Mirtazapine

Mirtazapine is approved by the United States Food and Drug Administration for the treatment of major depressive disorder in adults.{{cite book |vauthors=Jilani TN, Gibbons JR, Faizy RM, Saadabadi A |chapter=Mirtazapine |date=2022 |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK519059/ |title=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30085601 |access-date=5 December 2022 |archive-date=12 December 2022 |archive-url=https://web.archive.org/web/20221212213412/https://www.ncbi.nlm.nih.gov/books/NBK519059/ |url-status=live }}

Mirtazapine is primarily used for major depressive disorder and other mood disorders.{{cite journal | vauthors = Gorman JM | title = Mirtazapine: clinical overview | journal = The Journal of Clinical Psychiatry | volume = 60 | issue = Suppl 17 | pages = 9–13; discussion 46–8 | year = 1999 | pmid = 10446735 }}{{cite journal | vauthors = Benjamin S, Doraiswamy PM | title = Review of the use of mirtazapine in the treatment of depression | journal = Expert Opinion on Pharmacotherapy | volume = 12 | issue = 10 | pages = 1623–1632 | date = July 2011 | pmid = 21644844 | doi = 10.1517/14656566.2011.585459 | s2cid = 10212539 }} Onset of action appears faster than some selective serotonin reuptake inhibitors and similar to tricyclic antidepressants.

In 2010, the National Institute for Health and Care Excellence recommended generic selective serotonin reuptake inhibitors as first-line choices, as they are "equally effective as other antidepressants and have a favourable risk–benefit ratio."{{cite book|title=Pharmacological Interventions: 10.14. Clinical Practice Recommendations|chapter=Pharmacological Interventions|date=2010|publisher=National Collaborating Centre for Mental Health/British Psychological Society|url=https://www.ncbi.nlm.nih.gov/books/NBK63751/#ch10.s159|access-date=22 July 2017|archive-date=6 September 2020|archive-url=https://web.archive.org/web/20200906074156/https://www.ncbi.nlm.nih.gov/books/NBK63751/#ch10.s159|url-status=live}} For mirtazapine, it found "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 selective serotonin reuptake inhibitors in terms of reducing symptoms of depression, but the difference is not clinically significant. 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."{{cite book|title=Pharmacological Interventions: Third-Generation Antidepressants: 10.8.3. Mirtazapine|chapter=Pharmacological Interventions|date=2010|publisher=National Collaborating Centre for Mental Health/British Psychological Society|url=https://www.ncbi.nlm.nih.gov/books/NBK63751/#ch10.s68|access-date=22 July 2017|archive-date=6 September 2020|archive-url=https://web.archive.org/web/20200906074156/https://www.ncbi.nlm.nih.gov/books/NBK63751/#ch10.s68|url-status=live}}

A 2011 Cochrane review comparing mirtazapine to other antidepressants found that while it appeared to have a faster onset in people for whom it worked (measured at two weeks), its efficacy was about the same as other antidepressants after six weeks' use.{{cite journal | vauthors = Watanabe N, Omori IM, Nakagawa A, Cipriani A, Barbui C, Churchill R, Furukawa TA | title = Mirtazapine versus other antidepressive agents for depression | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD006528 | date = December 2011 | pmid = 22161405 | pmc = 4158430 | doi = 10.1002/14651858.CD006528.pub2 }}

A 2012 review focused on antidepressants and sleep found that mirtazapine reduced the time it took to fall asleep and improved the quality of sleep in many people with sleep disorders caused by depression, but that it could also disturb sleep in many people, especially at higher doses, causing restless leg syndrome in 8 to 28% of people and in rare cases causes REM sleep behavior disorder.{{cite journal | vauthors = Wichniak A, Wierzbicka A, Jernajczyk W | title = Sleep and antidepressant treatment | journal = Current Pharmaceutical Design | volume = 18 | issue = 36 | pages = 5802–5817 | date = 2012 | pmid = 22681161 | doi = 10.2174/138161212803523608 }} This seemingly paradoxical dose–response curve of mirtazapine with respect to somnolence is owed to the exceptionally high affinity of the drug for the histamine H₁, 5-HT_2A, and 5-HT_2C receptors; exhibiting near exclusive occupation of these receptors at doses ≤15 mg. However, at higher doses, inverse agonism and constitutive activation of the α_2A-, α_2B-, and α_2C-adrenergic receptors begins to offset activity at H₁ receptors leading to decreased somnolence and even a subjective sensation of "activation" in treated patients.{{Cite journal|vauthors=Leonard S|date=2015|title=Dose-Dependent Sedating and Stimulating Effects of Mirtazapine|url=https://proceedings.med.ucla.edu/wp-content/uploads/2016/11/Dose-Dependent-Sedating-and-Stimulating-Effects-of-Mirtazapine.pdf|journal=Proceedings of UCLA Healthcare|volume=19|access-date=27 August 2021|archive-date=23 September 2021|archive-url=https://web.archive.org/web/20210923115736/https://www.proceedings.med.ucla.edu/wp-content/uploads/2016/11/Dose-Dependent-Sedating-and-Stimulating-Effects-of-Mirtazapine.pdf|url-status=live}}

A 2018 analysis of 21 antidepressants found them to be fairly similar overall. It found tentative evidence for mirtazapine being in the more effective group and middle in tolerability.{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR | title = Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis | journal = Lancet | volume = 391 | issue = 10128 | pages = 1357–1366 | date = April 2018 | pmid = 29477251 | pmc = 5889788 | doi = 10.1016/S0140-6736(17)32802-7 }}

After one week of usage, mirtazapine was found to have an earlier onset of action compared to selective serotonin reuptake inhibitors.{{cite journal | vauthors = Thompson C | title = Onset of action of antidepressants: results of different analyses | journal = Human Psychopharmacology | volume = 17 | issue = Suppl 1 | pages = S27–S32 | date = June 2002 | pmid = 12404667 | doi = 10.1002/hup.386 | s2cid = 45925573 | doi-access = free }}{{cite book | isbn = 978-0-47-097948-8 | title = Maudsley Prescribing Guidelines in Psychiatry | edition = 11th | vauthors = Taylor D, Paton C, Shitij K | date = 2012 | publisher = Wiley-Blackwell | location = West Sussex }}

There is also some evidence supporting its use in treating the following conditions, for which it is sometimes prescribed off-label:

