Mirtazapine (originally branded Remeron, many generics) is an atypical antidepressant with noradrenergic and specific serotonergic activity. It blocks the α2 adrenergic auto- and heteroreceptors (enhancing norepinephrine release), and selectively antagonizes the 5-HT2 serotonin receptors in the central and peripheral nervous system. It also enhances serotonin neurotransmission at the 5-HT1 receptor and blocks the histaminergic (H1) and muscarinic receptors. Mirtazapine is not a serotonin or norepinephrine reuptake inhibitor but may increase serotonin and norepinephrine by other mechanisms of action.
Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) introduced by Organon International in the United States in 1996, 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. It is also racemic – occurs as a combination of both (R)-(−)- and (S)-(+)-stereoisomers, both of which are active.
Its patent expired in 2004, so generic versions are available.
- 1 Medical uses
- 2 Adverse reactions
- 3 Pharmacology
- 4 Pharmacokinetics
- 5 Chemistry
- 6 History
- 7 Brands
- 8 See also
- 9 References
- 10 Further reading
- 11 External links
Approved and off-label
In a meta-analysis published in 2009 that compared the efficacy and tolerability of 12 second-generation antidepressants, mirtazapine was found to be superior to all of the included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), reboxetine and bupropion in terms of antidepressant efficacy, while it was average in regard to tolerability. However, its superior efficacy over the other medications in the top four (escitalopram, sertraline and venlafaxine) did not reach statistical significance.
However, it has also been found useful in alleviating the following conditions and may be prescribed off-label for their treatment:
- Generalized anxiety disorder
- Social anxiety disorder
- Obsessive-compulsive disorder
- Panic disorder
- Post-traumatic stress disorder
- Low appetite/underweight
- Nausea and vomiting
- Headaches and migraine
Mirtazapine has had literature published on its efficacy in the experimental treatment of these conditions:
- Sleep apnea/hypopnea
- Inappropriate sexual behaviour and other secondary symptoms of autistic spectrum conditions and other pervasive developmental disorders
- Antipsychotic-induced akathisia.
- Drug withdrawal, dependence and detoxification
- Negative, depressive and cognitive symptoms of schizophrenia (as an adjunct)
- 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-doses too low to antagonise the D2 receptor, but sufficiently high doses to inversely agonise the 5-HT2A receptors.
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.
Efficacy and tolerability
In a major meta-analysis published in 2009 that compared the efficacy and tolerability of 12 second-generation antidepressants, mirtazapine was found to be superior to all of the included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), reboxetine and bupropion in terms of antidepressant efficacy, while it was average in regard to tolerability.
Compared to earlier antidepressants, mirtazapine has been found to be significantly superior to trazodone, while it has been shown to be approximately equivalent in efficacy to several of the tricyclic antidepressants including amitriptyline, doxepin and clomipramine. However, two other studies found mirtazapine to be significantly inferior to imipramine, another TCA.
In general, all antidepressants, including mirtazapine, require at least a week for their therapeutic benefits on depressive and anxious symptoms to become apparent. Mirtazapine has a faster onset of antidepressant action when compared to SSRIs, with an initial reduction in affective symptoms being seen within the first week of treatment, and the maximal change in improvement occurring over the course of the first two weeks, however ingesting small doses sporadically can cause some of the same short term side effects as opiates such as minor pain relief as well as constricting of the pupils.
Very common (≥10% incidence) adverse effects
Common (1%≤ incidence <10%) adverse effects
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. (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.)
In general, some antidepressants, especially SSRIs, 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.
Mirtazapine and other antidepressants may cause a discontinuation syndrome upon cessation. A gradual and slow reduction in dose is recommended to minimize discontinuation symptoms. 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.
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 TCAs, mirtazapine showed no significant cardiovascular adverse 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 TCAs.
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.
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. As examples, fluoxetine and paroxetine, inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while carbamazepine, an inducer, considerably decreases them.
According to information from the manufacturers, mirtazapine should not be started within two weeks of any MAOI usage; likewise, MAOIs should not be administered within two weeks of discontinuing mirtazapine. However, a single study regarding the combination reported it does not result in any incidence of serotonin-related toxicity. In addition, a case report claimed that mirtazapine can actually be used to treat serotonin syndrome. 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”.
