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Concurrent use with inhibitors or inducers of the [[cytochrome P450|cytochrome (CYP) P450]] [[isoenzyme]]s [[CYP1A2]], [[CYP2D6]], and/or [[CYP3A4]] can result in altered concentrations of mirtazapine, as these are the main [[enzyme]]s responsible for its metabolism.<ref name="pmid10885584" /><ref name="pmid11607047" /> As examples, [[fluoxetine]] and [[paroxetine]], inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while [[carbamazepine]], an inducer, considerably decreases them.<ref name="pmid10885584" />
Concurrent use with inhibitors or inducers of the [[cytochrome P450|cytochrome (CYP) P450]] [[isoenzyme]]s [[CYP1A2]], [[CYP2D6]], and/or [[CYP3A4]] can result in altered concentrations of mirtazapine, as these are the main [[enzyme]]s responsible for its metabolism.<ref name="pmid10885584" /><ref name="pmid11607047" /> As examples, [[fluoxetine]] and [[paroxetine]], inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while [[carbamazepine]], an inducer, considerably decreases them.<ref name="pmid10885584" />


According to information from the manufacturers, mirtazapine should not be started within two weeks of any [[MAOI|monoamine oxidase inhibitor (MAOI)]] usage; likewise, MAOIs should not be administered within two weeks of discontinuing mirtazapine.<ref>[http://www.drugs.com/monograph/mirtazapine.html Mirtazapine monograph]</ref> However, a single study regarding the combination reported it does not result in any incidence of serotonin-related toxicity.<ref name="pmid16460699">{{cite journal | vauthors = Gillman PK | title = A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action | journal = Biological Psychiatry | volume = 59 | issue = 11 | pages = 1046–51 | date = June 2006 | pmid = 16460699 | doi = 10.1016/j.biopsych.2005.11.016 }}</ref> In addition, a case report claimed that mirtazapine can actually be used to treat [[serotonin syndrome]].<ref name="pmid8741027">{{cite journal | vauthors = Hoes MJ, Zeijpveld JH | title = Mirtazapine as treatment for serotonin syndrome | journal = Pharmacopsychiatry | volume = 29 | issue = 2 | pages = 81 | date = March 1996 | pmid = 8741027 | doi = 10.1055/s-2007-979550 }}{{Unreliable medical source|date=October 2011}}</ref> Mirtazapine in combination with an SSRI, SNRI, or TCA as an [[Augmentation (psychiatry)|augmentation]] strategy is considered to be relatively safe and is often employed therapeutically,<ref name="pmid10333982"/><ref name="pmid16946177"/><ref name="pmid12590402"/><ref name="pmid12028939"/><ref name="pmid18204355"/> with a combination of [[venlafaxine]] and mirtazapine, sometimes referred to as "California rocket fuel".<ref name="isbn0-521-74609-4">{{cite book | author = Stahl, SM | title = Stahl's Essential Psychopharmacology Online: Print and Online | publisher = Cambridge University Press | location = Cambridge, UK | year = 2008 | pages = | isbn = 0-521-74609-4 | url = http://stahlonline.cambridge.org/prescribers_drug.jsf?page=0521683505c57_p325-330.html.therapeutics&name=Mirtazapine&title=Therapeutics }}</ref><ref>[http://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2009.09020186 Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder: A Double-Blind Randomized Study]</ref>
According to information from the manufacturers, mirtazapine should not be started within two weeks of any [[monoamine oxidase inhibitor]] (MAOI) usage; likewise, MAOIs should not be administered within two weeks of discontinuing mirtazapine.<ref>[http://www.drugs.com/monograph/mirtazapine.html Mirtazapine monograph]</ref> However, a single study regarding the combination reported it does not result in any incidence of serotonin-related toxicity.<ref name="pmid16460699" /> In addition, a case report claimed that mirtazapine can actually be used to treat [[serotonin syndrome]].<ref name="pmid8741027" /> Mirtazapine in combination with an SSRI, SNRI, or TCA as an [[Augmentation (psychiatry)|augmentation]] strategy is considered to be relatively safe and is often employed therapeutically,<ref name="pmid10333982"/><ref name="pmid16946177"/><ref name="pmid12590402"/><ref name="pmid12028939"/><ref name="pmid18204355"/> with a combination of [[venlafaxine]] and mirtazapine, sometimes referred to as "California rocket fuel".<ref name="isbn0-521-74609-4">{{cite book | author = Stahl, SM | title = Stahl's Essential Psychopharmacology Online: Print and Online | publisher = Cambridge University Press | location = Cambridge, UK | year = 2008 | pages = | isbn = 0-521-74609-4 | url = http://stahlonline.cambridge.org/prescribers_drug.jsf?page=0521683505c57_p325-330.html.therapeutics&name=Mirtazapine&title=Therapeutics }}</ref><ref>[http://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2009.09020186 Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder: A Double-Blind Randomized Study]</ref>