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• Generalized anxiety disorder{{cite journal | vauthors = Goodnick PJ, Puig A, DeVane CL, Freund BV | title = Mirtazapine in major depression with comorbid generalized anxiety disorder | journal = The Journal of Clinical Psychiatry | volume = 60 | issue = 7 | pages = 446–448 | date = July 1999 | pmid = 10453798 | doi = 10.4088/JCP.v60n0705 }}{{cite journal | vauthors = Rifkin-Zybutz R, MacNeill S, Davies SJ, Dickens C, Campbell J, Anderson IM, Chew-Graham CA, Peters TJ, Lewis G, Wiles N, Kessler D | title = Does anxiety moderate the effectiveness of mirtazapine in patients with treatment-resistant depression? A secondary analysis of the MIR trial | journal = Journal of Psychopharmacology | volume = 34 | issue = 12 | pages = 1342–1349 | date = December 2020 | pmid = 33143538 | pmc = 7708671 | doi = 10.1177/0269881120965939 | doi-access = free }}
• Social anxiety disorder{{cite journal | vauthors = Croom KF, Perry CM, Plosker GL | title = Mirtazapine: a review of its use in major depression and other psychiatric disorders | journal = CNS Drugs | volume = 23 | issue = 5 | pages = 427–452 | year = 2009 | pmid = 19453203 | doi = 10.2165/00023210-200923050-00006 | s2cid = 41694941 }}
• Obsessive–compulsive disorder
• Panic disorder
• Post-traumatic stress disorder
• Low appetite/underweight{{cite journal | vauthors = Landowski J | title = [Mirtazapine--an antidepressant] | language = pl | journal = Psychiatria Polska | volume = 36 | issue = 6 Suppl | pages = 125–130 | year = 2002 | pmid = 12647431 }}{{cite journal | vauthors = Chinuck RS, Fortnum H, Baldwin DR | title = Appetite stimulants in cystic fibrosis: a systematic review | journal = Journal of Human Nutrition and Dietetics | volume = 20 | issue = 6 | pages = 526–537 | date = December 2007 | pmid = 18001374 | doi = 10.1111/j.1365-277X.2007.00824.x | s2cid = 22500622 }}{{cite journal | vauthors = Davis MP, Khawam E, Pozuelo L, Lagman R | title = Management of symptoms associated with advanced cancer: olanzapine and mirtazapine. A World Health Organization project | journal = Expert Review of Anticancer Therapy | volume = 2 | issue = 4 | pages = 365–376 | date = August 2002 | pmid = 12647979 | doi = 10.1586/14737140.2.4.365 | s2cid = 72195061 }}
• Insomnia{{cite journal | vauthors = Clark MS, Smith PO, Jamieson B | title = FPIN's clinical inquiries: Antidepressants for the treatment of insomnia in patients with depression | journal = American Family Physician | volume = 84 | issue = 9 | pages = 1–2 | date = November 2011 | pmid = 22164891 | url = http://www.aafp.org/afp/2011/1101/od1.pdf | access-date = 11 July 2017 | archive-date = 9 July 2020 | archive-url = https://web.archive.org/web/20200709135601/https://www.aafp.org/afp/2011/1101/od1.pdf | url-status = live }}{{Cite journal|url=http://www.psychiatrictimes.com/sleep-disorders/effects-antidepressants-sleep|title=The Effects of Antidepressants on Sleep|journal=Psychiatric Times|date=13 June 2012|access-date=11 July 2017|vauthors=Winokur A, Demartinis N|volume=29|issue=6|archive-date=10 June 2020|archive-url=https://web.archive.org/web/20200610174804/https://www.psychiatrictimes.com/sleep-disorders/effects-antidepressants-sleep|url-status=dead}}
• Nausea and vomiting{{cite journal | vauthors = Li TC, Shiah IS, Sun CJ, Tzang RF, Huang KC, Lee WK | title = Mirtazapine relieves post-electroconvulsive therapy headaches and nausea: a case series and review of the literature | journal = The Journal of ECT | volume = 27 | issue = 2 | pages = 165–167 | date = June 2011 | pmid = 21602639 | doi = 10.1097/YCT.0b013e3181e63346 }}{{cite journal | vauthors = Kast RE, Foley KF | title = Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects | journal = European Journal of Cancer Care | volume = 16 | issue = 4 | pages = 351–354 | date = July 2007 | pmid = 17587360 | doi = 10.1111/j.1365-2354.2006.00760.x }}
• Itching{{cite journal | vauthors = Twycross R, Greaves MW, Handwerker H, Jones EA, Libretto SE, Szepietowski JC, Zylicz Z | title = Itch: scratching more than the surface | journal = QJM | volume = 96 | issue = 1 | pages = 7–26 | date = January 2003 | pmid = 12509645 | doi = 10.1093/qjmed/hcg002 | doi-access = free }}{{cite journal | vauthors = Greaves MW | title = Itch in systemic disease: therapeutic options | journal = Dermatologic Therapy | volume = 18 | issue = 4 | pages = 323–327 | year = 2005 | pmid = 16297004 | doi = 10.1111/j.1529-8019.2005.00036.x | s2cid = 3210356 | doi-access = free }}
• Headaches and migraine{{cite journal | vauthors = Colombo B, Annovazzi PO, Comi G | title = Therapy of primary headaches: the role of antidepressants | journal = Neurological Sciences | volume = 25 | issue = Suppl 3 | pages = S171–S175 | date = October 2004 | pmid = 15549531 | doi = 10.1007/s10072-004-0280-x | s2cid = 21285843 }}{{cite journal | vauthors = Tajti J, Almási J | title = [Effects of mirtazapine in patients with chronic tension-type headache. Literature review] | language = hu | journal = Neuropsychopharmacologia Hungarica | volume = 8 | issue = 2 | pages = 67–72 | date = June 2006 | pmid = 17073214 }}

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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 tremors than tricyclic antidepressants, and less likely to cause nausea and sexual dysfunction than selective serotonin reuptake inhibitors.

Very common (≥10% incidence) adverse effects include constipation, dry mouth, sleepiness, increased appetite (17%) and weight gain (>7% increase in <50% of children).{{cite web|title=Axit Mirtazapine PRODUCT INFORMATION|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05345-3|work=TGA eBusiness Services|publisher=alphapharm|access-date=15 October 2013|date=25 October 2011|archive-date=20 September 2020|archive-url=https://web.archive.org/web/20200920021431/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05345-3|url-status=live}}{{cite web|title=Mirtazapine 30 mg Tablets – Summary of Product Characteristics|date=20 March 2013|access-date=24 October 2013|format=PDF|url=http://www.medicines.org.uk/emc/medicine/25201/SPC/Mirtazapine+30+mg+Tablets/|work=electronic Medicines Compendium|publisher=Sandoz Limited|archive-url=https://web.archive.org/web/20170731104144/http://www.medicines.org.uk/emc/medicine/25201/SPC/Mirtazapine+30+mg+Tablets/|archive-date=31 July 2017}}{{cite web|title=mirtazapine (Rx) – Remeron, Remeron SolTab|work=Medscape|publisher=WebMD|access-date=24 October 2013|url=http://reference.medscape.com/drug/remeron-soltab-mirtazapine-342966|archive-date=29 October 2013|archive-url=https://web.archive.org/web/20131029200106/http://reference.medscape.com/drug/remeron-soltab-mirtazapine-342966|url-status=live}}{{cite web | title = Australian Medicines Handbook | url = http://www.amh.net.au/ | year = 2013 | publisher = Australian Medicines Handbook Pty Ltd | access-date = 5 October 2013 | archive-date = 27 September 2011 | archive-url = https://web.archive.org/web/20110927131220/http://www.amh.net.au/ | url-status = live }}{{cite book | title = British National Formulary (BNF) | year = 2013 | edition = 65th | publisher = Pharmaceutical Press | pages = 1120 | isbn = 978-0857110848 | url = https://archive.org/details/bnf65britishnati0000unse | url-access = registration }}{{cite web|title=Remeron (Mirtazapine) Drug Information|url=http://www.rxlist.com/remeron-drug/side-effects-interactions.htm|website=RxList|access-date=28 March 2016|archive-date=4 May 2017|archive-url=https://web.archive.org/web/20170504234252/http://www.rxlist.com/remeron-drug/side-effects-interactions.htm|url-status=live}}{{cite journal | vauthors = Hummel J, Westphal S, Weber-Hamann B, Gilles M, Lederbogen F, Angermeier T, Luley C, Deuschle M, Kopf D | title = Serum lipoproteins improve after successful pharmacologic antidepressant treatment: a randomized open-label prospective trial | journal = The Journal of Clinical Psychiatry | volume = 72 | issue = 7 | pages = 885–891 | date = July 2011 | pmid = 21294998 | doi = 10.4088/JCP.09m05853blu }}{{cite journal | vauthors = McIntyre RS, Soczynska JK, Konarski JZ, Kennedy SH | title = The effect of antidepressants on lipid homeostasis: a cardiac safety concern? | journal = Expert Opinion on Drug Safety | volume = 5 | issue = 4 | pages = 523–537 | date = July 2006 | pmid = 16774491 | doi = 10.1517/14740338.5.4.523 | s2cid = 23740352 }}

Common (1–10% incidence) adverse effects include weakness, confusion, dizziness, fasciculations (muscle twitches), peripheral edema (swelling, usually of the lower limbs), and negative lab results like elevated transaminases, elevated serum triglycerides, and elevated total cholesterol.

