Mirtazapine: Difference between revisions

Mirtazapine
Clinical data
Trade names	Remeron, Avanza, Axit, Mirtazon, Zispin
Other names	6-Azamianserin, Org 3770
AHFS/Drugs.com	Monograph
MedlinePlus	a697009
License data	US FDA: Mirtazapine;
Pregnancy; category	AU: B3; ;
Routes of; administration	Oral
ATC code	N06AX11 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: WARNINGRx-only;
Pharmacokinetic data
Bioavailability	50%
Protein binding	85%
Metabolism	Liver (CYP1A2, CYP2D6 and CYP3A4)
Elimination half-life	20–40 hours
Excretion	Urine (75%); Faeces (15%)
Identifiers
	IUPAC name (±)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine;
CAS Number	61337-67-5 ;
PubChem CID	4205;
IUPHAR/BPS	7241;
DrugBank	DB00370 ;
ChemSpider	4060 ;
UNII	A051Q2099Q;
KEGG	D00563 ;
ChEBI	CHEBI:6950 ;
ChEMBL	ChEMBL654 ;
CompTox Dashboard (EPA)	DTXSID0023325 ;
ECHA InfoCard	100.080.027
Chemical and physical data
Formula	C17H19N3
Molar mass	265.35 g/mol g·mol−1
3D model (JSmol)	Interactive image;
Density	1.22 g/cm3
Melting point	114 to 116 °C (237 to 241 °F)
Boiling point	432 °C (810 °F)
Solubility in water	Soluble in methanol and chloroform mg/mL (20 °C)
	SMILES n1cccc3c1N4C(c2ccccc2C3)CN(C)CC4;
	InChI InChI=1S/C17H19N3/c1-19-9-10-20-16(12-19)15-7-3-2-5-13(15)11-14-6-4-8-18-17(14)20/h2-8,16H,9-12H2,1H3 ; Key:RONZAEMNMFQXRA-UHFFFAOYSA-N ;
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Revision as of 21:58, 4 December 2015

Mirtazapine (brand names: Avanza, Axit, Mirtaz, Mirtazon, Remeron, Zispin)^[7] is a noradrenergic and specific serotonergic antidepressant (NaSSA) introduced by Organon International in the United States in 1996,^[3] 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.^[7] It is also racemic—occurs as a combination of both (R)- and (S)-stereoisomers, both of which are active.^[7]

Its patent expired in 2004, so generic versions are available.^[8]

Medical uses

Approved and off-label

Mirtazapine's primary use is the treatment of major depressive disorder and other mood disorders.^[9]^[10]

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

Investigational

Mirtazapine has had literature published on its efficacy in the experimental treatment of these conditions:

Sleep apnoea/hypopnoea^[29]^[30]
Inappropriate sexual behaviour and other secondary symptoms of autistic spectrum conditions and other pervasive developmental disorders^[31]^[32]^[33]^[34]
Antipsychotic-induced akathisia^[35]^[36]
Drug withdrawal, dependence and detoxification^[37]
Negative, depressive and cognitive symptoms of schizophrenia (as an adjunct)^[38]^[39]
A case report has been published in which mirtazapine reduced visual hallucinations in a patient with Parkinson's disease psychosis (PDP).^[40] 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—doses too low to antagonise the D₂ receptor, but sufficiently high doses to inversely agonise the 5-HT_2A receptors.^[41]

Feline and canine

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.^[42]^[43]

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.^[44]

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.^[44] However, its superior efficacy over the other medications in the top four (escitalopram, sertraline and venlafaxine) did not reach statistical significance.^[44]

Compared to earlier antidepressants, mirtazapine has been found to be significantly superior to trazodone,^[45] while it has been shown to be approximately equivalent in efficacy to several of the tricyclic antidepressants including amitriptyline, doxepin and clomipramine, though with a much improved tolerability profile.^[6]^[46] However, two other studies found mirtazapine to be significantly inferior to imipramine, another TCA.^[47]^[48] One study compared the combination of venlafaxine and mirtazapine to the monoamine oxidase inhibitor (MAOI) tranylcypromine alone and found them to be similarly effective, though tranylcypromine was much less tolerable in regard to side effects and drug interactions.^[49]

In general, all antidepressants, including mirtazapine, require at least a week for their therapeutic benefits on depressive and anxious symptoms to become apparent.^[50]^[51] 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.^[50]^[52]