Mirtazapine's combination with an [[Serotonin–norepinephrine reuptake inhibitor]] is especially considered to have synergistic effect on [[serotonin]] and [[Norepinephrine]], and like Venlafaxine, its combination with [[Duloxetine]]/Cymbalta is sometimes referred to as "Limerick Rocket Fuel".<ref>{{Cite journal|last=Nagao|first=Kei|last2=Kishi|first2=Taro|last3=Moriwaki|first3=Masatsugu|last4=Fujita|first4=Kiyoshi|last5=Hirano|first5=Shigeki|last6=Yamanouchi|first6=Yoshio|last7=Funahashi|first7=Toshihiko|last8=Iwata|first8=Nakao|date=2013|title=Comparative clinical profile of mirtazapine and duloxetine in practical clinical settings in Japan: a 4-week open-label, parallel-group study of major depressive disorder|journal=Neuropsychiatric Disease and Treatment|volume=9|pages=781–786|doi=10.2147/NDT.S43600|issn=1176-6328|pmc=3678901|pmid=23766648}}</ref><ref>{{Cite journal|last=|first=|date=|title=SNRI-NaSSA combination therapy for treatment-resistant depression|url=http://onlinelibrary.wiley.com/doi/10.1002/pnp.153/pdf|journal=Opinion/Wiley|volume=|pages=|doi=10.1002/pnp.153/pdf|via=}}</ref><ref>{{Cite web|url=https://www.researchgate.net/publication/265047831_Duloxetine-mirtazapine_combination_in_depressive_illness_The_case_for_Limerick_%27rocket_fuel%27|title=Duloxetine-mirtazapine combination in depressive illness: The case for Limerick 'rocket fuel'|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
Mirtazapine's combination with an [[Serotonin–norepinephrine reuptake inhibitor]] is especially considered to have synergistic effect on [[serotonin]] and [[Norepinephrine]], and like Venlafaxine, its combination with [[Duloxetine]]/Cymbalta is sometimes referred to as "Limerick Rocket Fuel".<ref>{{Cite journal|last=Nagao|first=Kei|last2=Kishi|first2=Taro|last3=Moriwaki|first3=Masatsugu|last4=Fujita|first4=Kiyoshi|last5=Hirano|first5=Shigeki|last6=Yamanouchi|first6=Yoshio|last7=Funahashi|first7=Toshihiko|last8=Iwata|first8=Nakao|date=2013|title=Comparative clinical profile of mirtazapine and duloxetine in practical clinical settings in Japan: a 4-week open-label, parallel-group study of major depressive disorder|journal=Neuropsychiatric Disease and Treatment|volume=9|pages=781–786|doi=10.2147/NDT.S43600|issn=1176-6328|pmc=3678901|pmid=23766648}}</ref><ref>{{Cite journal|last=|first=|date=|title=SNRI-NaSSA combination therapy for treatment-resistant depression|url=http://onlinelibrary.wiley.com/doi/10.1002/pnp.153/pdf|journal=Opinion/Wiley|volume=|pages=|doi=10.1002/pnp.153/pdf|via=}}</ref><ref>{{Cite web|url=https://www.researchgate.net/publication/265047831_Duloxetine-mirtazapine_combination_in_depressive_illness_The_case_for_Limerick_%27rocket_fuel%27|title=Duloxetine-mirtazapine combination in depressive illness: The case for Limerick 'rocket fuel'|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
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Antagonism of the 5-HT<sub>3</sub> receptor, an action mirtazapine shares with the approved antiemetic [[ondansetron]], significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and [[irritable bowel syndrome]] in afflicted individuals.<ref name="pmid11585276">{{cite journal | vauthors = Kast RE | title = Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy | journal = Supportive Care in Cancer | volume = 9 | issue = 6 | pages = 469–70 | date = September 2001 | pmid = 11585276 | doi = 10.1007/s005200000215 }}</ref> Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron.<ref name="pmid17587360"/> Blockade of the 5-HT<sub>3</sub> receptors has also shown to improve anxiety and to be effective in the treatment of [[drug addiction]] in several studies.<ref name="Costall_1990">{{cite journal | vauthors = Costall B, Naylor RJ, Tyers MB | title = The psychopharmacology of 5-HT<sub>3</sub> receptors | journal = Pharmacology & Therapeutics | volume = 47 | issue = 2 | pages = 181–202 | year = 1990 | pmid = 2203069 | doi = 10.1016/0163-7258(90)90086-H }}</ref> In conjunction with [[drug rehabilitation|substance abuse counseling]], mirtazapine has been investigated for the purpose of reducing [[methamphetamine]] use in dependent individuals with success.<ref name="pmid22065532" /> In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT<sub>2A</sub>, 5-HT<sub>2C</sub>, and 5-HT<sub>3</sub> receptors leading to a host of negative changes and side effects, the most prominent of which including anorexia, insomnia, sexual dysfunction (loss of [[libido]] and [[anorgasmia]]), nausea, and diarrhea, among others. As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.