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

In general, some antidepressants, especially selective serotonin reuptake inhibitors, can paradoxically exacerbate some peoples' depression or anxiety or cause suicidal ideation.{{cite journal | vauthors = Möller HJ | title = Is there evidence for negative effects of antidepressants on suicidality in depressive patients? A systematic review | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 256 | issue = 8 | pages = 476–496 | date = December 2006 | pmid = 17143567 | doi = 10.1007/s00406-006-0689-8 | s2cid = 22708700 }} 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, especially for people under the age of 25.

Mirtazapine may induce arthralgia (non-inflammatory joint pain).{{cite journal | vauthors = Passier A, van Puijenbroek E | title = Mirtazapine-induced arthralgia | journal = British Journal of Clinical Pharmacology | volume = 60 | issue = 5 | pages = 570–572 | date = November 2005 | pmid = 16236049 | pmc = 1884949 | doi = 10.1111/j.1365-2125.2005.02481.x }}

A case report published in 2000 noted an instance in which mirtazapine counteracted the action of clonidine, causing a dangerous rise in blood pressure.{{cite journal | vauthors = Abo-Zena RA, Bobek MB, Dweik RA | title = Hypertensive urgency induced by an interaction of mirtazapine and clonidine | journal = Pharmacotherapy | volume = 20 | issue = 4 | pages = 476–478 | date = April 2000 | pmid = 10772378 | doi = 10.1592/phco.20.5.476.35061 | s2cid = 9959199 }}

In a study comparing 32 antidepressants of all pharmacological classes, mirtazapine was one of the antidepressants most likely to cause nightmare disorder, sleepwalking, restless legs syndrome, night terrors and sleep paralysis.{{cite journal | vauthors = Natter J, Yokoyama T, Michel B | title = Relative frequency of drug-induced sleep disorders for 32 antidepressants in a large set of Internet user reviews | journal = Sleep | volume = 44 | issue = 12 | pages = zsab174 | date = December 2021 | pmid = 34252190 | doi = 10.1093/sleep/zsab174 | doi-access = free }}

Mirtazapine has been associated with an increased risk of death compared to other antidepressants in several studies. However, it is more likely that the residual differences between people prescribed mirtazapine rather than a selective serotonin reuptake inhibitor account for the difference in risk of mortality.{{cite journal | vauthors = Joseph RM, Jack RH, Morriss R, Knaggs RD, Butler D, Hollis C, Hippisley-Cox J, Coupland C | title = The risk of all-cause and cause-specific mortality in people prescribed mirtazapine: an active comparator cohort study using electronic health records | journal = BMC Med | volume = 20 | issue = 1 | pages = 43 | date = February 2022 | pmid = 35105363 | pmc = 8809032 | doi = 10.1186/s12916-022-02247-x | url = | doi-access = free }}

Stopping Mirtazapine and other antidepressants may cause withdrawal symptoms.{{cite journal | vauthors = Blier P | title = Pharmacology of rapid-onset antidepressant treatment strategies | journal = The Journal of Clinical Psychiatry | volume = 62 | issue = Suppl 15 | pages = 12–17 | year = 2001 | pmid = 11444761 }} A gradual and slow reduction in dose is recommended to minimize such symptoms.{{cite journal | vauthors = Vlaminck JJ, van Vliet IM, Zitman FG | title = [Withdrawal symptoms of antidepressants] | language = nl | journal = Nederlands Tijdschrift voor Geneeskunde | volume = 149 | issue = 13 | pages = 698–701 | date = March 2005 | pmid = 15819135 }} Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety, tinnitus, panic attacks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhea, nausea, vomiting, flu-like symptoms, allergy-like symptoms such as pruritus, headaches, and sometimes mania or hypomania.{{cite journal | vauthors = Klesmer J, Sarcevic A, Fomari V | title = Panic attacks during discontinuation of mirtazepine | journal = Canadian Journal of Psychiatry | volume = 45 | issue = 6 | pages = 570–571 | date = August 2000 | pmid = 10986577 }}{{cite journal | vauthors = MacCall C, Callender J | title = Mirtazapine withdrawal causing hypomania | journal = The British Journal of Psychiatry | volume = 175 | issue = 4 | pages = 390 | date = October 1999 | pmid = 10789310 | doi = 10.1192/bjp.175.4.390a | doi-access = free }}{{cite journal | vauthors = Ali S, Milev R | title = Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review of the literature | journal = Canadian Journal of Psychiatry | volume = 48 | issue = 4 | pages = 258–264 | date = May 2003 | pmid = 12776393 | doi = 10.1177/070674370304800410 | doi-access = free }}

Mirtazapine is considered to be relatively safe in the event of an overdose, although it is considered slightly more toxic in overdose than most of the selective serotonin reuptake inhibitors (except citalopram).{{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 = 238–250 | date = December 2008 | pmid = 19031375 | pmc = 3550116 | doi = 10.1007/bf03161207 }} Unlike the tricyclic antidepressants, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose.

Twelve reported fatalities have been attributed to mirtazapine overdose.{{cite journal | vauthors = Nikolaou P, Dona A, Papoutsis I, Spiliopoulou C, Maravelias C | title = Death Due to Mirtazapine Overdose | doi=10.1080/15563650902952273 | quote = Abstracts of the XXIX International Congress of the European Association of Poison Centres and Clinical Toxicologists, May 12–15, 2009, Stockholm, Sweden | year = 2009 | journal = Clinical Toxicology | volume = 47 | issue = 5 | pages = 436–510 |s2cid=218861198 | doi-access = free }}{{cite book | vauthors = Baselt RC | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 8th | publisher = Biomedical Publications | location = Foster City, CA | year = 2008 | pages = 1045–7 | isbn = 978-0-9626523-7-0 }} 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 selective serotonin reuptake inhibitors.{{cite journal | vauthors = Buckley NA, McManus PR | title = Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data | journal = BMJ | volume = 325 | issue = 7376 | pages = 1332–1333 | date = December 2002 | pmid = 12468481 | pmc = 137809 | doi = 10.1136/bmj.325.7376.1332 }}{{Unreliable medical source|date=October 2011}}

Concurrent use with inhibitors or inducers of the cytochrome P450 isoenzymes CYP1A2, CYP2D6, or CYP3A4 can result in altered concentrations of mirtazapine, as these are the main enzymes responsible for its metabolism. As examples, fluoxetine and paroxetine, inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while carbamazepine, an inducer, considerably decreases them. Liver impairment and moderate chronic kidney disease have been reported to decrease the oral clearance of mirtazapine by about 30%; severe kidney disease decreases it by 50%.