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.
|Molecular target||Binding affinity, Ki (nM)||Notes|
|5-HT2A receptor||69||The (S)-(+)-enantiomer is responsible for this antagonism.|
|5-HT2B receptor||?||~20-fold lower than for 5-HT2A/5-HT2C|
|5-HT2C receptor||39||Inverse agonist The (S)-(+)-enantiomer is responsible for this action.|
|5-HT3 receptor||?||Similar to 5-HT2A/5-HT2C (mouse neuroblastoma cell) (R)-(–)-enantiomer antagonises the 5-HT3 receptor.|
|α1 adrenergic receptor||500|||
|α2A adrenergic receptor||20||The (S)-(+)-enantiomer is responsible for this antagonism at autoreceptors. Heteroreceptors are blocked by both the (S)-(+)- and (R)-(–)-enantiomers.|
|α2C adrenergic receptor||18||The (S)-(+)-enantiomer is responsible for this antagonism at autoreceptors. Heteroreceptors are blocked by both the (S)-(+)- and (R)-(–)-enantiomers.|
Correspondence to clinical effects
Antagonization of the α2 adrenergic receptors, which function largely as autoreceptors and heteroreceptors enhances adrenergic and serotonergic neurotransmission, the notable ones being 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 5-HT cell firing and direct blockade of inhibitory α2 heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT. Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT1A receptor. Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs. Unlike most conventional antidepressants, however, at clinically used doses mirtazapine has no appreciable affinity for the serotonin, norepinephrine, or dopamine transporters and thus lacks any significant effects as a reuptake inhibitor of these neurotransmitters, nor does it have any significant inhibitory effects on monoamine oxidase.
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. 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. 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. 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 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. 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. It is also being investigated to help in substance abuse disorders with withdrawal effects and remission rates. but some studies have shown mixed benefit.
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. Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron. 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. 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 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 diarrhoea, 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.
Mirtazapine is a very strong H1 receptor inverse agonist and, as a result, it can cause powerful sedative and hypnotic effects. 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 commonly seen in clinical practise.
Like many other antidepressants, mirtazapine has been found to have antinociceptive properties in mice. However, unlike most other antidepressants, though similarly to venlafaxine, these effects are mostly mediated through downstream modulation of the endogenous opioid system, of which in the case of mirtazapine the μ opioid and κ3 opioid receptors are mainly involved. Interestingly, while virtually all antidepressants differ little in their maximal effectiveness in the treatment of major depression, mirtazapine and venlafaxine have demonstrated superior efficacy in treating severe types of depression such as psychotic depression and treatment-resistant depression. This may be due to their unique influence on the opioid system, which is a property that may give them an advantage over other antidepressants in cases of severe depressive symptomatology.
The (S)-(+)-enantiomer has a plasma half-life of 9.9±3 hours and the (R)-(–)-enantiomer has a plasma half-life of 18±2.5 hours. The overall elimination half-life is 20–40 hours.
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.
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, 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.
- Drugs.com internatioinal brand names for mirtazapine Page accessed August 25, 2016
- Timmer CJ, Sitsen JM, Delbressine LP (June 2000). "Clinical pharmacokinetics of mirtazapine". Clinical Pharmacokinetics. 38 (6): 461–74. doi:10.2165/00003088-200038060-00001. PMID 10885584.
- "REMERON (mirtazapine) tablet, film coated [Organon Pharmaceuticals USA]". DailyMed. Organon Pharmaceuticals USA. October 2012. Retrieved 24 October 2013.
- "Axit Mirtazapine PRODUCT INFORMATION". TGA eBusiness Services. alphapharm. 25 October 2011. Retrieved 15 October 2013.
- "Mirtazapine 30 mg Tablets - Summary of Product Characteristics" (PDF). electronic Medicines Compendium. Sandoz Limited. 20 March 2013. Retrieved 24 October 2013.
- Anttila SA, Leinonen EV (2001). "A review of the pharmacological and clinical profile of mirtazapine". CNS Drug Reviews. 7 (3): 249–64. doi:10.1111/j.1527-3458.2001.tb00198.x. PMID 11607047.
- "How Does Mirtazapine Induce Weight Gain?". Medscape. Retrieved 11 February 2016.
- Brayfield, A, ed. (30 January 2013). Mirtazapine. Martindale: The Complete Drug Reference. The Royal Pharmaceutical Society of Great Britain. Retrieved 3 November 2013.