<ref name="pmid10333982"/><ref name="pmid16946177">{{cite journal | vauthors = McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ | title = Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report | journal = The American Journal of Psychiatry | volume = 163 | issue = 9 | pages = 1531–41; quiz 1666 | date = September 2006 | pmid = 16946177 | doi = 10.1176/appi.ajp.163.9.1531 }}</ref><ref name="pmid12590402">{{cite journal | vauthors = Sennef C, Timmer CJ, Sitsen JM | title = Mirtazapine in combination with amitriptyline: a drug-drug interaction study in healthy subjects | journal = Human Psychopharmacology | volume = 18 | issue = 2 | pages = 91–101 | date = March 2003 | pmid = 12590402 | doi = 10.1002/hup.441 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid12028939">{{cite journal | vauthors = Gándara Martín Jde L, Agüera Ortiz L, Ferre Navarrete F, Rojo Rodés E, Ros Montalbán S | title = [Tolerability and efficacy of combined antidepressant therapy] | language = Spanish | journal = Actas Españolas de Psiquiatria | volume = 30 | issue = 2 | pages = 75–84 | year = 2002 | pmid = 12028939 | doi = | url = http://www.psiquiatria.com/articulos/atprimaria_y_sm/15413/ }}</ref><ref name="pmid18204355">{{cite journal | vauthors = Ravindran LN, Eisfeld BS, Kennedy SH | title = Combining mirtazapine and duloxetine in treatment-resistant depression improves outcomes and sexual function | journal = Journal of Clinical Psychopharmacology | volume = 28 | issue = 1 | pages = 107–8 | date = February 2008 | pmid = 18204355 | doi = 10.1097/JCP.0b013e318160d609 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid15560319">{{cite journal | vauthors = Caldis EV, Gair RD | title = Mirtazapine for treatment of nausea induced by selective serotonin reuptake inhibitors | journal = Canadian Journal of Psychiatry. Revue canadienne de psychiatrie | volume = 49 | issue = 10 | pages = 707 | date = October 2004 | pmid = 15560319 | doi = 10.1177/070674370404901014 }}</ref>
Antagonism of the 5-HT<sub>3</sub> receptor, an action mirtazapine shares with the approved antiemetic [[ondansetron]], significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and [[irritable bowel syndrome]] in afflicted individuals.<ref name="pmid11585276">{{cite journal | vauthors = Kast RE | title = Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy | journal = Supportive Care in Cancer | volume = 9 | issue = 6 | pages = 469–70 | date = September 2001 | pmid = 11585276 | doi = 10.1007/s005200000215 }}</ref> Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron.<ref name="pmid17587360"/> Blockade of the 5-HT<sub>3</sub> receptors has also shown to improve anxiety and to be effective in the treatment of [[drug addiction]] in several studies.<ref name="Costall_1990">{{cite journal | vauthors = Costall B, Naylor RJ, Tyers MB | title = The psychopharmacology of 5-HT<sub>3</sub> receptors | journal = Pharmacology & Therapeutics | volume = 47 | issue = 2 | pages = 181–202 | year = 1990 | pmid = 2203069 | doi = 10.1016/0163-7258(90)90086-H }}</ref> In conjunction with [[drug rehabilitation|substance abuse counseling]], mirtazapine has been investigated for the purpose of reducing [[methamphetamine]] use in dependent individuals with success.<ref name="pmid22065532" /> In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT<sub>2A</sub>, 5-HT<sub>2C</sub>, and 5-HT<sub>3</sub> receptors leading to a host of negative changes and side effects, the most prominent of which including anorexia, insomnia, sexual dysfunction (loss of [[libido]] and [[anorgasmia]]), nausea, and diarrhea, among others. As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.<ref name="pmid10333982"/><ref name="pmid16946177">{{cite journal | vauthors = McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ | title = Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report | journal = The American Journal of Psychiatry | volume = 163 | issue = 9 | pages = 1531–41; quiz 1666 | date = September 2006 | pmid = 16946177 | doi = 10.1176/appi.ajp.163.9.1531 }}</ref><ref name="pmid12590402">{{cite journal | vauthors = Sennef C, Timmer CJ, Sitsen JM | title = Mirtazapine in combination with amitriptyline: a drug-drug interaction study in healthy subjects | journal = Human Psychopharmacology | volume = 18 | issue = 2 | pages = 91–101 | date = March 2003 | pmid = 12590402 | doi = 10.1002/hup.441 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid12028939">{{cite journal | vauthors = Gándara Martín Jde L, Agüera Ortiz L, Ferre Navarrete F, Rojo Rodés E, Ros Montalbán S | title = [Tolerability and efficacy of combined antidepressant therapy] | language = Spanish | journal = Actas Españolas de Psiquiatria | volume = 30 | issue = 2 | pages = 75–84 | year = 2002 | pmid = 12028939 | doi = | url = http://www.psiquiatria.com/articulos/atprimaria_y_sm/15413/ }}</ref><ref name="pmid18204355">{{cite journal | vauthors = Ravindran LN, Eisfeld BS, Kennedy SH | title = Combining mirtazapine and duloxetine in treatment-resistant depression improves outcomes and sexual function | journal = Journal of Clinical Psychopharmacology | volume = 28 | issue = 1 | pages = 107–8 | date = February 2008 | pmid = 18204355 | doi = 10.1097/JCP.0b013e318160d609 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid15560319">{{cite journal | vauthors = Caldis EV, Gair RD | title = Mirtazapine for treatment of nausea induced by selective serotonin reuptake inhibitors | journal = Canadian Journal of Psychiatry. Revue canadienne de psychiatrie | volume = 49 | issue = 10 | pages = 707 | date = October 2004 | pmid = 15560319 | doi = 10.1177/070674370404901014 }}</ref>