Mirtazapine in combination with a selective serotonin reuptake inhibitor, serotonin–norepinephrine reuptake inhibitor, or tricyclic antidepressant as an augmentation strategy is considered to be relatively safe and is often employed therapeutically but caution should be given when combined with fluvoxamine. There is a combination of venlafaxine and mirtazapine, sometimes referred to as "California rocket fuel".{{cite book | vauthors = Stahl SM | title = Stahl's Essential Psychopharmacology Online: Print and Online | publisher = Cambridge University Press | location = Cambridge, UK | year = 2008 | isbn = 978-0-521-74609-0 | url = http://stahlonline.cambridge.org/prescribers_drug.jsf?page=0521683505c57_p325-330.html.therapeutics&name=Mirtazapine&title=Therapeutics | access-date = 21 January 2012 | archive-date = 19 June 2020 | archive-url = https://web.archive.org/web/20200619204935/https://stahlonline.cambridge.org/prescribers_drug.jsf?page=0521683505c57_p325-330.html.therapeutics&name=Mirtazapine&title=Therapeutics | url-status = live }}{{cite journal | vauthors = Silva J, Mota J, Azevedo P | title = California rocket fuel: And what about being a first line treatment? | journal = European Psychiatry | date=March 2016 | volume = 33 | pages = S551 | doi = 10.1016/j.eurpsy.2016.01.2033 | s2cid = 75595266 }} Several case reports document serotonin syndrome induced by the combination of mirtazapine with other agents (olanzapine,{{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 Neurologica Taiwanica | volume = 24 | issue = 4 | pages = 117–121 | date = December 2015 | pmid = 27333965 }} quetiapine,{{cite journal | vauthors = Saguin E, Keou S, Ratnam C, Mennessier C, Delacour H, Lahutte B | title = Severe rhabdomyolysis induced by quetiapine and mirtazapine in a French military soldier | journal = Journal of the Royal Army Medical Corps | volume = 164 | issue = 2 | pages = 127–129 | date = May 2018 | pmid = 29632134 | doi = 10.1136/jramc-2018-000939 | s2cid = 4737517 }} tramadol and venlafaxine{{cite journal | vauthors = Houlihan DJ | title = Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine | journal = The Annals of Pharmacotherapy | volume = 38 | issue = 3 | pages = 411–413 | date = March 2004 | pmid = 14970364 | doi = 10.1345/aph.1D344 | s2cid = 33912489 }}). Adding fluvoxamine to treatment with mirtazapine may cause a significant increase in mirtazapine concentration. This interaction may necessitate an adjustment of the mirtazapine dosage.{{cite journal | vauthors = Anttila AK, Rasanen L, Leinonen EV | title = Fluvoxamine augmentation increases serum mirtazapine concentrations three- to fourfold | journal = The Annals of Pharmacotherapy | volume = 35 | issue = 10 | pages = 1221–1223 | date = October 2001 | pmid = 11675851 | doi = 10.1345/aph.1A014 | s2cid = 44807359 }}{{Cite web |title=Fluvoxamine and mirtazapine Interactions |url=https://www.drugs.com/drug-interactions/fluvoxamine-with-mirtazapine-1128-0-1640-0.html |access-date=4 December 2022 |website=Drugs.com |archive-date=4 December 2022 |archive-url=https://web.archive.org/web/20221204190716/https://www.drugs.com/drug-interactions/fluvoxamine-with-mirtazapine-1128-0-1640-0.html |url-status=live }}

According to information from the manufacturers, mirtazapine should not be started within two weeks of any monoamine oxidase inhibitor usage; likewise, monoamine oxidase inhibitors should not be administered within two weeks of discontinuing mirtazapine.

The addition of mirtazapine to a monoamine oxidase inhibitor, while potentially having typical or idiosyncratic (unique to the individual) reactions not herein described, does not appear to cause serotonin syndrome. This is per the fact that the 5-HT_2A receptor is the predominant serotonin receptor thought to be involved in the pathophysiology of serotonin syndrome (with the 5-HT_1A receptor seeming to be protective). Mirtazapine is a potent 5-HT_2A receptor antagonist, and cyproheptadine, a medication that shares this property, mediates recovery from serotonin syndrome and is an antidote against it.{{cite journal | vauthors = Iqbal MM, Basil MJ, Kaplan J, Iqbal MT | title = Overview of serotonin syndrome | journal = Annals of Clinical Psychiatry | volume = 24 | issue = 4 | pages = 310–318 | date = November 2012 | pmid = 23145389 }}

There is a possible interaction that results in a hypertensive crisis when mirtazapine is given to a patient who has already been on steady doses of clonidine. This involves a subtle consideration, when patients have been on chronic therapy with clonidine and suddenly stop the dosing, a rapid hypertensive rebound sometimes (20%) occurs from increased sympathetic outflow. Clonidine's blood pressure lowering effects are due to stimulation of presynaptic α₂ autoreceptors in the CNS which suppress sympathetic outflow. Mirtazapine itself blocks these same α₂ autoreceptors, so the effect of adding mirtazapine to a patient stabilized on clonidine may precipitate withdrawal symptoms.{{cite web|url=https://www.reliasmedia.com/articles/46173-interaction-between-mirtazapine-and-clonidine|title=Interactions Between Mirtazapine and Clonidine|access-date=15 January 2021|archive-date=21 January 2021|archive-url=https://web.archive.org/web/20210121041118/https://www.reliasmedia.com/articles/46173-interaction-between-mirtazapine-and-clonidine|url-status=live}}

Mirtazapine has been used as a hallucinogen antidote to block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).{{cite journal | vauthors = Yates G, Melon E | title = Trip-killers: a concerning practice associated with psychedelic drug use | journal = Emerg Med J | volume = 41 | issue = 2 | pages = 112–113 | date = January 2024 | pmid = 38123961 | doi = 10.1136/emermed-2023-213377 | url = https://web.archive.org/web/20250511111827oe_/https://s3.amazonaws.com/crawl.prod.proquest.com/fpcache/71f445805bfb61341cbc438c8ae23bd3.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEBMaCXVzLWVhc3QtMSJIMEYCIQDETX7YpaG5THA%2FNbKR0d92wr6h%2Bgg9preNcKjAsEqo%2BQIhAIlPGGWOeUc23LqhBzRYbxvSXB9aqSe2vVonl4nacAhhKp0CCLz%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEQABoMNTE4MzQ2ODQ4MzQxIgy9ji58Qtbi%2BavuKeYq8QEDL1U5KZDQ0bXFyVapeqJgE%2FX6x8DcJfFU8DAXYZPSQEwrIdfPbZWcYsH340deru%2FUHnNaGGpuHFoVzui%2FMbqBz7MANcowj%2FL1%2BQZzQ5hXh5KM3BW8E6NRzrQyuPRmBy7kQUkx8%2BjTN%2BXSMgF%2FCAs6Dn9fScgBGz3ddkwRZXDkjasqMP65RCPKhagK68cyMbf3oX%2BKS8a4Kltc2rk3CnWEhOKrZU4mIxq07DikLAXQbl8YRZJIkeOhN5TgBaLWJqyn1td2VWCMymAaFsqtPWHwXnEfsolRlfDooe6QXfE2YwX5PxBVJU7GPXRgrAqPjwtJMOCHgsEGOpwBYif%2BaDMBdz3IEghuvCvorAS0mkHzdcOz%2Fi7AzuN9nch%2FIm8llhMsN41aAWHuSG25pnhhftauFsg7rbGsrW2nl2kq2upi9zP7y%2Fnqk93jcP0kr0jM8zU12bYoSTsToQJsshH4N%2BTQUMwlzRQfeVv8MXdq%2BgSTTzJrWNwT1yNzye3rSHjvOumbNl6sgBISw7QqRzhB6hZTuf8AcI%2B7&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20250511T111826Z&X-Amz-SignedHeaders=host&X-Amz-Credential=ASIAXRL7BHBKRAKCQVVB%2F20250511%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Expires=3600&X-Amz-Signature=20bb1b90e4c8dbaa4115c954387617ebe2f55269bdd517692f1380193ed3f769}}{{cite journal | vauthors = Suran M | title = Study Finds Hundreds of Reddit Posts on "Trip-Killers" for Psychedelic Drugs | journal = JAMA | volume = 331 | issue = 8 | pages = 632–634 | date = February 2024 | pmid = 38294772 | doi = 10.1001/jama.2023.28257 | url = }}

{{See also|Pharmacology of antidepressants|Tetracyclic antidepressant#Pharmacology}}

