Mirtazapine came into medical use in the United States in 1996. The patent expired in 2004, and generic versions are available. In 2017, it was the 119th most commonly prescribed medication in the United States, with more than six million prescriptions.
In 2010 NICE recommended generic SSRIs as first line choices, as they are "equally effective as other antidepressants and have a favourable risk–benefit ratio." 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 selective serotonin reuptake inhibitors (SSRI) 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."
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 two weeks), its efficacy is about the same as other antidepressants after six weeks' use.
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, especially at higher doses, causing restless leg syndrome in 8 to 28% of people and in rare cases causes REM sleep behavior disorder.
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.
After one week of usage, mirtazapine was found to have an earlier onset of action compared to SSRIs.
There is also some tentative evidence supporting its use in treating the following conditions, for which it is sometimes prescribed off-label:
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.
In general, some antidepressants, especially selective serotonin reuptake inhibitors (SSRI), can paradoxically exacerbate some peoples' depression or anxiety or cause suicidal ideation. 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.
A case report published in 2000 noted an instance in which mirtazapine counteracted the action of clonidine, causing a dangerous rise in blood pressure.
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 SSRIs (except citalopram). Unlike the tricyclic antidepressants, mirtazapine showed no significant cardiovascularadverse effects at 7 to 22 times the maximum recommended dose. Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to tricyclic antidepressants.
Twelve reported fatalities have been attributed to mirtazapine overdose. 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.
Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is considered to be relatively safe and is often employed therapeutically, with a combination of venlafaxine and mirtazapine, sometimes referred to as "California rocket fuel". Several case reports document serotonin syndrome induced by the combination of mirtazapine with other agents (olanzapine, quetiapine, tramadol and venlafaxine).
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.
The addition of mirtazapine to an monoamine oxidase inhibitor (MAOI), while potentially having typical or idiosyncratic (unique to the individual) reactions not herein described, does not appear to cause serotonin syndrome. 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). Mirtazapine is a potent 5-HT2A receptor antagonist, and cyproheptadine, a drug that shares this property, mediates recovery from serotonin syndrome and is an antidote against it.
The (S)-(+) enantiomer of mirtazapine is responsible for antagonism of the serotonin 5-HT2A and 5-HT2C receptors, while the (R)-(–) enantiomer is responsible for antagonism of the 5-HT3 receptor. Both enantiomers are involved in antagonism of the H1 and α2-adrenergic receptors, although the (S)-(+) enantiomer is the stronger antihistamine.
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.
Mirtazapine increases dopamine release in the prefrontal cortex. 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. 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. Mirtazapine has been shown to lower drug seeking behaviour in various human and animal studies. It is also being investigated in substance abuse disorders to reduce withdrawal effects and improve remission rates.
Mirtazapine is a very strong H1 receptor inverse agonist 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. 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 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.
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.:429
A case report has been published in which mirtazapine reduced visual hallucinations in a patient with Parkinson's disease psychosis (PDP). This is in alignment with recent findings that inverse agonists at the 5-HT2A 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-HT2A receptors.
Eight case reports have been reported in five papers on the use of mirtazapine in the treatment of hives as of 2017.
Mirtazapine also has some veterinary use in cats and dogs. 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.
Mirtazapine is indicated for bodyweight gain in cats experiencing poor appetite and weight loss resulting from chronic medical conditions. It is an ointment applied topically to the inner pinna (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 co-ordinate muscle movements, lack of energy/weakness, attention seeking and aggression).
^ abcTaylor D, Paton C, Shitij K (2012). Maudsley Prescribing Guidelines in Psychiatry (11th ed.). West Sussex: Wiley-Blackwell. ISBN978-0-47-097948-8.
^Goodnick PJ, Puig A, DeVane CL, Freund BV (July 1999). "Mirtazapine in major depression with comorbid generalized anxiety disorder". The Journal of Clinical Psychiatry. 60 (7): 446–8. doi:10.4088/JCP.v60n0705. PMID10453798.