- Schatzberg, AF; Cole, JO; DeBattista, C. "3". Manual of Clinical Psychopharmacology (7th ed.). Arlington, VA: American Psychiatric Publishing. ISBN 978-1-58562-377-8.
- Gorman JM (1999). "Mirtazapine: clinical overview". The Journal of Clinical Psychiatry. 60 Suppl 17: 9–13; discussion 46–8. PMID 10446735.
- Benjamin S, Doraiswamy PM (July 2011). "Review of the use of mirtazapine in the treatment of depression". Expert Opinion on Pharmacotherapy. 12 (10): 1623–32. doi:10.1517/14656566.2011.585459. PMID 21644844.
- Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C (February 2009). "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis". Lancet. 373 (9665): 746–58. doi:10.1016/S0140-6736(09)60046-5. PMID 19185342.
- 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. PMID 10453798.
- Croom KF, Perry CM, Plosker GL (2009). "Mirtazapine: a review of its use in major depression and other psychiatric disorders". CNS Drugs. 23 (5): 427–52. doi:10.2165/00023210-200923050-00006. PMID 19453203.
- Muehlbacher M, Nickel MK, Nickel C, Kettler C, Lahmann C, Pedrosa Gil F, Leiberich PK, Rother N, Bachler E, Fartacek R, Kaplan P, Tritt K, Mitterlehner F, Anvar J, Rother WK, Loew TH, Egger C (December 2005). "Mirtazapine treatment of social phobia in women: a randomized, double-blind, placebo-controlled study". Journal of Clinical Psychopharmacology. 25 (6): 580–3. doi:10.1097/01.jcp.0000186871.04984.8d. PMID 16282842.
- Koran LM, Quirk T, Lorberbaum JP, Elliott M (October 2001). "Mirtazapine treatment of obsessive-compulsive disorder". Journal of Clinical Psychopharmacology. 21 (5): 537–9. doi:10.1097/00004714-200110000-00016. PMID 11593084.[unreliable medical source?]
- Carpenter LL, Leon Z, Yasmin S, Price LH (June 1999). "Clinical experience with mirtazapine in the treatment of panic disorder". Annals of Clinical Psychiatry. 11 (2): 81–6. doi:10.3109/10401239909147053. PMID 10440525.[unreliable medical source?]
- Carli V, Sarchiapone M, Camardese G, Romano L, DeRisio S (July 2002). "Mirtazapine in the treatment of panic disorder". Archives of General Psychiatry. 59 (7): 661–2. doi:10.1001/archpsyc.59.7.661. PMID 12090820.[unreliable medical source?]
- Landowski J (2002). "[Mirtazapine--an antidepressant]". Psychiatria Polska (in Polish). 36 (6 Suppl): 125–30. PMID 12647431.
- Chinuck RS, Fortnum H, Baldwin DR (December 2007). "Appetite stimulants in cystic fibrosis: a systematic review". Journal of Human Nutrition and Dietetics. 20 (6): 526–37. doi:10.1111/j.1365-277X.2007.00824.x. PMID 18001374.
- 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:10.1586/14737220.127.116.115. PMID 12647979.
- Hartmann PM (January 1999). "Mirtazapine: a newer antidepressant". American Family Physician. 59 (1): 159–61. PMID 9917581.
- Jindal RD (2009). "Insomnia in patients with depression: some pathophysiological and treatment considerations". CNS Drugs. 23 (4): 309–29. doi:10.2165/00023210-200923040-00004. PMID 19374460.
- Nutt DJ (June 2002). "Tolerability and safety aspects of mirtazapine". Human Psychopharmacology. 17 Suppl 1: S37–41. doi:10.1002/hup.388. PMID 12404669.
- Li 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. PMID 21602639.
- Kast 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. PMID 17587360.
- Twycross R, Greaves MW, Handwerker H, Jones EA, Libretto SE, Szepietowski JC, Zylicz Z (January 2003). "Itch: scratching more than the surface". Qjm. 96 (1): 7–26. doi:10.1093/qjmed/hcg002. PMID 12509645.
- Greaves MW (2005). "Itch in systemic disease: therapeutic options". Dermatologic Therapy. 18 (4): 323–7. doi:10.1111/j.1529-8019.2005.00036.x. PMID 16297004.
- Colombo B, Annovazzi PO, Comi G (October 2004). "Therapy of primary headaches: the role of antidepressants". Neurological Sciences. 25 Suppl 3: S171–5. doi:10.1007/s10072-004-0280-x. PMID 15549531.