Mirtazapine is sometimes described as a noradrenergic and specific serotonergic antidepressant (NaSSA), although the actual evidence in support of this label has been regarded as poor. It is a tetracyclic piperazine-azepine.{{cite web|title=Mirtazapine|url=https://www.drugbank.ca/drugs/DB00370|website=Drugbank|access-date=16 January 2020|archive-date=19 August 2020|archive-url=https://web.archive.org/web/20200819113616/https://www.drugbank.ca/drugs/DB00370|url-status=live}}

Mirtazapine has antihistamine, α₂-blocker, and antiserotonergic activity.{{cite journal | vauthors = Frazer A | title = Pharmacology of antidepressants | journal = Journal of Clinical Psychopharmacology | volume = 17 | issue = Suppl 1 | pages = 2S–18S | date = April 1997 | pmid = 9090573 | doi = 10.1097/00004714-199704001-00002 }} It is specifically a potent antagonist or inverse agonist of the α_2A-, α_2B-, and α_2C-adrenergic receptors, the serotonin 5-HT_2A, 5-HT_2C, and the histamine H₁ receptor. Unlike many other antidepressants, it does not inhibit the reuptake of serotonin, norepinephrine, or dopamine, nor does it inhibit monoamine oxidase.{{cite journal | vauthors = Fisar Z, Hroudová J, Raboch J | title = Inhibition of monoamine oxidase activity by antidepressants and mood stabilizers | journal = Neuro Endocrinology Letters | volume = 31 | issue = 5 | pages = 645–656 | year = 2010 | pmid = 21200377 }} Similarly, mirtazapine has weak or no activity as an anticholinergic or blocker of sodium or calcium channels, in contrast to most tricyclic antidepressants. In accordance, it has better tolerability and low toxicity in overdose.{{cite journal | vauthors = Richelson E | title = Pharmacology of antidepressants | journal = Mayo Clinic Proceedings | volume = 76 | issue = 5 | pages = 511–527 | date = May 2001 | pmid = 11357798 | doi = 10.4065/76.5.511 | doi-access = free }} As an H₁ receptor antagonist, mirtazapine is extremely potent, and is in fact one of the most potent H₁ receptor inverse agonists among tricyclic and tetracyclic antidepressants and most antihistamines in general.{{cite book| vauthors = Brunton L, Chabner BA, Knollman B |title=Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition|url=https://books.google.com/books?id=e_yAOpyyaowC|date=14 January 2011|publisher=McGraw Hill Professional|isbn=978-0-07-176939-6|page=410}}{{cite book|vauthors=Schatzberg AF, Nemeroff CB|title=The American Psychiatric Association Publishing Textbook of Psychopharmacology|url=https://books.google.com/books?id=v9wnDwAAQBAJ&pg=PA322|date=10 May 2017|publisher=American Psychiatric Pub|isbn=978-1-61537-122-8|pages=322–|access-date=14 August 2017|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110194022/https://books.google.com/books?id=v9wnDwAAQBAJ&pg=PA322|url-status=live}} Antagonism of the H₁ receptor is by far the strongest activity of mirtazapine, with the drug acting as a selective H₁ receptor antagonist at low concentrations.

The (S)-(+) enantiomer of mirtazapine is responsible for antagonism of the serotonin 5-HT_2A and 5-HT_2C receptors, while the (R)-(–) enantiomer is responsible for antagonism of the 5-HT₃ receptor.{{cite book|veditors=Brayfield A|chapter=Mirtazapine|title=Martindale: The Complete Drug Reference|publisher=The Royal Pharmaceutical Society of Great Britain|access-date=3 November 2013|date=30 January 2013|chapter-url=http://www.medicinescomplete.com/mc/martindale/current/11022-r.htm|archive-date=14 January 2021|archive-url=https://web.archive.org/web/20210114165327/https://about.medicinescomplete.com/|url-status=live}} Both enantiomers are involved in antagonism of the H₁ and α₂-adrenergic receptors, although the (S)-(+) enantiomer is the stronger antihistamine.

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).{{cite journal | vauthors = Olianas MC, Dedoni S, Onali P | title = The atypical antidepressant mianserin exhibits agonist activity at κ-opioid receptors | journal = British Journal of Pharmacology | volume = 167 | issue = 6 | pages = 1329–1341 | date = November 2012 | pmid = 22708686 | pmc = 3504997 | doi = 10.1111/j.1476-5381.2012.02078.x }}

Antagonism of the α₂-adrenergic receptors, which function largely as inhibitory autoreceptors and heteroreceptors, enhances adrenergic and serotonergic neurotransmission, notably central 5-HT_1A 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.{{cite journal | vauthors = De Boer T, Nefkens F, Van Helvoirt A | title = The alpha 2-adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo | journal = European Journal of Pharmacology | volume = 253 | issue = 1–2 | pages = R5–R6 | date = February 1994 | pmid = 7912194 | doi = 10.1016/0014-2999(94)90778-1 }}{{Unreliable medical source|date=October 2011}}{{cite journal | vauthors = Berendsen HH, Broekkamp CL | title = Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine | journal = Psychopharmacology | volume = 133 | issue = 3 | pages = 275–282 | date = October 1997 | pmid = 9361334 | doi = 10.1007/s002130050402 | s2cid = 230492 }}{{cite journal | vauthors = Nakayama K, Sakurai T, Katsu H | title = Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation | journal = Brain Research Bulletin | volume = 63 | issue = 3 | pages = 237–241 | date = April 2004 | pmid = 15145142 | doi = 10.1016/j.brainresbull.2004.02.007 | s2cid = 14393829 }}{{Unreliable medical source|date=October 2011}} Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT_1A receptor. Increased activation of the central 5-HT_1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs.{{cite journal | vauthors = Blier P, Abbott FV | title = Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain | journal = Journal of Psychiatry & Neuroscience | volume = 26 | issue = 1 | pages = 37–43 | date = January 2001 | pmid = 11212592 | pmc = 1408043 | url = http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-26/issue-1/pdf/pg37.pdf | access-date = 20 June 2009 | url-status = dead | archive-url = https://web.archive.org/web/20160306214237/https://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-26/issue-1/pdf/pg37.pdf | archive-date = 6 March 2016 }}

Antagonism of the 5-HT₂ subfamily of receptors and inverse agonism of the 5-HT_2C receptor appears to be in part responsible for mirtazapine's efficacy in the treatment of depressive states.{{cite journal | vauthors = Millan MJ | title = Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies | journal = Therapie | volume = 60 | issue = 5 | pages = 441–460 | year = 2005 | pmid = 16433010 | doi = 10.2515/therapie:2005065 }}{{cite journal | vauthors = Dekeyne A, Millan MJ | title = Discriminative stimulus properties of the atypical antidepressant, mirtazapine, in rats: a pharmacological characterization | journal = Psychopharmacology | volume = 203 | issue = 2 | pages = 329–341 | date = April 2009 | pmid = 18709360 | doi = 10.1007/s00213-008-1259-8 | doi-access = free }}