Mirtazapine does not have [[serotonergic]] activity and does not cause serotonergic side effects or [[serotonin syndrome]].<ref name="pmid16342227">{{cite journal | vauthors = Gillman PK | title = A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status | journal = Hum Psychopharmacol | volume = 21 | issue = 2 | pages = 117–25 | year = 2006 | pmid = 16342227 | doi = 10.1002/hup.750 | url = }}</ref><ref name="pmid16460699">{{cite journal | vauthors = Gillman PK | title = A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action | journal = Biological Psychiatry | volume = 59 | issue = 11 | pages = 1046–51 | date = June 2006 | pmid = 16460699 | doi = 10.1016/j.biopsych.2005.11.016 }}</ref> This is in accordance with the fact that it is not a [[serotonin reuptake inhibitor]] or MAOI, nor a [[serotonin receptor agonist]].<ref name="pmid16342227" /><ref name="pmid16460699" /> There are no reports of serotonin syndrome in association with mirtazapine alone, and mirtazapine has not been found to cause serotonin syndrome in overdose.<ref name="pmid16342227" /><ref name="pmid16460699" /><ref name="pmid24228948">{{cite journal | vauthors = Berling I, Isbister GK | title = Mirtazapine overdose is unlikely to cause major toxicity | journal = Clin Toxicol (Phila) | volume = 52 | issue = 1 | pages = 20–4 | year = 2014 | pmid = 24228948 | pmc = 3894718 | doi = 10.3109/15563650.2013.859264 | url = }}</ref> However, there are a handful of [[case report]]s of serotonin syndrome occurring with mirtazapine in combination with serotonergic drugs like SSRIs, although such reports are unusual and very rare and do not necessarily implicate mirtazapine as causative.<ref name="pmid16342227" /><ref name="pmid19994622">{{cite journal | vauthors = Freijo Guerrero J, Tardón Ruiz de Gauna L, Gómez JJ, Aguilera Celorrio L | title = [Serotonin syndrome after administration of mirtazapine in a critical care unit] | language = Spanish; Castilian | journal = Rev Esp Anestesiol Reanim | volume = 56 | issue = 8 | pages = 515–6 | year = 2009 | pmid = 19994622 | doi = | url = }}</ref><ref name="pmid20430060">{{cite journal | vauthors = Butler MC, Di Battista M, Warden M | title = Sertraline-induced serotonin syndrome followed by mirtazapine reaction | journal = Prog. Neuropsychopharmacol. Biol. Psychiatry | volume = 34 | issue = 6 | pages = 1128–9 | year = 2010 | pmid = 20430060 | doi = 10.1016/j.pnpbp.2010.04.015 | url = }}</ref><ref name="pmid22752315">{{cite journal | vauthors = Decoutere L, De Winter S, Vander Weyden L, Spriet I, Schrooten M, Tournoy J, Fagard K | title = A venlafaxine and mirtazapine-induced serotonin syndrome confirmed by de- and re-challenge | journal = Int J Clin Pharm | volume = 34 | issue = 5 | pages = 686–8 | year = 2012 | pmid = 22752315 | doi = 10.1007/s11096-012-9666-7 | url = }}</ref><ref name="pmid24977717">{{cite journal | vauthors = Ansermot N, Hodel PF, Eap CB | title = Serotonin toxicity after addition of mirtazapine to escitalopram | journal = J Clin Psychopharmacol | volume = 34 | issue = 4 | pages = 540–1 | year = 2014 | pmid = 24977717 | doi = 10.1097/JCP.0000000000000170 | url = }}</ref><ref name="pmid27333965">{{cite journal | vauthors = Wu CS, Tong SH, Ong CT, Sung SF | title = Serotonin Syndrome Induced by Combined Use of Mirtazapine and Olanzapine Complicated with Rhabdomyolysis, Acute Renal Failure, and Acute Pulmonary Edema-A Case Report | journal = Acta Neurol Taiwan | volume = 24 | issue = 4 | pages = 117–21 | year = 2015 | pmid = 27333965 | doi = | url = }}</ref> The addition of mirtazapine to an MAOI does not cause serotonin syndrome, and has been considered to be a safe combination.<ref name="pmid16342227" /><ref name="pmid16460699" /> Moreover, mirtazapine may actually be useful in the treatment of serotonin syndrome, with at least one publication finding it to be effective in resolving the syndrome.<ref name="pmid16342227" /><ref name="pmid8741027">{{cite journal | vauthors = Hoes MJ, Zeijpveld JH | title = Mirtazapine as treatment for serotonin syndrome | journal = Pharmacopsychiatry | volume = 29 | issue = 2 | pages = 81 | year = 1996 | pmid = 8741027 | doi = 10.1055/s-2007-979550 | url = }}</ref><ref name="pmid20655983">{{cite journal | vauthors = Shioda K, Nisijima K, Yoshino T, Kato S | title = Mirtazapine abolishes hyperthermia in an animal model of serotonin syndrome | journal = Neurosci. Lett. | volume = 482 | issue = 3 | pages = 216–9 | year = 2010 | pmid = 20655983 | doi = 10.1016/j.neulet.2010.07.039 | url = }}</ref> This is in accordance with the fact that the 5-HT<sub>2A</sub> receptor is the predominant serotonin receptor thought to be involved in the pathophysiology of serotonin syndrome (with the 5-HT<sub>1A</sub> receptor seeming to be protective).<ref name="pmid16342227" /><ref name="pmid16460699" /> Mirtazapine is a potent 5-HT<sub>2A</sub> receptor antagonist, and drugs that share this property, like [[cyproheptadine]], oppose serotonin syndrome and are well-established clinically as [[antidote]]s against it.<ref name="pmid16342227" /><ref name="pmid23145389">{{cite journal | vauthors = Iqbal MM, Basil MJ, Kaplan J, Iqbal MT | title = Overview of serotonin syndrome | journal = Ann Clin Psychiatry | volume = 24 | issue = 4 | pages = 310–8 | year = 2012 | pmid = 23145389 | doi = | url = }}</ref>


