excretion in the urine, where 75% of the drug is excreted,<ref>{{cite journal | vauthors=((Al-Majed, A.)), ((Bakheit, A. H.)), ((Alharbi, R. M.)), ((Abdel Aziz, H. A.)) | journal=Profiles of Drug Substances, Excipients, and Related Methodology | title=Mirtazapine | volume=43 | pages=209–254 | date= 2018 | issn=1871-5125 | doi=10.1016/bs.podrm.2018.01.002}}</ref>  and about 15% is eliminated in feces.<ref>{{cite book | veditors=((Schatzberg, A. F.)), ((Nemeroff, C. B.)) | date= 2009 | title=The American Psychiatric Publishing textbook of psychopharmacology | publisher=American Psychiatric Pub | edition=4th ed | isbn=9781585623099}}</ref>

Mirtazapine is considered to be relatively safe in the event of an [[overdose]],<ref>{{cite book | veditors=((Taylor, D.)), ((Paton, C.)), ((Kapur, S.)) | date= 2012 | title=The Maudsley prescribing guidelines in psychiatry | publisher=Wiley | edition=11. ed | isbn=9780470979488}}</ref> although it is considered slightly more toxic in overdose than most of the SSRIs (except [[citalopram]]).<ref>{{cite journal | vauthors = White N, Litovitz T, Clancy C | title = Suicidal antidepressant overdoses: a comparative analysis by antidepressant type | journal = Journal of Medical Toxicology | volume = 4 | issue = 4 | pages = 238–50 | date = December 2008 | pmid = 19031375 | pmc = 3550116 | doi = 10.1007/bf03161207 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550116/pdf/13181_2009_Article_BF03161207.pdf | format = PDF }}</ref> Unlike the TCAs, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose.<ref>{{cite journal | vauthors=((Fawcett, J.)), ((Barkin, R. L.)) | journal=Journal of Affective Disorders | title=Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression | volume=51 | issue=3 | pages=267–285 | date=1 December 1998 | url=https://www.sciencedirect.com/science/article/pii/S0165032798002249 | issn=0165-0327 | doi=10.1016/S0165-0327(98)00224-9}}</ref> Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to TCAs.<ref name="pmid9807651">{{cite journal | vauthors = Holzbach R, Jahn H, Pajonk FG, Mähne C | title = Suicide attempts with mirtazapine overdose without complications | journal = Biological Psychiatry | volume = 44 | issue = 9 | pages = 925–6 | date = November 1998 | pmid = 9807651 | doi = 10.1016/S0006-3223(98)00081-X }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid9861579">{{cite journal | vauthors = Retz W, Maier S, Maris F, Rösler M | title = Non-fatal mirtazapine overdose | journal = International Clinical Psychopharmacology | volume = 13 | issue = 6 | pages = 277–9 | date = November 1998 | pmid = 9861579 | doi = 10.1097/00004850-199811000-00007 }}{{Unreliable medical source|date=October 2011}}</ref>