- 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. PMID 17073214.
- Kohler M, Bloch KE, Stradling JR (May 2009). "Pharmacological approaches to the treatment of obstructive sleep apnoea". Expert Opinion on Investigational Drugs. 18 (5): 647–56. doi:10.1517/13543780902877674. PMID 19388881.
- Marshall NS, Yee BJ, Desai AV, Buchanan PR, Wong KK, Crompton R, Melehan KL, Zack N, Rao SG, Gendreau RM, Kranzler J, Grunstein RR (June 2008). "Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea". Sleep. 31 (6): 824–31. PMC . PMID 18548827.
- Masi G (2004). "Pharmacotherapy of pervasive developmental disorders in children and adolescents". CNS Drugs. 18 (14): 1031–52. doi:10.2165/00023210-200418140-00006. PMID 15584771.
- Marek GJ, Carpenter LL, McDougle CJ, Price LH (February 2003). "Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders". Neuropsychopharmacology. 28 (2): 402–12. doi:10.1038/sj.npp.1300057. PMID 12589395.
- 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. PMID 11642476.
- 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. PMID 19364298.
- Kumar R, Sachdev PS (May 2009). "Akathisia and second-generation antipsychotic drugs". Current Opinion in Psychiatry. 22 (3): 293–99. doi:10.1097/YCO.0b013e32832a16da. PMID 19378382.
- 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. PMID 18460588.
- Graves SM, Rafeyan R, Watts J, Napier TC (December 2012). "Mirtazapine, and mirtazapine-like compounds as possible pharmacotherapy for substance abuse disorders: evidence from the bench and the bedside". Pharmacology & Therapeutics. 136 (3): 343–53. doi:10.1016/j.pharmthera.2012.08.013. PMC . PMID 22960395.
- Ritsner, MS (2013). Polypharmacy in Psychiatry Practice, Volume I. Springer Science+Business Media Dordrecht. ISBN 9789400758056.
- Vidal C, Reese C, Fischer BA, Chiapelli J, Himelhoch S (Jul 2015). "Meta-Analysis of Efficacy of Mirtazapine as an Adjunctive Treatment of Negative Symptoms in Schizophrenia". Clinical Schizophrenia & Related Psychoses. Walsh Medical Media. 9 (2): 88–95. doi:10.3371/CSRP.VIRE.030813. PMID 23491969.
- 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. PMID 23909968.
- Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
- "Remeron for Cats".
- "Mirtazapine (Remeron)".
- van Moffaert M, de Wilde J, Vereecken A, Dierick M, Evrard JL, Wilmotte J, Mendlewicz J (March 1995). "Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalized patients with major depression". International Clinical Psychopharmacology. 10 (1): 3–9. doi:10.1097/00004850-199503000-00001. PMID 7622801.
- Fawcett 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. PMID 10333982.
- Bruijn JA, Moleman P, Mulder PG, van den Broek WW, van Hulst AM, van der Mast RC, van de Wetering BJ (October 1996). "A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients". Psychopharmacology. 127 (3): 231–7. doi:10.1007/BF02246131. PMID 8912401.
- Bruijn JA, Moleman P, Mulder PG, van den Broek WW (May 1999). "Depressed in-patients respond differently to imipramine and mirtazapine". Pharmacopsychiatry. 32 (3): 87–92. doi:10.1055/s-2007-979200. PMID 10463374.
- Thompson C (June 2002). "Onset of action of antidepressants: results of different analyses". Human Psychopharmacology. 17 Suppl 1: S27–32. doi:10.1002/hup.386. PMID 12404667.
- Taylor, D; Paton, C; Shitij, K (2012). Maudsley Prescribing Guidelines in Psychiatry (11th ed.). West Sussex: Wiley-Blackwell. ISBN 978-0-47-097948-8.
- Lavergne F, Berlin I, Gamma A, Stassen H, Angst J (March 2005). "Onset of improvement and response to mirtazapine in depression: a multicenter naturalistic study of 4771 patients". Neuropsychiatric Disease and Treatment. 1 (1): 59–68. doi:10.2147/nedt.18.104.22.168296. PMC . PMID 18568129.
- "mirtazapine (Rx) - Remeron, Remeron SolTab". Medscape. WebMD. Retrieved 24 October 2013.
- "Australian Medicines Handbook". Australian Medicines Handbook Pty Ltd. 2013.