Mirtazapine increases dopamine release in the prefrontal cortex.[https://web.archive.org/web/20180109064133/https://pdfs.semanticscholar.org/4ab3/7aa1be6b898432f5faf5d5ff4a780e106a7b.pdf Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation.] Accordingly, it was shown that by blocking the α₂-adrenergic receptors and 5-HT_2C receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats.{{cite journal | vauthors = Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A, Dekeyne A, Nicolas JP, Lejeune F | title = Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram | journal = The European Journal of Neuroscience | volume = 12 | issue = 3 | pages = 1079–1095 | date = March 2000 | pmid = 10762339 | doi = 10.1046/j.1460-9568.2000.00982.x | s2cid = 23098292 | doi-access = free }} In addition, mirtazapine's antagonism of 5-HT_2A receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor.{{cite journal | vauthors = Fawcett J, Barkin RL | title = Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression | journal = Journal of Affective Disorders | volume = 51 | issue = 3 | pages = 267–285 | date = December 1998 | pmid = 10333982 | doi = 10.1016/S0165-0327(98)00224-9 }} Mirtazapine has been shown to lower drug seeking behaviour (more specifically to methamphetamine) in various human and animal studies.{{cite journal | vauthors = Graves SM, Napier TC | title = SB 206553, a putative 5-HT2C inverse agonist, attenuates methamphetamine-seeking in rats | journal = BMC Neuroscience | volume = 13 | issue = 1 | pages = 65 | date = June 2012 | pmid = 22697313 | pmc = 3441362 | doi = 10.1186/1471-2202-13-65 | doi-access = free }}{{cite journal | vauthors = Colfax GN, Santos GM, Das M, Santos DM, Matheson T, Gasper J, Shoptaw S, Vittinghoff E | title = Mirtazapine to reduce methamphetamine use: a randomized controlled trial | journal = Archives of General Psychiatry | volume = 68 | issue = 11 | pages = 1168–1175 | date = November 2011 | pmid = 22065532 | pmc = 3437988 | doi = 10.1001/archgenpsychiatry.2011.124 }}{{cite journal | vauthors = Herrold AA, Shen F, Graham MP, Harper LK, Specio SE, Tedford CE, Napier TC | title = Mirtazapine treatment after conditioning with methamphetamine alters subsequent expression of place preference | journal = Drug and Alcohol Dependence | volume = 99 | issue = 1–3 | pages = 231–239 | date = January 2009 | pmid = 18945553 | doi = 10.1016/j.drugalcdep.2008.08.005 }} It is also being investigated in substance abuse disorders to reduce withdrawal effects and improve remission rates.{{cite journal | vauthors = Rose ME, Grant JE | title = Pharmacotherapy for methamphetamine dependence: a review of the pathophysiology of methamphetamine addiction and the theoretical basis and efficacy of pharmacotherapeutic interventions | journal = Annals of Clinical Psychiatry | volume = 20 | issue = 3 | pages = 145–155 | year = 2008 | pmid = 18633741 | doi = 10.1080/10401230802177656 }}{{cite journal | vauthors = Brackins T, Brahm NC, Kissack JC | title = Treatments for methamphetamine abuse: a literature review for the clinician | journal = Journal of Pharmacy Practice | volume = 24 | issue = 6 | pages = 541–550 | date = December 2011 | pmid = 22095579 | doi = 10.1177/0897190011426557 | s2cid = 37335642 }}{{cite journal | vauthors = Brensilver M, Heinzerling KG, Shoptaw S | title = Pharmacotherapy of amphetamine-type stimulant dependence: an update | journal = Drug and Alcohol Review | volume = 32 | issue = 5 | pages = 449–460 | date = September 2013 | pmid = 23617468 | pmc = 4251965 | doi = 10.1111/dar.12048 }}

Mirtazapine significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and irritable bowel syndrome in affected individuals.{{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 = 469–470 | date = September 2001 | pmid = 11585276 | doi = 10.1007/s005200000215 | s2cid = 24132032 }} Mirtazapine may be used as an inexpensive antiemetic alternative to Ondansetron. In conjunction with substance abuse counseling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success. In contrast to mirtazapine, the selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, and some tricyclic antidepressants acutely increase the general activity of the 5-HT_2A, 5-HT_2C, and 5-HT₃ receptors, leading to a number of negative changes and side effects, the most prominent of which include anorexia, insomnia, nausea, and diarrhea, among others. However, most of these adverse effects are temporary, since down regulation of 5-HT_2A receptors eventually occurs following chronic SSRI treatment, and desensitization of 5-HT₃ receptors often occurs within a week or less. This is precisely why SSRIs have a delayed antidepressant and anxiolytic effect, and occasionally, an acute anxiogenic effect before down regulation occurs. Mirtazapine, on the other hand, is an antagonist of the 5-HT_2A receptor, and antagonists at this receptor typically induce reverse tolerance.{{cite journal | vauthors = Yadav PN, Kroeze WK, Farrell MS, Roth BL | title = Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 339 | issue = 1 | pages = 99–105 | date = October 2011 | pmid = 21737536 | pmc = 3186284 | doi = 10.1124/jpet.111.183780 }} Thus, the antidepressant and anxiolytic effects of mirtazapine occur more rapidly than with SSRIs. Furthermore, its reduced incidence of sexual dysfunction (such as loss of libido and anorgasmia) could be a product of negligible binding to the serotonin transporter and antagonism of the 5-HT_2A receptors; however, Mirtazapine's high affinity towards and inverse agonism of the 5-HT_2C receptors may greatly attenuate those pro-sexual factors (as evidenced by the pro-sexual effects of drugs like m-CPP and lorcaserin which agonize 5-HT_2C receptors in a reasonably selective manner). As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.{{cite journal | vauthors = Caldis EV, Gair RD | title = Mirtazapine for treatment of nausea induced by selective serotonin reuptake inhibitors | journal = Canadian Journal of Psychiatry | volume = 49 | issue = 10 | pages = 707 | date = October 2004 | pmid = 15560319 | doi = 10.1177/070674370404901014 | doi-access = free }}

Mirtazapine does not have pro-serotonergic activity and thus does not cause serotonin syndrome.{{cite journal | vauthors = Gillman PK | title = A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status | journal = Human Psychopharmacology | volume = 21 | issue = 2 | pages = 117–125 | date = March 2006 | pmid = 16342227 | doi = 10.1002/hup.750 | s2cid = 23442056 }}{{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 = 1046–1051 | date = June 2006 | pmid = 16460699 | doi = 10.1016/j.biopsych.2005.11.016 | s2cid = 12179122 }} This is in accordance with the fact that it is not a serotonin reuptake inhibitor or monoamine oxidase inhibitor, nor a serotonin receptor agonist. There are no reports of serotonin syndrome in association with mirtazapine alone, and mirtazapine has not been found to cause serotonin syndrome in overdose.{{cite journal | vauthors = Berling I, Isbister GK | title = Mirtazapine overdose is unlikely to cause major toxicity | journal = Clinical Toxicology | volume = 52 | issue = 1 | pages = 20–24 | date = January 2014 | pmid = 24228948 | pmc = 3894718 | doi = 10.3109/15563650.2013.859264 }} However, there are a handful of case reports of serotonin syndrome occurring with mirtazapine in combination with serotonergic drugs like selective serotonin reuptake inhibitors, although such reports are very rare, and do not necessarily implicate mirtazapine as causative.{{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 = es | journal = Revista Espanola de Anestesiologia y Reanimacion | volume = 56 | issue = 8 | pages = 515–516 | date = October 2009 | pmid = 19994622 | doi = 10.1016/s0034-9356(09)70444-x }}{{cite journal | vauthors = Butler MC, Di Battista M, Warden M | title = Sertraline-induced serotonin syndrome followed by mirtazapine reaction | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 34 | issue = 6 | pages = 1128–1129 | date = August 2010 | pmid = 20430060 | doi = 10.1016/j.pnpbp.2010.04.015 | s2cid = 20985498 }}{{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 = International Journal of Clinical Pharmacy | volume = 34 | issue = 5 | pages = 686–688 | date = October 2012 | pmid = 22752315 | doi = 10.1007/s11096-012-9666-7 | s2cid = 38692665 }}

(R)-(–)-mirtazapine is a potent 5-HT₃ blocker. It may relieve chemotherapy-related and advanced cancer-related nausea.