Adverse reactions

Side effects

Information sources:^[3]^[4]^[5]^[53]^[54]^[55]

Very common (≥10% incidence) adverse effects

Constipation (13%)
Dry mouth (25%)
Increased appetite (17%)
Somnolence (54%), sedation, sleepiness
Weight gain (≥7% weight gain, only in pediatrics is this very common)

Common (1%≤ incidence <10%) adverse effects

ALT (SGPT) level raised (2%)
Asthenia (8%)
Disturbance in thinking (3%)
Dizziness (7%)
Peripheral oedema
Serum triglycerides raised (increases to 500 mg/dL (5,65 mmol/L) or greater: 6%)

Uncommon (0.1%≤ incidence <1%)

Headache

Rare (incidence <0.1%)

Template:MultiCol

Aggression
Agitation
Alopecia
Anxiety
Arthralgia
Blood dyscrasias (agranulocytosis, anemia, aplastic anemia, eosinophilia, granulocytopenia, neutropenia, pancytopenia, thrombocytopenia)
Bullous dermatitis
Chest pain
Cirrhosis
Confusion
Depression
Erythema multiforme
Exanthem
Excessive sweating
Glaucoma

| class="col-break " |

Template:EndMultiCol

Unknown frequency

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.^[6]^[46] These adverse effects include decreased appetite, weight loss, insomnia, nausea and vomiting, diarrhoea, urinary retention, increased body temperature, excessive sweating, pupil dilation and sexual dysfunction.^[6]^[46]

In general, some antidepressants, especially SSRIs, can paradoxically exacerbate some peoples' depression or anxiety or cause suicidal ideation.^[56] 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.

Discontinuation

Mirtazapine and other antidepressants may cause a withdrawal syndrome upon discontinuation.^[6]^[57]^[58] A gradual and slow reduction in dose is recommended to minimize withdrawal symptoms.^[59] Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety, panic attacks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhoea, nausea, vomiting, flu-like symptoms such as allergies and pruritus, headaches and sometimes hypomania or mania.^[57]^[60]^[61]^[62]^[63]

Overdose

Mirtazapine is considered to be relatively safe in the event of an overdose,^[51] although it is considered slightly more toxic in overdose than most of the SSRIs (except citalopram).^[64] Unlike the TCAs, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose.^[46] Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to TCAs.^[65]^[66]

Twelve reported fatalities have been attributed to mirtazapine overdose.^[67]^[68] 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.^[69]

Pharmacology

Binding profile

Mirtazapine is an antagonist/inverse agonist at the following receptors:^[70]^[71]

Molecular target	Binding affinity, K_i (nM)^[72]	Notes
5-HT_2A receptor	69	The (S)-(+) enantiomer is responsible for this antagonism.^[7]
5-HT_2B receptor	?	~20-fold lower than for 5-HT_2A/5-HT_2C^[73]
5-HT_2C receptor	39	Inverse agonist^[74] The (S)-(+) enantiomer is responsible for this action.^[7]
5-HT₃ receptor	?	Similar to 5-HT_2A/5-HT_2C (mouse neuroblastoma cell)^[75] R-(–) enantiomer antagonises the 5-HT₃ receptor.^[7]
5-HT₇ receptor	265
α₁-adrenergic receptor	500	^[76]
α_2A-adrenergic receptor	20	The S-(+) enantiomer is responsible for this antagonism at autoreceptors.^[7] Heteroreceptors are blocked by both the (S)-(+) and (R)-(–) enantiomers.^[4]
α_2C-adrenergic receptor	18	The S-(+) enantiomer is responsible for this antagonism at autoreceptors.^[7] Heteroreceptors are blocked by both the (S)-(+) and (R)-(–) enantiomers.^[4]
D₁ receptor	4167
D₂ receptor	>5454
D₃ receptor	5723
H₁ receptor	1.6	^[77]
mACh receptors	670	^[76]

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.^[70]^[71]

Mirtazapine has recently been found to act as a weak (EC₅₀ 7.2 μM) κ-opioid receptor partial agonist.^[78]

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-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 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.^[6]^[9]^[79]^[80]^[81] Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT_1A receptor.^[80] Increased activation of the central 5-HT_1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs.^[82] 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,^[83] nor does it have any significant inhibitory effects on monoamine oxidase.^[84]