===H<sub>1</sub> receptor===
===H<sub>1</sub> receptor===

Revision as of 00:27, 15 August 2017

Mirtazapine
Clinical data
Trade namesRemeron, others
Other namesMepirzapine; 6-Azamianserin; ORG-3770[1][2]
AHFS/Drugs.comMonograph
MedlinePlusa697009
License data
Pregnancy
category
  • AU: B3
Routes of
administration		Oral (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability50%[4][5][6][7]
Protein binding85%[4][5][6][7]
MetabolismLiver (CYP1A2, CYP2D6, CYP3A4)[4][5][6][7][8]
MetabolitesDesmethylmirtazapine (contributes 3–10% of activity)[8]
Elimination half-life20–40 hours[4][5][6][7]
ExcretionUrine: 75%[4]
Feces: 15%[4][5][6][7]
Identifiers
  • (±)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.080.027 Edit this at Wikidata
Chemical and physical data
FormulaC17H19N3
Molar mass265.35 g/mol g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Density1.22 g/cm3
Melting point114 to 116 °C (237 to 241 °F)
Boiling point432 °C (810 °F)
Solubility in waterSoluble in methanol and chloroform mg/mL (20 °C)
  • n1cccc3c1N4C(c2ccccc2C3)CN(C)CC4
  • 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 checkY
  • Key:RONZAEMNMFQXRA-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Mirtazapine, sold under the brand name Remeron among others, is an atypical antidepressant with noradrenergic and specific serotonergic activity. It blocks the α2-adrenergic receptor, thereby enhancing norepinephrine and serotonin release, and selectively antagonizes the serotonin 5-HT2 receptors. It is thought to indirectly enhances serotonin neurotransmission at the 5-HT1A receptor, and also blocks the histamine H1 receptor. Mirtazapine is not a serotonin or norepinephrine reuptake inhibitor but increases serotonin and norepinephrine action by other mechanisms.[9]

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) developed by Organon International in the Netherlands, and introduced in the United States in 1996,[5] and is used primarily in the treatment of depression. It is also commonly used as an anxiolytic, hypnotic, antiemetic and appetite stimulant. In structure, mirtazapine can also be classified as a tetracyclic antidepressant (TeCA) and is the 6-aza analogue of mianserin.[10]

Its patent expired in 2004, so generic versions are available.[11]

Medical uses

Approved and off-label

Mirtazapine's primary use is the treatment of major depressive disorder and other mood disorders.[12][13]

However, it has also been found useful in alleviating the following conditions and is sometimes prescribed off-label for their treatment:

Effectiveness and tolerability

A 2011 Cochrane review that compared mirtazapine to other antidepressants, found that while it appears to have a faster onset in people for whom it works (measured at 2 weeks), it is about the same as other antidepressants at 6 weeks.[32]

A 2012 review focused on antidepressants and sleep found that in many people with sleep disorders caused by depression, mirtazapine reduces the time it takes to fall asleep and increases the quality of sleep, but that in some people it can disturb sleep, causing restless leg syndrome in 8 to 28% of people, and in rare cases causes REM sleep behavior disorder.[33]

In 2010 NICE published a guideline for treating depression that included a review of antidepressants. It recommended generic SSRIs as first line choices, as they are "are equally effective as other antidepressants and have a favourable risk–benefit ratio."[34] With respect to mirtazapine, it found: "There is no difference between mirtazapine and other antidepressants on any efficacy measure, although in terms of achieving remission mirtazapine appears to have a statistical though not clinical advantage. In addition, mirtazapine has a statistical advantage over SSRIs in terms of reducing symptoms of depression, but the difference is not clinically important. However, there is strong evidence that patients taking mirtazapine are less likely to leave treatment early because of side effects, although this is not the case for patients reporting side effects or leaving treatment early for any reason."[35]

In general, all antidepressants, including mirtazapine, require at least a week for their therapeutic benefits on depressive and anxious symptoms to become apparent.[36][37]

