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 attenuate 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 experiencing anorexia due to medical conditions such as chronic kidney disease. It is especially useful for treating combined poor appetite and nausea in cats.
Efficacy and tolerability
In clinical studies, mirtazapine has been found to be an effective antidepressant with a generally tolerable side-effect profile relative to other antidepressants.
In general, all antidepressants, including mirtazapine, require a few weeks for their therapeutic benefits on depressive and anxious symptoms to become apparent. Unlike most antidepressants, however, mirtazapine has demonstrated itself to have a faster onset of antidepressant action 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. Hence, it may be a better choice for patients in whom hastened relief is urgently needed, such as those who are considered to be a suicide risk.
In general, some antidepressants, especially SSRIs, can paradoxically exacerbate some patients' depression or anxiety or cause suicidal ideation. Despite its sedating action, mirtazapine is also believed to be capable of this, and for this reason in the United States and certain other countries it carries a black box label warning of these potential effects.
Mirtazapine is considered to be relatively safe in the event of an overdose. Unlike the TCAs, 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 TCAs.
The cardiovascular risk statement above has a catch. If a person is on the drug clonidine or other centrally acting alpha 2 agonists, even normal doses of mirtazepine risks a hypertensive crisis, this being due to it acting exactly opposite as clonidine on alpha 2 receptors. See: http://www.medscape.com/viewarticle/409538_3
Twelve reported fatalities have been attributed to mirtazapine overdose in literature. 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.
On 10 June 2013 Lee Webster was convicted of the manslaughter of Jason Wood at MaidstoneCrown Court. He had added 27 mirtazapine tablets to Wood's drink while both were drunk. Wood was a dwarf with a body weight of 6 stone (38 kilogram).
All affinities listed were assayed using human materials except those for α1-adrenergic and mACh that are for rat tissues, due to human values being unavailable.
Though not known to have ever been screened at this site, it is possible that mirtazapine may act on the 5-HT6 receptor as well. Supporting this speculation is the fact that its analogue mianserin (which, regarding structure, can also be called 6-desazamirtazapine) has been shown to have high affinity for 5-HT6 and does not produce cAMP accumulation (indicating it is an antagonist).
Antagonism of the 5-HT2 subfamily of receptors and inverse agonisim 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 mitrazapine 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 antiemeticondansetron, 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 diarrhea, among others. As a result, mirtazapine 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, and thus is virtually devoid of any anticholinergic properties at clinical doses.
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. It has been suggested that this may be due to their unique influence on the opioid system, which is a property that has been hypothesized to somehow give them an advantage over other antidepressants in cases of severe depressive symptomatology.
Mirtazapine is typically prescribed in doses 15 mg, 30 mg and 45 mg. However, clinical doses as high as 120 mg have been reported in the medical literature.
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 that 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.
Liver and moderate renal impairment has been reported to decrease the oral clearance of mirtazapine by approximately 30%; severe renal impairment decreases it by 50%.
^ abKast, RE; Foley, KF (July 2007). "Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects". Eur J Cancer Care (Engl)16 (4): 351–4. doi:10.1111/j.1365-2354.2006.00760.x. PMID17587360.Cite uses deprecated parameters (help)
^Tajti, J; Almási, J (June 2006). "[Effects of mirtazapine in patients with chronic tension-type headache. Literature review]". Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakológiai Egyesület Lapja = Official Journal of the Hungarian Association of Psychopharmacology (in Hungarian) 8 (2): 67–72. PMID17073214.Cite uses deprecated parameters (help)
^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". J Child Adolesc Psychopharmacol11 (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". J Child Adolesc Psychopharmacol19 (2): 203–6. doi:10.1089/cap.2008.020. PMID19364298.Cite uses deprecated parameters (help)
^Hieber, R; Dellenbaugh, T; Nelson, LA (June 2008). "Role of mirtazapine in the treatment of antipsychotic-induced akathisia". Annals of Pharmacotherapy42 (6): 841–6. doi:10.1345/aph.1K672. PMID18460588.Cite uses deprecated parameters (help)
^Vidal, C; Reese, C; Fischer, BA; Chiapelli, J; Himelhoch, S (March 2013). "Meta-Analysis of Efficacy of Mirtazapine as an Adjunctive Treatment of Negative Symptoms in Schizophrenia". Clinical Schizophrenia & Related Psychoses (Walsh Medical Media): 1–24. doi:10.3371/CSRP.VIRE.030813. ISSN1935-1232. 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". Psychogeriatrics13 (2): 103–107. doi:10.1111/j.1479-8301.2012.00432.x. PMID23909968.
^Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry (in English). West Sussex: Wiley-Blackwell. ISBN978-0-470-97948-8.Cite uses deprecated parameters (help)edit
^ abcCipriani, 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". Lancet373 (9665): 746–58. doi:10.1016/S0140-6736(09)60046-5. PMID19185342.Cite uses deprecated parameters (help)
^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". Int Clin Psychopharmacol10 (1): 3–9. doi:10.1097/00004850-199503000-00001. PMID7622801.Cite uses deprecated parameters (help)
^ abcdefgFawcett, 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". J Affect Disord51 (3): 267–85. doi:10.1016/S0165-0327(98)00224-9. PMID10333982.Cite uses deprecated parameters (help)
^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 (Berl.)127 (3): 231–7. doi:10.1007/BF02246131. PMID8912401.Cite uses deprecated parameters (help)
^Bruijn, JA; Moleman, P; Mulder, PG; van den Broek, WW (May 1999). "Depressed in-patients respond differently to imipramine and mirtazapine". Pharmacopsychiatry32 (3): 87–92. doi:10.1055/s-2007-979200. PMID10463374.Cite uses deprecated parameters (help)
^ abcMcGrath, 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". Am J Psychiatry163 (9): 1531–41; quiz 1666. doi:10.1176/appi.ajp.163.9.1531. PMID16946177.Cite uses deprecated parameters (help)
^British National Formulary (BNF) (65th ed.). Pharmaceutical Press. p. 1120. ISBN978-0857110848.
^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 Neuroscience256 (8): 476–96. doi:10.1007/s00406-006-0689-8. PMID17143567.Cite uses deprecated parameters (help)
^Ali, S; Milev, R (May 2003). "Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review of the literature". Can J Psychiatry48 (4): 258–64. PMID12776393.Cite uses deprecated parameters (help)
^Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry (in English). West Sussex: Wiley-Blackwell. ISBN978-0-470-97948-8.Cite uses deprecated parameters (help)edit
^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 Toxicology47 (5): 436. 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.
^ abFernández, 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 Chemistry48 (6): 1709–12. doi:10.1021/jm049632c. PMID15771415.Cite uses deprecated parameters (help)
^ abde 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". Neuropharmacology27 (4): 399–408. doi:10.1016/0028-3908(88)90149-9. PMID3419539.Cite uses deprecated parameters (help)
^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". J Clin Psychiatry. 57 Suppl 4: 19–25. PMID8636062.
^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". Neuropharmacology33 (3–4): 501–7. doi:10.1016/0028-3908(94)90081-7. PMID7984289.
^ abBrunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (in English) (12th ed.). New York: McGraw-Hill Professional. ISBN978-0071624428.edit
^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 Chemistry45 (15): 3280–5. doi:10.1021/jm010566d. PMID12109911.Cite uses deprecated parameters (help)
^Boess, FG; Monsma, FJ; Carolo, C; Meyer, V; Rudler, A; Zwingelstein, C; Sleight, AJ (1997). "Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells". Neuropharmacology36 (4–5): 713–20. doi:10.1016/S0028-3908(97)00019-1. PMID9225298.
^Fisar, Z; Hroudová, J; Raboch, J (2010). "Inhibition of monoamine oxidase activity by antidepressants and mood stabilizers". Neuro Endocrinology Letters31 (5): 645–56. PMID21200377.
^Millan, MJ (2005). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies". Therapie60 (5): 441–60. doi:10.2515/therapie:2005065. PMID16433010.
^Dekeyne, A; Millan, MJ (April 2009). "Discriminative stimulus properties of the atypical antidepressant, mirtazapine, in rats: a pharmacological characterization". Psychopharmacology (Berl.)203 (2): 329–41. doi:10.1007/s00213-008-1259-8. PMID18709360.Cite uses deprecated parameters (help)
^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 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.Cite uses deprecated parameters (help)
^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". J. Neurochem.111 (2): 614–23. doi:10.1111/j.1471-4159.2009.06356.x. PMID19702657.Cite uses deprecated parameters (help)
^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". Prog. Brain Res.172: 287–305. doi:10.1016/S0079-6123(08)00914-X+=. PMID18772038.
^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 Alcohol Depend99 (1–3): 231–9. doi:10.1016/j.drugalcdep.2008.08.005. PMID18945553.Cite uses deprecated parameters (help)
^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". Ann Clin Psychiatry20 (3): 145–55. doi:10.1080/10401230802177656. PMID18633741.
^Brackins, T; Brahm, NC; Kissack, JC (December 2011). "Treatments for methamphetamine abuse: a literature review for the clinician". J Pharm Pract24 (6): 541–50. doi:10.1177/0897190011426557. PMID22095579.Cite uses deprecated parameters (help)
^Brensilver, M; Heinzerling, KG; Shoptaw, S (September 2013). "Pharmacotherapy of amphetamine-type stimulant dependence: An update". Drug Alcohol Rev32 (5): 449–60. doi:10.1111/dar.12048. PMID23617468.Cite uses deprecated parameters (help)
^Kast, RE (September 2001). "Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy". Support Care Cancer9 (6): 469–70. doi:10.1007/s005200000215. PMID11585276.Cite uses deprecated parameters (help)
^Costall, B; Naylor, RJ; Tyers, MB (1990). "The psychopharmacology of 5-HT3 receptors". Pharmacology & Therapeutics47 (2): 181. doi:10.1016/0163-7258(90)90086-H.
^ abcdSchreiber, 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?". J. Mol. Neurosci.18 (1–2): 143–9. doi:10.1385/JMN:18:1-2:143. PMID11931344.