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.^[85]^[86] The 5-HT_2C 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.^[87]^[88] 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.^[89] 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.^[6]^[46] The newest research however has shown that mirtazapine is actually an inverse agonist of the 5-HT_2C receptor. 5-HT_2C inverse agonists have been shown to inhibit mesoaccumbens dopamine outflow^[90] attenuating the rewarding properties of various substances like morphine. This inhibition of dopamine may be stronger than thought as substances with 5-HT_2C inverse agonist properties may have more activity to regulate dopamine neurotransmission than ones with competitive antagonism.^[91] With its newly understood properties of 5-HT_2C 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.^[74]^[92]^[93] It is also being investigated to help in substance abuse disorders with withdrawal effects and remission rates.^[74]^[94] but some studies have shown mixed benefit.^[74]^[95]^[96]

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.^[97] Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron.^[24] 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.^[98] In conjunction with substance abuse counseling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success.^[92] In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT_2A, 5-HT_2C, 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.^[46]^[49]^[99]^[100]^[101]^[102]

Mirtazapine is a very strong H₁ receptor inverse agonist and, as a result, it can cause powerful sedative and hypnotic effects.^[6] 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.^[103] 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.^[104]

Like many other antidepressants, mirtazapine has been found to have antinociceptive properties in mice.^[105] 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.^[105] 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.^[105] 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.^[105]

Pharmacokinetics

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.^[2] The overall elimination half-life is 20–40 hours.

Dosage

Mirtazapine is typically prescribed in doses for humans of 15, 30 and 45 mg. However, clinical doses as high as 120 mg have been reported in the medical literature.^[106]

Interactions

Concurrent use with inhibitors or inducers of the cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and/or CYP3A4 can result in altered concentrations of mirtazapine, as these are the main enzymes responsible for its metabolism.^[2]^[6] As examples, fluoxetine and paroxetine, inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while carbamazepine, an inducer, considerably decreases them.^[2]

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.^[107] However, a single study regarding the combination reported it does not result in any incidence of serotonin-related toxicity.^[108] In addition, a case report claimed that mirtazapine can actually be used to treat serotonin syndrome.^[109] Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is considered to be relatively safe and is often employed therapeutically,^[46]^[49]^[99]^[100]^[101] with a combination of venlafaxine and mirtazapine sometimes referred to as “California rocket fuel”.^[110]

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.^[111]

Liver and moderate renal impairment have been reported to decrease the oral clearance of mirtazapine by about 30%; severe renal impairment decreases it by 50%.^[2]

Chemistry

Mirtazapine is a racemic mixture of enantiomers. The (S)-(+)-enantiomer is known as esmirtazapine.

A four-step chemical synthesis of mirtazapine has been published.^[112]^[113]

References

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External links

[FDA-AllBoxedWarnings-1] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.

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[DM-3] ^ ^a ^b ^c ^d ^e ^f ^g "REMERON (mirtazapine) tablet, film coated [Organon Pharmaceuticals USA]". DailyMed. Organon Pharmaceuticals USA. October 2012. Retrieved 24 October 2013.

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[EMC-5] ^ ^a ^b ^c ^d ^e ^f "Mirtazapine 30 mg Tablets - Summary of Product Characteristics" (PDF). electronic Medicines Compendium. Sandoz Limited. 20 March 2013. Retrieved 24 October 2013.