Mirtazapine is a very strong H₁ receptor antagonist and, as a result, it can cause powerful sedative and hypnotic effects. 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.{{cite journal | vauthors = Sato H, Ito C, Tashiro M, Hiraoka K, Shibuya K, Funaki Y, Iwata R, Matsuoka H, Yanai K | title = Histamine H₁ receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers | journal = Psychopharmacology | volume = 230 | issue = 2 | pages = 227–234 | date = November 2013 | pmid = 23728612 | doi = 10.1007/s00213-013-3146-1 | s2cid = 3052216 }} After a short period of chronic treatment, however, the H₁ receptor tends to sensitize 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 affected individuals. It may also contribute to weight gain, however. In contrast to the H₁ receptor, mirtazapine has only low affinity for the muscarinic acetylcholine receptors, although anticholinergic side effects like dry mouth, constipation, and mydriasis are still sometimes seen in clinical practice.{{cite journal | vauthors = Burrows GD, Kremer CM | title = Mirtazapine: clinical advantages in the treatment of depression | journal = Journal of Clinical Psychopharmacology | volume = 17 | issue = Suppl 1 | pages = 34S–39S | date = April 1997 | pmid = 9090576 | doi = 10.1097/00004714-199704001-00005 }}

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 N-demethylation and hydroxylation via cytochrome P450 enzymes, CYP1A2, CYP2D6, CYP3A4.{{cite journal | vauthors = Zhu Y, Chen G, Zhang K, Chen C, Chen W, Zhu M, Jiang H | title = High-Throughput Metabolic Soft-Spot Identification in Liver Microsomes by LC/UV/MS: Application of a Single Variable Incubation Time Approach | journal = Molecules | volume = 27 | issue = 22 | pages = 8058 | date = November 2022 | pmid = 36432161 | pmc = 9693510 | doi = 10.3390/molecules27228058 | doi-access = free }} The overall elimination half-life is 20–40 hours, and this is independent of dosage. It is conjugated in the kidney for excretion in the urine, where 75% of the drug is excreted,{{cite book |vauthors = Al-Majed A, Bakheit AH, Alharbi RM, Abdel Aziz HA |title=Mirtazapine |journal= |series=Profiles of Drug Substances, Excipients and Related Methodology |date=1 January 2018 |volume=43 |pages=209–254 |doi=10.1016/bs.podrm.2018.01.002 |pmid=29678261 |isbn=9780128151259 }} and about 15% is eliminated in feces.{{rp|430}} Desmethylmirtazapine is an active metabolite of mirtazapine which is believed to contribute about 3-10% to the drug's overall effects and has a half-life of about 25 hours.

Mirtazapine is a tetracyclic piperazinoazepine; mianserin was developed by the same team of organic chemists and mirtazapine differs from it via the addition of a nitrogen atom in one of the rings.{{rp|429}}{{cite web|title=Mirtazapine label – Australia|url=http://secure.healthlinks.net.au/content/msd/pi.cfm?product=mkpavant|publisher=GuildLink, a wholly owned subsidiary company of the Pharmacy Guild of Australia.|date=27 May 2016|access-date=22 July 2017|archive-date=21 November 2018|archive-url=https://web.archive.org/web/20181121120001/http://secure.healthlinks.net.au/content/msd/pi.cfm?product=mkpavant|url-status=usurped}}{{cite journal | vauthors = Kelder J, Funke C, De Boer T, Delbressine L, Leysen D, Nickolson V | title = A comparison of the physicochemical and biological properties of mirtazapine and mianserin | journal = The Journal of Pharmacy and Pharmacology | volume = 49 | issue = 4 | pages = 403–411 | date = April 1997 | pmid = 9232538 | doi = 10.1111/j.2042-7158.1997.tb06814.x | s2cid = 12270528 | doi-access = free }} It is a racemic mixture of enantiomers. The (S)-(+)-enantiomer is known as esmirtazapine.

Analogues of mirtazapine include mianserin, setiptiline, and aptazapine.

A chemical synthesis of mirtazapine has been published. The first step of synthesis is a condensation reaction between the molecule 2-chloro 3-cyanopyridine and the molecule 1-methyl-3-phenylpiperazine.{{cite journal | doi = 10.1080/00304940709458595| title = Improved Synthesis of Mirtazapine| journal = Organic Preparations and Procedures International| volume = 39| issue = 4| pages = 399–402| year = 2007| vauthors = Srinivasa Rao DV, Dandala R, Handa VK, Sivakumaran M, Raghava Reddy AV, Naidu A | s2cid = 98056931}}

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.{{cite book| vauthors = Schatzberg AF | veditors = Schatzberg AF, Nemeroff CB |title=The American Psychiatric Publishing Textbook of Psychopharmacology|date=2009|publisher=American Psychiatric Pub.|location=Washington, D.C.|isbn=9781585623099|edition=4th|chapter=Chapter 21: Mirtazapine}}{{rp|429}}{{cite journal| vauthors = Kaspersen FM, Van Rooij FA, Sperling EG, Wieringa JH |title=The synthesis of org 3770 labelled with 3H, 13C AND 14C|journal=Journal of Labelled Compounds and Radiopharmaceuticals|date=September 1989|volume=27|issue=9|pages=1055–1068|doi=10.1002/jlcr.2580270911}}{{cite web|title=Remeron New FDA Drug Approvalh|url=http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/135/remeron-mirtazapine|website=Centerwatch|access-date=26 August 2016|archive-date=5 August 2019|archive-url=https://web.archive.org/web/20190805013642/https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/135/remeron-mirtazapine|url-status=live}}

File:Mirtazapine generic.png

Mirtazapine is the English and French generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|JAN|Japanese Accepted Name}}.{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA696|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=696–}}{{cite web|url=https://www.drugs.com/international/mirtazapine.html|title=Mirtazapine - Drugs.com|access-date=14 August 2017|archive-date=17 November 2018|archive-url=https://web.archive.org/web/20181117063153/https://www.drugs.com/international/mirtazapine.html|url-status=live}}{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA183|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|page=183}} Its generic name in Spanish, Italian, and Portuguese is mirtazapina and in German, Turkish and Swedish is mirtazapin.

Mirtazapine is marketed under many brand names worldwide, including Adco-Mirteron, Afloyan, Amirel, Arintapin Smelt, Avanza, Axit, Azapin, Beron, Bilanz, Blumirtax, 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, Mirtanza, Mirtapax, Mirtapil, Mirtapine, Mirtaron, Mirtastad, Mirtax, Mirtaz, Mirtazap, Mirtazapin, Mirtazapina, Mirtazapine, Mirtazapinum, Mirtazelon, Mirtazon, Mirtazonal, Mirtel, Mirtimash, Mirtin, Mirtine, Mirtor, Mirzapine, Mirzaten, Mirzest, Mitaprex, Mitaxind, Mitocent, Mitrazin, Mizapin, Motofen, Mytra, Norset, Noxibel, Pharmataz, Promyrtil, Rapizapine, Ramure, Razapina, Redepra, Reflex, Remergil, Remergon, Remeron, Remirta, Rexer, Saxib, Sinmaron, Smilon, Tazepin, Tazimed, Tetrazic, Tifona, U-Mirtaron, U-zepine, Valdren, Vastat, Velorin, Yarocen, Zania, Zapex, Zapsy,Zestat, Zismirt, Zispin, Zuleptan, and Zulin.