- British National Formulary (BNF) (65th ed.). Pharmaceutical Press. p. 1120. ISBN 978-0857110848.
- "Remeron (Mirtazapine) Drug Information". RxList. Retrieved 28 March 2016.
- 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. PMID 17143567.
- Abo-Zena RA1, Bobek MB, Dweik RA. Hypertensive urgency induced by an interaction of mirtazapine and clonidine. Pharmacotherapy. 2000 Apr;20(4):476-8. PMID 10772378
- Benazzi F (June 1998). "Mirtazapine withdrawal symptoms". Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 43 (5): 525. PMID 9653542.[unreliable medical source?]
- Blier P (2001). "Pharmacology of rapid-onset antidepressant treatment strategies". The Journal of Clinical Psychiatry. 62 Suppl 15: 12–7. PMID 11444761.
- Vlaminck JJ, van Vliet IM, Zitman FG (March 2005). "[Withdrawal symptoms of antidepressants]". Nederlands Tijdschrift Voor Geneeskunde (in Dutch and Flemish). 149 (13): 698–701. PMID 15819135.
- Berigan TR (June 2001). "Mirtazapine-Associated Withdrawal Symptoms: A Case Report". Primary Care Companion to the Journal of Clinical Psychiatry. 3 (3): 143. doi:10.4088/PCC.v03n0307a. PMC . PMID 15014614.[unreliable medical source?]
- Klesmer J, Sarcevic A, Fomari V (August 2000). "Panic attacks during discontinuation of mirtazepine". Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 45 (6): 570–1. PMID 10986577.[unreliable medical source?]
- MacCall C, Callender J (October 1999). "Mirtazapine withdrawal causing hypomania". The British Journal of Psychiatry. 175 (4): 390. doi:10.1192/bjp.175.4.390a. PMID 10789310.[unreliable medical source?]
- Ali S, Milev R (May 2003). "Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review of the literature". Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 48 (4): 258–64. PMID 12776393.
- White N, Litovitz T, Clancy C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type" (PDF). Journal of Medical Toxicology. 4 (4): 238–50. doi:10.1007/bf03161207. PMC . PMID 19031375.
- Holzbach R, Jahn H, Pajonk FG, Mähne C (November 1998). "Suicide attempts with mirtazapine overdose without complications". Biological Psychiatry. 44 (9): 925–6. doi:10.1016/S0006-3223(98)00081-X. PMID 9807651.[unreliable medical source?]
- Retz W, Maier S, Maris F, Rösler M (November 1998). "Non-fatal mirtazapine overdose". International Clinical Psychopharmacology. 13 (6): 277–9. doi:10.1097/00004850-199811000-00007. PMID 9861579.[unreliable medical source?]
- Nikolaou, P; Dona, A; Papoutsis, I; Spiliopoulou, C; Maravelias, C. "Death Due to Mirtazapine Overdose". 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. ISBN 978-0-9626523-7-0.
- Buckley NA, McManus PR (December 2002). "Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data". Bmj. 325 (7376): 1332–3. doi:10.1136/bmj.325.7376.1332. PMC . PMID 12468481.[unreliable medical source?]
- Mirtazapine monograph
- Gillman PK (June 2006). "A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action". Biological Psychiatry. 59 (11): 1046–51. doi:10.1016/j.biopsych.2005.11.016. PMID 16460699.
- Hoes MJ, Zeijpveld JH (March 1996). "Mirtazapine as treatment for serotonin syndrome". Pharmacopsychiatry. 29 (2): 81. doi:10.1055/s-2007-979550. PMID 8741027.[unreliable medical source?]
- 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 (September 2006). "Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report". The American Journal of Psychiatry. 163 (9): 1531–41; quiz 1666. doi:10.1176/appi.ajp.163.9.1531. PMID 16946177.
- Sennef C, Timmer CJ, Sitsen JM (March 2003). "Mirtazapine in combination with amitriptyline: a drug-drug interaction study in healthy subjects". Human Psychopharmacology. 18 (2): 91–101. doi:10.1002/hup.441. PMID 12590402.[unreliable medical source?]
- Gándara Martín Jde L, Agüera Ortiz L, Ferre Navarrete F, Rojo Rodés E, Ros Montalbán S (2002). "[Tolerability and efficacy of combined antidepressant therapy]". Actas Españolas De PsiquiatríA (in Spanish). 30 (2): 75–84. PMID 12028939.