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 <!--Pharmacokinetic data-->
-| bioavailability = 50%<ref name="pmid10885584">{{cite journal | author = Timmer, CJ; Sitsen, JM; Delbressine, LP | title = Clinical pharmacokinetics of mirtazapine | journal = Clinical Pharmacokinetics | volume = 38 | issue = 6 | pages = 461–74 |date=June 2000 | pmid = 10885584 | doi = 10.2165/00003088-200038060-00001| url = http://content.wkhealth.com/linkback/openurl?issn=0312-5963&volume=38&issue=6&spage=461}}</ref><ref name = DM/><ref name = AXIT/><ref name = EMC/>
+| bioavailability = 50%<ref name="pmid10885584">{{cite journal | vauthors = Timmer CJ, Sitsen JM, Delbressine LP | title = Clinical pharmacokinetics of mirtazapine | journal = Clinical Pharmacokinetics | volume = 38 | issue = 6 | pages = 461–74 | date = Jun 2000 | pmid = 10885584 | doi = 10.2165/00003088-200038060-00001 | url = http://content.wkhealth.com/linkback/openurl?issn=0312-5963&volume=38&issue=6&spage=461 }}</ref><ref name = DM/><ref name = AXIT/><ref name = EMC/>
 | protein_bound = 85%<ref name="pmid10885584" /><ref name = DM/><ref name = AXIT/><ref name = EMC/>
-| metabolism = [[Liver]] ([[CYP1A2]], [[CYP2D6]] and [[CYP3A4]])<ref name="pmid10885584" /><ref name = DM/><ref name = AXIT/><ref name = EMC/><ref name="pmid11607047">{{cite journal | author = Anttila, SA; Leinonen, EV | title = A review of the pharmacological and clinical profile of mirtazapine | journal = CNS Drug Reviews | volume = 7 | issue = 3 | pages = 249–64 | year = 2001 | pmid = 11607047 | doi = 10.1111/j.1527-3458.2001.tb00198.x| url = }}</ref>
+| metabolism = [[Liver]] ([[CYP1A2]], [[CYP2D6]] and [[CYP3A4]])<ref name="pmid10885584" /><ref name = DM/><ref name = AXIT/><ref name = EMC/><ref name="pmid11607047">{{cite journal | vauthors = Anttila SA, Leinonen EV | title = A review of the pharmacological and clinical profile of mirtazapine | journal = CNS Drug Reviews | volume = 7 | issue = 3 | pages = 249–64 | year = 2001 | pmid = 11607047 | doi = 10.1111/j.1527-3458.2001.tb00198.x }}</ref>
 | elimination_half-life = 20–40 hours<ref name="pmid10885584" /><ref name = DM/><ref name = AXIT/><ref name = EMC/>
 | excretion = Urine (75%)<ref name="pmid10885584" /><br />Faeces (15%)<ref name="pmid10885584" /><ref name = DM/><ref name = AXIT/><ref name = EMC/>
@@ Line 73: / Line 73: @@
 Its patent expired in 2004, so generic versions are available.<ref>{{cite book|author=Schatzberg, AF; Cole, JO; DeBattista, C|title=Manual of Clinical Psychopharmacology|edition=7th|publisher=American Psychiatric Publishing|location=Arlington, VA|ISBN=978-1-58562-377-8|chapter=3}}</ref>
-==Medical uses==
+== Medical uses ==
-===Approved and off-label===
+=== Approved and off-label ===
-Mirtazapine's primary use is the [[therapy|treatment]] of [[major depressive disorder]] and other [[mood disorder]]s.<ref name="pmid10446735">{{cite journal | author = Gorman, JM | title = Mirtazapine: clinical overview | journal = J Clin Psychiatry | volume = 60 Suppl 17 | issue = | pages = 9–13; discussion 46–8 | year = 1999 | pmid = 10446735 | doi = }}</ref><ref name="pmid21644844">{{cite journal | author = 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 = 1623–32 |date=July 2011 | pmid = 21644844 | doi = 10.1517/14656566.2011.585459 | url = http://informahealthcare.com/doi/abs/10.1517/14656566.2011.585459}}</ref>
+Mirtazapine's primary use is the [[therapy|treatment]] of [[major depressive disorder]] and other [[mood disorder]]s.<ref name="pmid10446735">{{cite journal | vauthors = Gorman JM | title = Mirtazapine: clinical overview | journal = The Journal of Clinical Psychiatry | volume = 60 Suppl 17 | issue =  | pages = 9–13; discussion 46-8 | year = 1999 | pmid = 10446735 | doi =  }}</ref><ref name="pmid21644844">{{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 = 1623–32 | date = Jul 2011 | pmid = 21644844 | doi = 10.1517/14656566.2011.585459 | url = http://informahealthcare.com/doi/abs/10.1517/14656566.2011.585459 }}</ref>
 However, it has also been found useful in alleviating the following conditions and may be prescribed off-label for their treatment:
 {{colbegin|2}}
-* [[Generalized anxiety disorder]]<ref name="pmid11607047" /><ref name="pmid10453798">{{cite journal | author = Goodnick, PJ; Puig, A; DeVane, CL; Freund, BV | title = Mirtazapine in major depression with comorbid generalized anxiety disorder | journal = J Clin Psychiatry | volume = 60 | issue = 7 | pages = 446–8 |date=July 1999 | pmid = 10453798 | doi = 10.4088/JCP.v60n0705 }}</ref>
+* [[Generalized anxiety disorder]]<ref name="pmid11607047" /><ref name="pmid10453798">{{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 = 446–8 | date = Jul 1999 | pmid = 10453798 | doi = 10.4088/JCP.v60n0705 }}</ref>
-* [[Social anxiety disorder]]<ref name="pmid19453203">{{cite journal | author = 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 = 427–52 | year = 2009 | pmid = 19453203 | doi = 10.2165/00023210-200923050-00006 | url = http://content.wkhealth.com/linkback/openurl?issn=1172-7047&volume=23&issue=5&spage=427}}</ref><ref name="pmid16282842">{{cite journal | author = Muehlbacher, M; Nickel, MK; Nickel, C| title = Mirtazapine treatment of social phobia in women: a randomized, double-blind, placebo-controlled study | journal = Journal of Clinical Psychopharmacology | volume = 25 | issue = 6 | pages = 580–3 |date=December 2005 | pmid = 16282842 | doi = 10.1097/01.jcp.0000186871.04984.8d| url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0271-0749&volume=25&issue=6&spage=580|display-authors=etal}}</ref>
+* [[Social anxiety disorder]]<ref name="pmid19453203">{{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 = 427–52 | year = 2009 | pmid = 19453203 | doi = 10.2165/00023210-200923050-00006 | url = http://content.wkhealth.com/linkback/openurl?issn=1172-7047&volume=23&issue=5&spage=427 }}</ref><ref name="pmid16282842">{{cite journal | vauthors = 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 | title = Mirtazapine treatment of social phobia in women: a randomized, double-blind, placebo-controlled study | journal = Journal of Clinical Psychopharmacology | volume = 25 | issue = 6 | pages = 580–3 | date = Dec 2005 | pmid = 16282842 | doi = 10.1097/01.jcp.0000186871.04984.8d | url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0271-0749&volume=25&issue=6&spage=580 }}</ref>
-* [[Obsessive-compulsive disorder]]<ref name="pmid19453203" /><ref name="pmid11593084">{{cite journal | author = Koran, LM; Quirk, T; Lorberbaum, JP; Elliott, M | title = Mirtazapine treatment of obsessive-compulsive disorder | journal = J Clin Psychopharmacol | volume = 21 | issue = 5 | pages = 537–9 |date=October 2001 | pmid = 11593084 | doi = 10.1097/00004714-200110000-00016 }}{{Unreliable medical source|date=October 2011}}</ref>
+* [[Obsessive-compulsive disorder]]<ref name="pmid19453203" /><ref name="pmid11593084">{{cite journal | vauthors = Koran LM, Quirk T, Lorberbaum JP, Elliott M | title = Mirtazapine treatment of obsessive-compulsive disorder | journal = Journal of Clinical Psychopharmacology | volume = 21 | issue = 5 | pages = 537–9 | date = Oct 2001 | pmid = 11593084 | doi = 10.1097/00004714-200110000-00016 }}{{Unreliable medical source|date=October 2011}}</ref>
-* [[Panic disorder]]<ref name="pmid19453203" /><ref name="pmid10440525">{{cite journal | author = Carpenter, LL; Leon, Z; Yasmin, S; Price, LH | title = Clinical experience with mirtazapine in the treatment of panic disorder | journal = Ann Clin Psychiatry | volume = 11 | issue = 2 | pages = 81–6 |date=June 1999 | pmid = 10440525 | doi = 10.3109/10401239909147053 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid12090820">{{cite journal | author = Carli, V; Sarchiapone, M; Camardese, G; Romano, L; DeRisio, S | title = Mirtazapine in the treatment of panic disorder | journal = Arch. Gen. Psychiatry | volume = 59 | issue = 7 | pages = 661–2 |date=July 2002 | pmid = 12090820 | doi = 10.1001/archpsyc.59.7.661 }}{{Unreliable medical source|date=October 2011}}</ref>