Side effects

A 15 mg tablet of generic mirtazapine

A 2011 Cochrane review found that compared with other antidepressants, it is more likely to cause weight gain and sleepiness, but it is less likely to cause tremor than tricyclic antidepressants, and less likely to cause nausea and sexual dysfunction than SSRIs.[32]

Very common (≥10% incidence) adverse effects include constipation, dry mouth, sleepiness, increased appetite, and weight gain.[5][6][7][38][39][40][41][42][43]

Common (1–10% incidence) adverse effects include weakness, confusion, dizziness, peripheral edema, and negative lab results like elevated transaminases, elevated serum triglycerides, and elevated total cholesterol.[7]

Mirtazapine is not considered to have a risk of many of the side effects often associated with other antidepressants like the SSRIs, and may actually improve certain ones when taken in conjunction with them.[8][44] (Those adverse effects include decreased appetite, weight loss, insomnia, nausea and vomiting, diarrhoea, urinary retention, increased body temperature, excessive sweating, pupil dilation and sexual dysfunction.[8][44])

In general, some antidepressants, especially SSRIs, can paradoxically exacerbate some peoples' depression or anxiety or cause suicidal ideation.[45] Despite its sedating action, mirtazapine is also believed to be capable of this, so in the United States and certain other countries, it carries a black box label warning of these potential effects.

A case report published in 2000 noted an instance in which mirtazapine counteracted the action of clonidine, causing a dangerous rise in blood pressure.[46]

Discontinuation

Mirtazapine and other antidepressants may cause a discontinuation syndrome upon cessation.[8][47][48] A gradual and slow reduction in dose is recommended to minimize discontinuation symptoms.[49] Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety, panic attacks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhea, nausea, vomiting, flu-like symptoms such as allergies and pruritus, headaches and sometimes hypomania or mania.[47][50][51][52][53]

Overdose

Mirtazapine is considered to be relatively safe in the event of an overdose,[37] although it is considered slightly more toxic in overdose than most of the SSRIs (except citalopram).[54] Unlike the TCAs, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose.[44] Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to TCAs.[55][56]

Twelve reported fatalities have been attributed to mirtazapine overdose.[57][58] The fatal toxicity index (deaths per million prescriptions) for mirtazapine is 3.1 (95% CI: 0.1 to 17.2). This is similar to that observed with SSRIs.[59]

Interactions

Concurrent use with inhibitors or inducers of the cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and/or CYP3A4 can result in altered concentrations of mirtazapine, as these are the main enzymes responsible for its metabolism.[4][8] As examples, fluoxetine and paroxetine, inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while carbamazepine, an inducer, considerably decreases them.[4]

According to information from the manufacturers, mirtazapine should not be started within two weeks of any monoamine oxidase inhibitor (MAOI) usage; likewise, MAOIs should not be administered within two weeks of discontinuing mirtazapine.[60] However, a single study regarding the combination reported it does not result in any incidence of serotonin-related toxicity.[61] In addition, a case report claimed that mirtazapine can actually be used to treat serotonin syndrome.[62] Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is considered to be relatively safe and is often employed therapeutically,[44][63][64][65][66] with a combination of venlafaxine and mirtazapine, sometimes referred to as "California rocket fuel".[67][68]

Mirtazapine's combination with an Serotonin–norepinephrine reuptake inhibitor is especially considered to have synergistic effect on serotonin and Norepinephrine, and like Venlafaxine, its combination with Duloxetine/Cymbalta is sometimes referred to as "Limerick Rocket Fuel".[69][70][71]

Another case report described mirtazapine as inducing hypertension in a clonidine-treated patient, likely due to occupancy of α2 autoreceptors by mirtazapine limiting the efficacy of concurrent clonidine therapy.[72]

Liver and moderate renal impairment have been reported to decrease the oral clearance of mirtazapine by about 30%; severe renal impairment decreases it by 50%.[4]

Pharmacology

Mirtazapine
Site Ki (nM) Species Ref
H1 0.14–1.6 Human [73][8][74]
H2 >10,000 Rat [75]
5-HT1A 3,330–5,010 Human [74][8]
5-HT1B 3,534–12,600 Human [74][8]
5-HT1D 794–5,010 Human [74][8]
5-HT1E 728 Human [74]
5-HT1F 583 Human [74]
5-HT2A 6.3–69 Human [8][73][74]
5-HT2B 200 Human [8]
5-HT2C 8.9–39 Human [73][8][74]
5-HT3 7.9 Human [8]
5-HT4L >10,000 Human [74]
5-HT5A 670 Human [74]
5-HT6 ND ND ND[74]
5-HT7 265 Human [73][74]
α1A 316–1,815 Human [74][75][74]
α2A 20 Human [73][74]
α2B 88 Human [74]
α2C 18 Human [73][74]
β >10,000 Human [74]
mAChTooltip Muscarinic acetylcholine receptor 670 Human [8][76][77]
D1 4,167 Rat [73]
D2 >5,454 Human [73][74]
D3 5,723 Human [73][74]
D4 2,518 Human [74]
SERTTooltip Serotonin transporter >10,000 Human [78][74]
NETTooltip Norepinephrine transporter ≥4,600 Human [76][78]
DATTooltip Dopamine transporter >10,000 Human [78][74]
VGSCTooltip Voltage-gated sodium channel 6,905 Rat [74]
VDCCTooltip Voltage-dependent calcium channel >10,000 Rat [74]
See also: Pharmacology of antidepressants and Tetracyclic antidepressant § Pharmacology