- Ravindran LN, Eisfeld BS, Kennedy SH (February 2008). "Combining mirtazapine and duloxetine in treatment-resistant depression improves outcomes and sexual function". Journal of Clinical Psychopharmacology. 28 (1): 107–8. doi:10.1097/JCP.0b013e318160d609. PMID 18204355.[unreliable medical source?]
- Stahl, SM (2008). Stahl's Essential Psychopharmacology Online: Print and Online. Cambridge, UK: Cambridge University Press. ISBN 0-521-74609-4.
- Abo-Zena RA, Bobek MB, Dweik RA (April 2000). "Hypertensive urgency induced by an interaction of mirtazapine and clonidine". Pharmacotherapy. 20 (4): 476–8. doi:10.1592/phco.20.5.476.35061. PMID 10772378.[unreliable medical source?]
- Fernández J, Alonso JM, Andrés JI, Cid JM, Díaz A, Iturrino L, Gil P, Megens A, Sipido VK, Trabanco AA (March 2005). "Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents". Journal of Medicinal Chemistry. 48 (6): 1709–12. doi:10.1021/jm049632c. PMID 15771415.
- 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. PMID 3419539.
- Roth, BL; Driscol, J. "PDSD Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 2013-07-27.
- de Boer T (1996). "The pharmacologic profile of mirtazapine". The Journal of Clinical Psychiatry. 57 Suppl 4: 19–25. PMID 8636062.
- Graves SM, Napier TC (2012). "SB 206553, a putative 5-HT2C inverse agonist, attenuates methamphetamine-seeking in rats". BMC Neuroscience. 13 (1): 65. doi:10.1186/1471-2202-13-65. PMC . PMID 22697313.
- Kooyman AR, Zwart R, Vanderheijden PM, Van Hooft JA, Vijverberg HP (1994). "Interaction between enantiomers of mianserin and ORG3770 at 5-HT3 receptors in cultured mouse neuroblastoma cells". Neuropharmacology. 33 (3-4): 501–7. doi:10.1016/0028-3908(94)90081-7. PMID 7984289.
- Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
- Wikström HV, Mensonides-Harsema MM, Cremers TI, Moltzen EK, Arnt J (July 2002). "Synthesis and pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin and its enantiomers in comparison with the two antidepressants mianserin and mirtazapine". Journal of Medicinal Chemistry. 45 (15): 3280–5. doi:10.1021/jm010566d. PMID 12109911.
- Olianas MC, Dedoni S, Onali P (November 2012). "The atypical antidepressant mianserin exhibits agonist activity at κ-opioid receptors". British Journal of Pharmacology. 167 (6): 1329–41. doi:10.1111/j.1476-5381.2012.02078.x. PMID 22708686.
- De Boer T, Nefkens F, Van Helvoirt A (February 1994). "The alpha 2-adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo". European Journal of Pharmacology. 253 (1-2): R5–6. doi:10.1016/0014-2999(94)90778-1. PMID 7912194.[unreliable medical source?]
- Berendsen 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. PMID 9361334.
- Nakayama K, Sakurai T, Katsu H (April 2004). "Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation". Brain Research Bulletin. 63 (3): 237–41. doi:10.1016/j.brainresbull.2004.02.007. PMID 15145142.[unreliable medical source?]
- Blier P, Abbott FV (January 2001). "Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain" (PDF). Journal of Psychiatry & Neuroscience. 26 (1): 37–43. PMC . PMID 11212592.
- Tatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". European Journal of Pharmacology. 340 (2-3): 249–58. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821.
- Fisar Z, Hroudová J, Raboch J (2010). "Inhibition of monoamine oxidase activity by antidepressants and mood stabilizers". Neuro Endocrinology Letters. 31 (5): 645–56. PMID 21200377.
- 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. PMID 16433010.
- Dekeyne A, Millan MJ (April 2009). "Discriminative stimulus properties of the atypical antidepressant, mirtazapine, in rats: a pharmacological characterization". Psychopharmacology. 203 (2): 329–41. doi:10.1007/s00213-008-1259-8. PMID 18709360.
- De Deurwaerdère P, Navailles S, Berg KA, Clarke WP, Spampinato U (March 2004). "Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens". The Journal of Neuroscience. 24 (13): 3235–41. doi:10.1523/JNEUROSCI.0112-04.2004. PMID 15056702.[unreliable medical source?]