^Davis MP, Khawam E, Pozuelo L, Lagman R (August 2002). "Management of symptoms associated with advanced cancer: olanzapine and mirtazapine. A World Health Organization project". Expert Review of Anticancer Therapy. 2 (4): 365–76. doi:10.1586/1473718.104.22.1685. PMID12647979.
^ abLi TC, Shiah IS, Sun CJ, Tzang RF, Huang KC, Lee WK (June 2011). "Mirtazapine relieves post-electroconvulsive therapy headaches and nausea: a case series and review of the literature". The Journal of ECT. 27 (2): 165–7. doi:10.1097/YCT.0b013e3181e63346. PMID21602639.
^ abKast RE, Foley KF (July 2007). "Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects". European Journal of Cancer Care. 16 (4): 351–4. doi:10.1111/j.1365-2354.2006.00760.x. PMID17587360.
^Tajti J, Almási J (June 2006). "Effects of mirtazapine in patients with chronic tension-type headache. Literature review". Neuropsychopharmacologia Hungarica (in Hungarian). 8 (2): 67–72. PMID17073214.
^Hummel J, Westphal S, Weber-Hamann B, Gilles M, Lederbogen F, Angermeier T, Luley C, Deuschle M, Kopf D (July 2011). "Serum lipoproteins improve after successful pharmacologic antidepressant treatment: a randomized open-label prospective trial". The Journal of Clinical Psychiatry. 72 (7): 885–91. doi:10.4088/JCP.09m05853blu. PMID21294998.
^McIntyre RS, Soczynska JK, Konarski JZ, Kennedy SH (July 2006). "The effect of antidepressants on lipid homeostasis: a cardiac safety concern?". Expert Opinion on Drug Safety. 5 (4): 523–37. doi:10.1517/14740322.214.171.1243. PMID16774491.
^ abcdefFawcett J, Barkin RL (December 1998). "Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression". Journal of Affective Disorders. 51 (3): 267–85. doi:10.1016/S0165-0327(98)00224-9. PMID10333982.
^Möller HJ (December 2006). "Is there evidence for negative effects of antidepressants on suicidality in depressive patients? A systematic review". European Archives of Psychiatry and Clinical Neuroscience. 256 (8): 476–96. doi:10.1007/s00406-006-0689-8. PMID17143567.
^Nikolaou P, Dona A, Papoutsis I, Spiliopoulou C, Maravelias C. "Death Due to Mirtazapine Overdose". Cite journal requires |journal= (help) in "Abstracts of the XXIX International Congress of the European Association of Poison Centres and Clinical Toxicologists, May 12–15, 2009, Stockholm, Sweden". Clinical Toxicology. 47 (5): 436–510. 2009. doi:10.1080/15563650902952273.
^Baselt, RC (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1045–7. ISBN978-0-9626523-7-0.
^Silva J, Mota J, Azevedo P (March 2016). "California rocket fuel: And what about being a first line treatment?". European Psychiatry. 33: S551. doi:10.1016/j.eurpsy.2016.01.2033.
^Wu, Chi-Shun; Tong, Show-Hwa; Ong, Cheung-Ter; Sung, Sheng-Feng (December 2015). "Serotonin Syndrome Induced by Combined Use of Mirtazapine and Olanzapine Complicated with Rhabdomyolysis, Acute Renal Failure, and Acute Pulmonary Edema-A Case Report". Acta Neurologica Taiwanica. 24 (4): 117–121. ISSN1028-768X. PMID27333965.
^Saguin, Emeric; Keou, S.; Ratnam, C.; Mennessier, C.; Delacour, H.; Lahutte, B. (May 2018). "Severe rhabdomyolysis induced by quetiapine and mirtazapine in a French military soldier". Journal of the Royal Army Medical Corps. 164 (2): 127–129. doi:10.1136/jramc-2018-000939. ISSN0035-8665. PMID29632134.
^ abcdefgGillman PK (2006). "A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status". Hum Psychopharmacol. 21 (2): 117–25. doi:10.1002/hup.750. PMID16342227.