Mirtazapine has antihistamine, α2-blocker, and antiserotonergic activity.[8][79] It is specifically a potent antagonist or inverse agonist of the the α2A-, α2B-, and α2C-adrenergic receptors, the serotonin 5-HT2A, 5-HT2B, 5-HT2C and 5-HT3 receptors, and the histamine H1 receptor.[8][79] Unlike many other antidepressants, it does not inhibit the reuptake of serotonin, norepinephrine, or dopamine,[8][79] nor does it inhibit monoamine oxidase.[80] Similarly, mirtazapine has weak or no activity as an anticholinergic or blocker of sodium or calcium channels, in contrast to many other TeCAs and TCAs.[8][79][74] In accordance, it has better tolerability and low toxicity in overdose.[8][81] As an H1 receptor antagonist, mirtazapine is extremely potent, and is in fact the most potent of all the TCAs and TeCAs.[76][82][83] Antagonism of the H1 receptor is by far the most potent activity of mirtazapine, with the drug acting as a selective H1 receptor antagonist at low concentrations.[8][74]

The (S)-(+) enantiomer of mirtazapine is responsible for antagonism of the serotonin 5-HT2A and 5-HT2C receptors,[10] while the (R)-(–) enantiomer is responsible for antagonism of the 5-HT3 receptor.[10] Both enantiomers are involved in antagonism of the H1 and α2-adrenergic receptors,[10][6] although the (S)-(+) enantiomer is the stronger antihistamine.[84]

Although not clinically relevant, mirtazapine has been found to act as a partial agonist of the κ-opioid receptor at high concentrations (EC50 = 7.2 μM).[85]

α2-Adrenergic receptor

Antagonism of the α2-adrenergic receptors, which function largely as inhibitory autoreceptors and heteroreceptors, enhances adrenergic and serotonergic neurotransmission, notably central 5-HT1A receptor mediated transmission in the dorsal raphe nucleus and hippocampus; hence, mirtazapine's classification as a NaSSA. Indirect α1 adrenoceptor-mediated enhancement of serotonin cell firing and direct blockade of inhibitory α2 heteroreceptors located on serotonin terminals are held responsible for the increase in extracellular serotonin.[8][12][86][87][88] Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT1A receptor.[87] Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs.[89]

5-HT2 and 5-HT3 receptors

Antagonism of the 5-HT2 subfamily of receptors and inverse agonism of the 5-HT2C receptor appears to be in part responsible for mirtazapine's efficacy in the treatment of depressive states.[90][91] The 5-HT2C receptor is known to inhibit the release of the neurotransmitters dopamine and norepinephrine in various parts of the brains of rodents, notably in reward pathways such as the ventral tegmental area.[92][93] Accordingly, it was shown that by blocking the α2-adrenergic receptors and 5-HT2C receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats.[94] In addition, mirtazapine's antagonism of 5-HT2A receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor.[8][44] The newest research however has shown that mirtazapine is actually an inverse agonist of the 5-HT2C receptor. 5-HT2C inverse agonists have been shown to inhibit mesoaccumbens dopamine outflow[95] attenuating the rewarding properties of various substances like morphine. This inhibition of dopamine may be stronger than thought as substances with 5-HT2C inverse agonist properties may have more activity to regulate dopamine neurotransmission than ones with competitive antagonism.[96] With its newly understood properties of 5-HT2C inverse agonism, it is being investigated and shown to lower drug seeking behaviour, conditioned place preference and the rewarding effects of substances such as methamphetamine in various human and animal studies.[97][98][99] It is also being investigated to help in substance abuse disorders with withdrawal effects and remission rates.[97][100] but some studies have shown mixed benefit.[97][101][102]

Antagonism of the 5-HT3 receptor, an action mirtazapine shares with the approved antiemetic ondansetron, significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and irritable bowel syndrome in afflicted individuals.[103] Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron.[27] Blockade of the 5-HT3 receptors has also shown to improve anxiety and to be effective in the treatment of drug addiction in several studies.[104] In conjunction with substance abuse counseling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success.[98] In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors leading to a host of negative changes and side effects, the most prominent of which including anorexia, insomnia, sexual dysfunction (loss of libido and anorgasmia), nausea, and diarrhea, among others. As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.[44][63][64][65][66][105]