+* [[Panic disorder]]<ref name="pmid19453203" /><ref name="pmid10440525">{{cite journal | vauthors = Carpenter LL, Leon Z, Yasmin S, Price LH | title = Clinical experience with mirtazapine in the treatment of panic disorder | journal = Annals of Clinical Psychiatry | volume = 11 | issue = 2 | pages = 81–6 | date = Jun 1999 | pmid = 10440525 | doi = 10.3109/10401239909147053 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid12090820">{{cite journal | vauthors = Carli V, Sarchiapone M, Camardese G, Romano L, DeRisio S | title = Mirtazapine in the treatment of panic disorder | journal = Archives of General Psychiatry | volume = 59 | issue = 7 | pages = 661–2 | date = Jul 2002 | pmid = 12090820 | doi = 10.1001/archpsyc.59.7.661 }}{{Unreliable medical source|date=October 2011}}</ref>
 * [[Post-traumatic stress disorder]]<ref name="pmid19453203" />
-* [[Loss of appetite|Low appetite]]/[[underweight]]<ref name="pmid12647431">{{cite journal | author = Landowski, J | title = [Mirtazapine--an antidepressant] | language = Polish | journal = Psychiatria Polska | volume = 36 | issue = 6 Suppl | pages = 125–30 | year = 2002 | pmid = 12647431 | doi = | url = }}</ref><ref name="pmid18001374">{{cite journal | author = Chinuck, RS; Fortnum, H; Baldwin, DR | title = Appetite stimulants in cystic fibrosis: a systematic review | journal = Journal of Human Nutrition and Dietetics : the Official Journal of the British Dietetic Association | volume = 20 | issue = 6 | pages = 526–37 |date=December 2007 | pmid = 18001374 | doi = 10.1111/j.1365-277X.2007.00824.x | url = http://dx.doi.org/10.1111/j.1365-277X.2007.00824.x}}</ref><ref name="pmid12647979">{{cite journal | author = 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 = 365–76 |date=August 2002 | pmid = 12647979 | doi = 10.1586/14737140.2.4.365 | url = http://www.future-drugs.com/doi/abs/10.1586/14737140.2.4.365?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed}}</ref>
+* [[Loss of appetite|Low appetite]]/[[underweight]]<ref name="pmid12647431">{{cite journal | vauthors = Landowski J | title = [Mirtazapine--an antidepressant] | language = Polish | journal = Psychiatria Polska | volume = 36 | issue = 6 Suppl | pages = 125–30 | year = 2002 | pmid = 12647431 | doi =  }}</ref><ref name="pmid18001374">{{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 = 526–37 | date = Dec 2007 | pmid = 18001374 | doi = 10.1111/j.1365-277X.2007.00824.x | url = http://dx.doi.org/10.1111/j.1365-277X.2007.00824.x }}</ref><ref name="pmid12647979">{{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 = 365–76 | date = Aug 2002 | pmid = 12647979 | doi = 10.1586/14737140.2.4.365 | url = http://www.future-drugs.com/doi/abs/10.1586/14737140.2.4.365?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed }}</ref>
-* [[Insomnia]]<ref name="pmid9917581">{{cite journal | author = Hartmann, PM | title = Mirtazapine: a newer antidepressant | journal = Am Fam Physician | volume = 59 | issue = 1 | pages = 159–61 |date=January 1999 | pmid = 9917581 | doi = }}</ref><ref name="pmid19374460">{{cite journal | author = Jindal, RD | title = Insomnia in patients with depression: some pathophysiological and treatment considerations | journal = CNS Drugs | volume = 23 | issue = 4 | pages = 309–29 | year = 2009 | pmid = 19374460 | doi = 10.2165/00023210-200923040-00004| url = http://content.wkhealth.com/linkback/openurl?issn=1172-7047&volume=23&issue=4&spage=309}}</ref>
+* [[Insomnia]]<ref name="pmid9917581">{{cite journal | vauthors = Hartmann PM | title = Mirtazapine: a newer antidepressant | journal = American Family Physician | volume = 59 | issue = 1 | pages = 159–61 | date = Jan 1999 | pmid = 9917581 | doi =  }}</ref><ref name="pmid19374460">{{cite journal | vauthors = Jindal RD | title = Insomnia in patients with depression: some pathophysiological and treatment considerations | journal = CNS Drugs | volume = 23 | issue = 4 | pages = 309–29 | year = 2009 | pmid = 19374460 | doi = 10.2165/00023210-200923040-00004 | url = http://content.wkhealth.com/linkback/openurl?issn=1172-7047&volume=23&issue=4&spage=309 }}</ref>