- Bubar MJ, Cunningham KA (April 2007). "Distribution of serotonin 5-HT2C receptors in the ventral tegmental area". Neuroscience. 146 (1): 286–97. doi:10.1016/j.neuroscience.2006.12.071. PMC . PMID 17367945.[unreliable medical source?]
- 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. PMID 10762339.
- Leggio GM, Cathala A, Neny M, Rouge-Pont F, Drago F, Piazza PV, Spampinato U (October 2009). "In vivo evidence that constitutive activity of serotonin2C receptors in the medial prefrontal cortex participates in the control of dopamine release in the rat nucleus accumbens: differential effects of inverse agonist versus antagonist". Journal of Neurochemistry. 111 (2): 614–23. doi:10.1111/j.1471-4159.2009.06356.x. PMID 19702657.
- Berg KA, Harvey JA, Spampinato U, Clarke WP (2008). "Physiological and therapeutic relevance of constitutive activity of 5-HT 2A and 5-HT 2C receptors for the treatment of depression". Progress in Brain Research. 172: 287–305. doi:10.1016/S0079-6123(08)00914-X. PMID 18772038.
- Colfax GN, Santos GM, Das M, Santos DM, Matheson T, Gasper J, Shoptaw S, Vittinghoff E (November 2011). "Mirtazapine to reduce methamphetamine use: a randomized controlled trial". Archives of General Psychiatry. 68 (11): 1168–75. doi:10.1001/archgenpsychiatry.2011.124. PMC . PMID 22065532.
- 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. PMID 18945553.
- Rose 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. PMID 18633741.
- Brackins 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. PMID 22095579.
- Brensilver M, Heinzerling KG, Shoptaw S (September 2013). "Pharmacotherapy of amphetamine-type stimulant dependence: an update". Drug and Alcohol Review. 32 (5): 449–60. doi:10.1111/dar.12048. PMID 23617468.
- Kast RE (September 2001). "Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy". Supportive Care in Cancer. 9 (6): 469–70. doi:10.1007/s005200000215. PMID 11585276.
- Costall, B; Naylor, RJ; Tyers, MB (1990). "The psychopharmacology of 5-HT3 receptors". Pharmacology & Therapeutics. 47 (2): 181–202. doi:10.1016/0163-7258(90)90086-H.
- Caldis EV, Gair RD (October 2004). "Mirtazapine for treatment of nausea induced by selective serotonin reuptake inhibitors". Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 49 (10): 707. PMID 15560319.
- Burrows GD, Kremer CM (April 1997). "Mirtazapine: clinical advantages in the treatment of depression". Journal of Clinical Psychopharmacology. 17 Suppl 1: 34S–39S. doi:10.1097/00004714-199704001-00005. PMID 9090576.
- Schreiber S, Bleich A, Pick CG (2002). "Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression?". Journal of Molecular Neuroscience. 18 (1-2): 143–9. doi:10.1385/JMN:18:1-2:143. PMID 11931344.
- Rao DV, Dandala R, Bharathi C, Handa VK, Sivakumaran M, Naidub A (2006). "Synthesis of potential related substances of mirtazapine". Arkivoc. 2006 (15): 127–32. doi:10.3998/ark.5550190.0007.f15.
- US patent 4062848, Van der Burg WJ, "Tetracyclic compounds", published 1977-12-13, issued 1977-12-13
- Mirtazapine. Chapter 21 in The American Psychiatric Publishing Textbook of Psychopharmacology, Fourth Edition. Eds by Schatzberg AF and Nemeroff CB. American Psychiatric Publishing, Inc. 2009. ISBN 978-1585623099
- Kaspersen FM, van Rooij FAM, Sperling EMG: The synthesis of Org 3770 labeled with 3-H, 13-C and 14-C. J Labelled Comp Radiopharma 27:1055–1068, 1989
- "Remeron New FDA Drug Approvalh". Centerwatch.
- Stimmel GL, Dopheide JA, Stahl SM (1997). "Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects". Pharmacotherapy. 17 (1): 10–21. doi:10.1002/j.1875-9114.1997.tb03674.x. PMID 9017762.
- Anttila SA, Leinonen EV (2001). "A review of the pharmacological and clinical profile of mirtazapine". CNS Drug Reviews. 7 (3): 249–64. doi:10.1111/j.1527-3458.2001.tb00198.x. PMID 11607047.