Mirtazapine does not have serotonergic activity and does not cause serotonergic side effects or serotonin syndrome.[106][61] This is in accordance with the fact that it is not a serotonin reuptake inhibitor or MAOI, nor a serotonin receptor agonist.[106][61] There are no reports of serotonin syndrome in association with mirtazapine alone, and mirtazapine has not been found to cause serotonin syndrome in overdose.[106][61][107] However, there are a handful of case reports of serotonin syndrome occurring with mirtazapine in combination with serotonergic drugs like SSRIs, although such reports are unusual and very rare and do not necessarily implicate mirtazapine as causative.[106][108][109][110][111][112] The addition of mirtazapine to an MAOI does not cause serotonin syndrome, and has been considered to be a safe combination.[106][61] Moreover, mirtazapine may actually be useful in the treatment of serotonin syndrome, with at least one publication finding it to be effective in resolving the syndrome.[106][62][113] This is in accordance with the fact that the 5-HT2A receptor is the predominant serotonin receptor thought to be involved in the pathophysiology of serotonin syndrome (with the 5-HT1A receptor seeming to be protective).[106][61] Mirtazapine is a potent 5-HT2A receptor antagonist, and drugs that share this property, like cyproheptadine, oppose serotonin syndrome and are well-established clinically as antidotes against it.[106][114]

H1 receptor

Mirtazapine is a very strong H1 receptor inverse agonist and, as a result, it can cause powerful sedative and hypnotic effects.[8] A single 15 mg dose of mirtazapine to healthy volunteers has been found to result in over 80% occupancy of the H1 receptor and to induce intense sleepiness.[84] After a short period of chronic treatment, however, the H1 receptor tends to desensitize and the antihistamine effects become more tolerable. Many patients may also dose at night to avoid the effects, and this appears to be an effective strategy for combating them. Blockade of the H1 receptor may improve pre-existing allergies, pruritus, nausea, and insomnia in afflicted individuals. It may also contribute to weight gain, however. In contrast to the H1 receptor, mirtazapine has very low affinity for the mACh receptors, although anticholinergic side effects like dry mouth, constipation, and mydriasis are still sometimes seen in clinical practise.[115]

Pharmacokinetics

The (S)-(+)-enantiomer has an elimination half-life of 9.9 ± 3 hours and the (R)-(–)-enantiomer has an elimination half-life of 18 ± 2.5 hours.[4]

It is found mostly bound to plasma proteins. The overall elimination half-life is 20–40 hours. It is metabolized primarily in the liver by demethylation and hydroxylation. About 75% is eliminated in feces and 25% in urine.[116]: 430 

Chemistry

Mirtazapine is a tetracyclic piperazinoazepine; mianserin was developed by the same team of organic chemists and mirtazapine differs from it via addition of a nitrogen atom in one of the rings.[116]: 429 [117][118] It is a racemic mixture of enantiomers. The (S)-(+)-enantiomer is known as esmirtazapine.

Analogues of mirtazapine include mianserin, setiptiline, and aptazapine.

Synthesis

A four-step chemical synthesis of mirtazapine has been published.[119]

History

Mirtazapine was first synthesized at Organon and published in 1989, was first approved for use in major depressive disorder in the Netherlands in 1994, and was introduced in the United States in 1996 under the brand name Remeron.[116]: 429 [120][121]

Society and culture

Generic names

Mirtazapine is the English and French generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip Japanese Accepted Name.[1][2][122] Its generic name in Spanish is mirtazapina, in German is mirtazapin, and in Latin is mirtazapinum.[1][2]

Brand names

Mirtazapine is marketed under many brand names worldwide, including Adco-Mirteron, Afloyan, Amirel, Arintapin Smelt, Avanza, Azapin, Beron, Bilanz, Calixta, Ciblex, Combar, Comenter, Depreram, Divaril, Esprital, Maz, Menelat, Mepirzapine, Merdaten, Meronin, Mi Er Ning, Milivin, Minelza, Minivane, Mirastad, Mirazep, Miro, Miron, Mirrador, Mirt, Mirta, Mirtabene, Mirtadepi, Mirtagamma, Mirtagen, Mirtalan, Mirtamor, Mirtamylan, Mirtan, Mirtaneo, Mirtapax, Mirtapil, Mirtapine, Mirtaron, Mirtastad, Mirtax, Mirtaz, Mirtazap, Mirtazapin, Mirtazapina, Mirtazapine, Mirtazapinum, Mirtazelon, Mirtazon, Mirtazonal, Mirtel, Mirtimash, Mirtin, Mirtine, Mirzapine, Mirzaten, Mirzest, Mitaprex, Mitaxind, Mitocent, Mitrazin, Mizapin, Motofen, Mytra, Norset, Noxibel, Pharmataz, Promyrtil, Ramure, Redepra, Reflex, Remergil, Remergon, Remeron, Remirta, Rexer, Saxib, Sinmaron, Smilon, Tazepin, Tazimed, Tetrazic, Tifona, U-Mirtaron, U-zepine, Valdren, Vastat, Velorin, Yarocen, Zania, Zapex, Zestat, Zismirt, Zispin, Zuleptan, and Zulin.[2]

Research

The use of mirtazapine has been explored in several additional conditions:

Veterinary use

Mirtazapine is sometimes prescribed as an appetite stimulant for cats or dogs experiencing anorexia due to medical conditions such as chronic kidney disease. It is especially useful for treating combined poor appetite and nausea in cats and dogs.[136][137]

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Further reading

External links

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