-* [[Nausea]]/[[vomiting]]<ref name="pmid12404669">{{cite journal | author = Nutt, DJ | title = Tolerability and safety aspects of mirtazapine | journal = Human Psychopharmacology | volume = 17 Suppl 1 | issue = | pages = S37–41 |date=June 2002 | pmid = 12404669 | doi = 10.1002/hup.388 | url = http://dx.doi.org/10.1002/hup.388}}</ref><ref name="pmid21602639">{{cite journal | author = 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 = 165–7 |date=June 2011 | pmid = 21602639 | doi = 10.1097/YCT.0b013e3181e63346 | url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1095-0680&volume=27&issue=2&spage=165}}</ref><ref name="pmid17587360">{{cite journal | author = Kast, RE; Foley, KF | title = Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects | journal = Eur J Cancer Care (Engl) | volume = 16 | issue = 4 | pages = 351–4 |date=July 2007 | pmid = 17587360 | doi = 10.1111/j.1365-2354.2006.00760.x }}</ref>
+* [[Nausea]]/[[vomiting]]<ref name="pmid12404669">{{cite journal | vauthors = Nutt DJ | title = Tolerability and safety aspects of mirtazapine | journal = Human Psychopharmacology | volume = 17 Suppl 1 | issue =  | pages = S37-41 | date = Jun 2002 | pmid = 12404669 | doi = 10.1002/hup.388 | url = http://dx.doi.org/10.1002/hup.388 }}</ref><ref name="pmid21602639">{{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 = 165–7 | date = Jun 2011 | pmid = 21602639 | doi = 10.1097/YCT.0b013e3181e63346 | url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1095-0680&volume=27&issue=2&spage=165 }}</ref><ref name="pmid17587360">{{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 = 351–4 | date = Jul 2007 | pmid = 17587360 | doi = 10.1111/j.1365-2354.2006.00760.x }}</ref>
-* [[Itching]]<ref name="pmid12509645">{{cite journal | author = Twycross, R; Greaves, MW; Handwerker, H| title = Itch: scratching more than the surface | journal = QJM : Monthly Journal of the Association of Physicians | volume = 96 | issue = 1 | pages = 7–26 |date=January 2003 | pmid = 12509645 | doi = 10.1093/qjmed/hcg002| url = http://qjmed.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12509645|display-authors=etal}}</ref><ref name="pmid16297004">{{cite journal | author = Greaves, MW | title = Itch in systemic disease: therapeutic options | journal = Dermatologic Therapy | volume = 18 | issue = 4 | pages = 323–7 | year = 2005 | pmid = 16297004 | doi = 10.1111/j.1529-8019.2005.00036.x | url = http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1396-0296&date=2005&volume=18&issue=4&spage=323}}</ref>
+* [[Itching]]<ref name="pmid12509645">{{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 = Jan 2003 | pmid = 12509645 | doi = 10.1093/qjmed/hcg002 | url = http://qjmed.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12509645 }}</ref><ref name="pmid16297004">{{cite journal | vauthors = Greaves MW | title = Itch in systemic disease: therapeutic options | journal = Dermatologic Therapy | volume = 18 | issue = 4 | pages = 323–7 | year = 2005 | pmid = 16297004 | doi = 10.1111/j.1529-8019.2005.00036.x | url = http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1396-0296&date=2005&volume=18&issue=4&spage=323 }}</ref>
-* [[Headache]]s and [[migraine]]<ref name="pmid21602639" /><ref name="pmid15549531">{{cite journal | author = Colombo, B; Annovazzi, PO; Comi, G | title = Therapy of primary headaches: the role of antidepressants | journal = Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | volume = 25 Suppl 3 | issue = | pages = S171–5 |date=October 2004 | pmid = 15549531 | doi = 10.1007/s10072-004-0280-x | url = http://dx.doi.org/10.1007/s10072-004-0280-x}}</ref><ref name="pmid17073214">{{cite journal | author = Tajti, J; Almási, J | title = [Effects of mirtazapine in patients with chronic tension-type headache. Literature review] | language = Hungarian | journal = Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakológiai Egyesület Lapja = Official Journal of the Hungarian Association of Psychopharmacology | volume = 8 | issue = 2 | pages = 67–72 |date=June 2006 | pmid = 17073214 | doi = | url = }}</ref>