^Iqbal MM, Basil MJ, Kaplan J, Iqbal MT (2012). "Overview of serotonin syndrome". Ann Clin Psychiatry. 24 (4): 310–8. PMID23145389.
^Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
^ abcTatsumi M, Groshan K, Blakely RD, Richelson E (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". Eur. J. Pharmacol. 340 (2–3): 249–58. doi:10.1016/s0014-2999(97)01393-9. PMID9537821.
^ abcdefghijklmnopqrstuvwxyzVan der Mey M, Windhorst AD, Klok RP, Herscheid JD, Kennis LE, Bischoff F, Bakker M, Langlois X, Heylen L, Jurzak M, Leysen JE (2006). "Synthesis and biodistribution of [11C]R107474, a new radiolabeled alpha2-adrenoceptor antagonist". Bioorg. Med. Chem. 14 (13): 4526–34. doi:10.1016/j.bmc.2006.02.029. PMID16517171.
^ abcdAppl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (2012). "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics". Naunyn Schmiedebergs Arch. Pharmacol. 385 (2): 145–70. doi:10.1007/s00210-011-0704-0. PMID22033803.
^de Boer TH, Maura G, Raiteri M, de Vos CJ, Wieringa J, Pinder RM (April 1988). "Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers". Neuropharmacology. 27 (4): 399–408. doi:10.1016/0028-3908(88)90149-9. PMID3419539.
^ abcBrayfield, A, ed. (30 January 2013). Mirtazapine. Martindale: The Complete Drug Reference. The Royal Pharmaceutical Society of Great Britain. Retrieved 3 November 2013.
^ abSato H, Ito C, Tashiro M, Hiraoka K, Shibuya K, Funaki Y, Iwata R, Matsuoka H, Yanai K (2013). "Histamine H₁ receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers". Psychopharmacology. 230 (2): 227–34. doi:10.1007/s00213-013-3146-1. PMID23728612.
^ abBerendsen HH, Broekkamp CL (October 1997). "Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine". Psychopharmacology. 133 (3): 275–82. doi:10.1007/s002130050402. PMID9361334.
^Millan MJ (2005). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies". Thérapie. 60 (5): 441–60. doi:10.2515/therapie:2005065. PMID16433010.
^Millan MJ, Gobert A, Rivet JM, et al. (March 2000). "Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of α2-adrenergic and serotonin2C receptors: a comparison with citalopram". Eur. J. Neurosci. 12 (3): 1079–95. doi:10.1046/j.1460-9568.2000.00982.x. PMID10762339.
^Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A, Dekeyne A, Nicolas JP, Lejeune F (March 2000). "Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram". The European Journal of Neuroscience. 12 (3): 1079–95. doi:10.1046/j.1460-9568.2000.00982.x. PMID10762339.
^Herrold AA, Shen F, Graham MP, Harper LK, Specio SE, Tedford CE, Napier TC (January 2009). "Mirtazapine treatment after conditioning with methamphetamine alters subsequent expression of place preference". Drug and Alcohol Dependence. 99 (1–3): 231–9. doi:10.1016/j.drugalcdep.2008.08.005. PMID18945553.
^ abRose ME, Grant JE (2008). "Pharmacotherapy for methamphetamine dependence: a review of the pathophysiology of methamphetamine addiction and the theoretical basis and efficacy of pharmacotherapeutic interventions". Annals of Clinical Psychiatry. 20 (3): 145–55. doi:10.1080/10401230802177656. PMID18633741.
^ abBrackins T, Brahm NC, Kissack JC (December 2011). "Treatments for methamphetamine abuse: a literature review for the clinician". Journal of Pharmacy Practice. 24 (6): 541–50. doi:10.1177/0897190011426557. PMID22095579.
^Freijo Guerrero J, Tardón Ruiz de Gauna L, Gómez JJ, Aguilera Celorrio L (2009). "[Serotonin syndrome after administration of mirtazapine in a critical care unit]". Rev Esp Anestesiol Reanim (in Spanish). 56 (8): 515–6. doi:10.1016/s0034-9356(09)70444-x. PMID19994622.