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

• Found ineffective for Sleep apnea/hypopnea{{cite journal | vauthors = Kohler M, Bloch KE, Stradling JR | title = Pharmacological approaches to the treatment of obstructive sleep apnoea | journal = Expert Opinion on Investigational Drugs | volume = 18 | issue = 5 | pages = 647–656 | date = May 2009 | pmid = 19388881 | doi = 10.1517/13543780902877674 | s2cid = 57089477 | url = https://www.zora.uzh.ch/id/eprint/28318/1/28318_manuscript.pdf | access-date = 23 December 2021 | archive-date = 12 April 2022 | archive-url = https://web.archive.org/web/20220412003252/https://www.zora.uzh.ch/id/eprint/28318/1/28318_manuscript.pdf | url-status = dead }}{{cite journal | vauthors = Marshall NS, Yee BJ, Desai AV, Buchanan PR, Wong KK, Crompton R, Melehan KL, Zack N, Rao SG, Gendreau RM, Kranzler J, Grunstein RR | title = Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea | journal = Sleep | volume = 31 | issue = 6 | pages = 824–831 | date = June 2008 | pmid = 18548827 | pmc = 2442407 | doi = 10.1093/sleep/31.6.824 }}
• Secondary symptoms of autistic spectrum conditions and other pervasive developmental disorders{{cite journal | vauthors = Masi G | title = Pharmacotherapy of pervasive developmental disorders in children and adolescents | journal = CNS Drugs | volume = 18 | issue = 14 | pages = 1031–1052 | year = 2004 | pmid = 15584771 | doi = 10.2165/00023210-200418140-00006 | s2cid = 25531695 }}{{cite journal | vauthors = Marek GJ, Carpenter LL, McDougle CJ, Price LH | title = Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders | journal = Neuropsychopharmacology | volume = 28 | issue = 2 | pages = 402–412 | date = February 2003 | pmid = 12589395 | doi = 10.1038/sj.npp.1300057 | doi-access = free }}
• Antipsychotic-induced akathisia.{{cite journal | vauthors = Kumar R, Sachdev PS | title = Akathisia and second-generation antipsychotic drugs | journal = Current Opinion in Psychiatry | volume = 22 | issue = 3 | pages = 293–299 | date = May 2009 | pmid = 19378382 | doi = 10.1097/YCO.0b013e32832a16da | s2cid = 31506138 }}{{cite journal | vauthors = Hieber R, Dellenbaugh T, Nelson LA | title = Role of mirtazapine in the treatment of antipsychotic-induced akathisia | journal = The Annals of Pharmacotherapy | volume = 42 | issue = 6 | pages = 841–846 | date = June 2008 | pmid = 18460588 | doi = 10.1345/aph.1K672 | s2cid = 19733585 }}
• Drug withdrawal, dependence and detoxification{{cite journal | vauthors = Graves SM, Rafeyan R, Watts J, Napier TC | title = Mirtazapine, and mirtazapine-like compounds as possible pharmacotherapy for substance abuse disorders: evidence from the bench and the bedside | journal = Pharmacology & Therapeutics | volume = 136 | issue = 3 | pages = 343–353 | date = December 2012 | pmid = 22960395 | pmc = 3483434 | doi = 10.1016/j.pharmthera.2012.08.013 }}
• Negative, depressive and cognitive symptoms of schizophrenia (as an adjunct){{cite book | isbn = 9789400758056 | title = Polypharmacy in Psychiatry Practice, Volume I | vauthors = Ritsner, MS | veditors = Ritsner MS | year = 2013 | publisher = Springer Science+Business Media Dordrecht | doi = 10.1007/978-94-007-5805-6 | s2cid = 7705779 }}
• A case report has been published in which mirtazapine reduced visual hallucinations in a patient with Parkinson's disease psychosis (PDP).{{cite journal | vauthors = Tagai K, Nagata T, Shinagawa S, Tsuno N, Ozone M, Nakayama K | title = Mirtazapine improves visual hallucinations in Parkinson's disease: a case report | journal = Psychogeriatrics | volume = 13 | issue = 2 | pages = 103–107 | date = June 2013 | pmid = 23909968 | doi = 10.1111/j.1479-8301.2012.00432.x | s2cid = 1154368 | doi-access = free }} This is in alignment with recent findings that inverse agonists at the 5-HT_2A receptors are efficacious in attenuating the symptoms of Parkinson's disease psychosis. As is supported by the common practice of prescribing low-dose quetiapine and clozapine for PDP at doses too low to antagonize the D₂ receptor, but sufficiently high doses to inversely agonize the 5-HT_2A receptors.
• Eight case reports have been reported in five papers on the use of mirtazapine in the treatment of hives as of 2017.{{cite journal | vauthors = Eskeland S, Halvorsen JA, Tanum L | title = Antidepressants have Anti-inflammatory Effects that may be Relevant to Dermatology: A Systematic Review | journal = Acta Dermato-Venereologica | volume = 97 | issue = 8 | pages = 897–905 | date = August 2017 | pmid = 28512664 | doi = 10.2340/00015555-2702 | doi-access = free | hdl = 10852/63759 | hdl-access = free }}
• Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B). Found ineffective and potentially harmful.{{cite journal |vauthors= Higginson IJ, Brown ST, Oluyase OO, May P, Maddocks M, Costantini M, Bajwah S, Normand C, Bausewein C, Simon T, Ryan K, Currow D, Johnson M, Hart S, Mather H, Krajnik M, Tanzi S, Ghirotto L, Bolton C, Janowiak P, Turola E, Jolley C, Murden G, Wilcock A, Farsides B, Brown JM | date=September 2024 |title= Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B). |journal=The Lancet Respiratory Medicine | volume=42 | doi=10.1016/S2213-2600(24)00187-5 | doi-access=free | pmid=39278621}}

Mirtazapine also has some veterinary use in cats and dogs. Mirtazapine is sometimes prescribed as an appetite stimulant for cats or dogs experiencing loss of appetite due to medical conditions such as chronic kidney disease. It is especially useful for treating combined poor appetite and nausea in cats and dogs.{{cite journal|title=Mirtazapine (Remeron)|website=Vin.com|url=http://www.veterinarypartner.com/Content.plx?P=A&A=2552|date=8 August 2017|vauthors=Gfeller R, Thomas M, Mayo I|access-date=12 January 2013|archive-date=6 December 2010|archive-url=https://web.archive.org/web/20101206073647/http://www.veterinarypartner.com/Content.plx?P=A|url-status=live}}{{cite journal | vauthors = Agnew W, Korman R | title = Pharmacological appetite stimulation: rational choices in the inappetent cat | journal = Journal of Feline Medicine and Surgery | volume = 16 | issue = 9 | pages = 749–756 | date = September 2014 | pmid = 25146662 | doi = 10.1177/1098612X14545273 | s2cid = 37126352 | pmc = 11185246 }}

Mirtazapine is indicated for bodyweight gain in cats experiencing poor appetite and weight loss resulting from chronic medical conditions.{{cite web | title=Mirataz EPAR | website=European Medicines Agency | date=11 October 2019 | url=https://www.ema.europa.eu/en/medicines/veterinary/EPAR/mirataz | access-date=12 July 2020 | archive-date=29 October 2020 | archive-url=https://web.archive.org/web/20201029151621/https://www.ema.europa.eu/en/medicines/veterinary/EPAR/mirataz | url-status=live }} Text was copied from this source, which is copyright European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged.{{cite web | title=Mirataz- mirtazapine ointment | website=DailyMed | date=8 May 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f4a55914-6b6e-4e81-a84c-3999aa7bd79e | access-date=12 July 2020 | archive-date=12 July 2020 | archive-url=https://web.archive.org/web/20200712223906/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f4a55914-6b6e-4e81-a84c-3999aa7bd79e | url-status=live }}

There are two options for administration: tablets given orally, and an ointment applied topically to the inner surface of the ear.

The most common side effects include signs of local irritation or inflammation at the site where the ointment is applied and behavioural changes (increased meowing, hyperactivity, disoriented state or inability to coordinate muscle movements, lack of energy/weakness, attention-seeking, and aggression).

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