^Butler MC, Di Battista M, Warden M (2010). "Sertraline-induced serotonin syndrome followed by mirtazapine reaction". Prog. Neuropsychopharmacol. Biol. Psychiatry. 34 (6): 1128–9. doi:10.1016/j.pnpbp.2010.04.015. PMID20430060.
^Decoutere L, De Winter S, Vander Weyden L, Spriet I, Schrooten M, Tournoy J, Fagard K (2012). "A venlafaxine and mirtazapine-induced serotonin syndrome confirmed by de- and re-challenge". Int J Clin Pharm. 34 (5): 686–8. doi:10.1007/s11096-012-9666-7. PMID22752315.
^ abcSchatzberg, Alan F. (2009). "Chapter 21: Mirtazapine". In Schatzberg, Alan F.; Nemeroff, Charles B. (eds.). The American Psychiatric Publishing Textbook of Psychopharmacology (4th ed.). Washington, D.C.: American Psychiatric Pub. ISBN9781585623099.
^Kelder, J; Funke, C; De Boer, T; Delbressine, L; Leysen, D; Nickolson, V (April 1997). "A comparison of the physicochemical and biological properties of mirtazapine and mianserin". The Journal of Pharmacy and Pharmacology. 49 (4): 403–11. doi:10.1111/j.2042-7158.1997.tb06814.x. PMID9232538.
^Srinivasa Rao, D. V. N; Dandala, R; Handa, V. K; Sivakumaran, M; Raghava Reddy, A. V; Naidu, A (2007). "Improved Synthesis of Mirtazapine". Organic Preparations and Procedures International. 39 (4): 399. doi:10.1080/00304940709458595.
^Kaspersen, Frans M.; Van Rooij, Fons A. M.; Sperling, Eric G. M.; Wieringa, Joop H. (September 1989). "The synthesis of org 3770 labelled with 3H, 13C AND 14C". Journal of Labelled Compounds and Radiopharmaceuticals. 27 (9): 1055–1068. doi:10.1002/jlcr.2580270911.
^Posey DJ, Guenin KD, Kohn AE, Swiezy NB, McDougle CJ (2001). "A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders". Journal of Child and Adolescent Psychopharmacology. 11 (3): 267–77. doi:10.1089/10445460152595586. PMID11642476.
^Coskun M, Karakoc S, Kircelli F, Mukaddes NM (April 2009). "Effectiveness of mirtazapine in the treatment of inappropriate sexual behaviors in individuals with autistic disorder". Journal of Child and Adolescent Psychopharmacology. 19 (2): 203–6. doi:10.1089/cap.2008.020. PMID19364298.
^Hieber R, Dellenbaugh T, Nelson LA (June 2008). "Role of mirtazapine in the treatment of antipsychotic-induced akathisia". The Annals of Pharmacotherapy. 42 (6): 841–6. doi:10.1345/aph.1K672. PMID18460588.
^Vidal C, Reese C, Fischer BA, Chiapelli J, Himelhoch S (July 2015). "Meta-Analysis of Efficacy of Mirtazapine as an Adjunctive Treatment of Negative Symptoms in Schizophrenia". Clinical Schizophrenia & Related Psychoses. 9 (2): 88–95. doi:10.3371/CSRP.VIRE.030813. PMID23491969.
^Tagai K, Nagata T, Shinagawa S, Tsuno N, Ozone M, Nakayama K (June 2013). "Mirtazapine improves visual hallucinations in Parkinson's disease: a case report". Psychogeriatrics. 13 (2): 103–7. doi:10.1111/j.1479-8301.2012.00432.x. PMID23909968.
^Agnew, W; Korman, R (September 2014). "Pharmacological appetite stimulation: rational choices in the inappetent cat". Journal of Feline Medicine and Surgery. 16 (9): 749–56. doi:10.1177/1098612X14545273. PMID25146662.