+* [[Headache]]s and [[migraine]]<ref name="pmid21602639" /><ref name="pmid15549531">{{cite journal | vauthors = Colombo B, Annovazzi PO, Comi G | title = Therapy of primary headaches: the role of antidepressants | journal = Neurological Sciences | volume = 25 Suppl 3 | issue =  | pages = S171-5 | date = Oct 2004 | pmid = 15549531 | doi = 10.1007/s10072-004-0280-x | url = http://dx.doi.org/10.1007/s10072-004-0280-x }}</ref><ref name="pmid17073214">{{cite journal | vauthors = Tajti J, Almási J | title = [Effects of mirtazapine in patients with chronic tension-type headache. Literature review] | language = Hungarian | journal = Neuropsychopharmacologia Hungarica | volume = 8 | issue = 2 | pages = 67–72 | date = Jun 2006 | pmid = 17073214 | doi =  }}</ref>
 {{colend}}
-===Investigational===
+=== Investigational ===
 Mirtazapine has had literature published on its efficacy in the experimental treatment of these conditions:
-* [[Sleep apnoea]]/[[hypopnoea]]<ref name="pmid19388881">{{cite journal | author = 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 = 647–56 |date=May 2009 | pmid = 19388881 | doi = 10.1517/13543780902877674 | url = http://informahealthcare.com/doi/abs/10.1517/13543780902877674%20}}</ref><ref name="pmid18548827">{{cite journal | author = 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 = 824–31 |date=June 2008 | pmid = 18548827 | pmc = 2442407 | doi = }}</ref>
+* [[Sleep apnoea]]/[[hypopnoea]]<ref name="pmid19388881">{{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 = 647–56 | date = May 2009 | pmid = 19388881 | doi = 10.1517/13543780902877674 | url = http://informahealthcare.com/doi/abs/10.1517/13543780902877674%20 }}</ref><ref name="pmid18548827">{{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 = 824–31 | date = Jun 2008 | pmid = 18548827 | pmc = 2442407 | doi =  }}</ref>
-* Inappropriate sexual behaviour and other secondary symptoms of [[autistic spectrum|autistic spectrum condition]]s and other [[pervasive developmental disorder]]s<ref name="pmid15584771">{{cite journal | author = Masi, G | title = Pharmacotherapy of pervasive developmental disorders in children and adolescents | journal = CNS Drugs | volume = 18 | issue = 14 | pages = 1031–52 | year = 2004 | pmid = 15584771 | doi = 10.2165/00023210-200418140-00006| url = http://content.wkhealth.com/linkback/openurl?issn=1172-7047&volume=18&issue=14&spage=1031}}</ref><ref name="pmid12589395">{{cite journal | author = 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 : Official Publication of the American College of Neuropsychopharmacology | volume = 28 | issue = 2 | pages = 402–12 |date=February 2003 | pmid = 12589395 | doi = 10.1038/sj.npp.1300057 | url = http://dx.doi.org/10.1038/sj.npp.1300057}}</ref><ref name="pmid11642476">{{cite journal | author = Posey, DJ; Guenin, KD; Kohn, AE; Swiezy, NB; McDougle, CJ | title = A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders | journal = J Child Adolesc Psychopharmacol | volume = 11 | issue = 3 | pages = 267–77 | year = 2001 | pmid = 11642476 | doi = 10.1089/10445460152595586 }}</ref><ref name="pmid19364298">{{cite journal | author = Coskun, M; Karakoc, S; Kircelli, F; Mukaddes, NM | title = Effectiveness of mirtazapine in the treatment of inappropriate sexual behaviors in individuals with autistic disorder | journal = J Child Adolesc Psychopharmacol | volume = 19 | issue = 2 | pages = 203–6 |date=April 2009 | pmid = 19364298 | doi = 10.1089/cap.2008.020 }}</ref>
+* Inappropriate sexual behaviour and other secondary symptoms of [[autistic spectrum|autistic spectrum condition]]s and other [[pervasive developmental disorder]]s<ref name="pmid15584771">{{cite journal | vauthors = Masi G | title = Pharmacotherapy of pervasive developmental disorders in children and adolescents | journal = CNS Drugs | volume = 18 | issue = 14 | pages = 1031–52 | year = 2004 | pmid = 15584771 | doi = 10.2165/00023210-200418140-00006 | url = http://content.wkhealth.com/linkback/openurl?issn=1172-7047&volume=18&issue=14&spage=1031 }}</ref><ref name="pmid12589395">{{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 = 402–12 | date = Feb 2003 | pmid = 12589395 | doi = 10.1038/sj.npp.1300057 | url = http://dx.doi.org/10.1038/sj.npp.1300057 }}</ref><ref name="pmid11642476">{{cite journal | vauthors = Posey DJ, Guenin KD, Kohn AE, Swiezy NB, McDougle CJ | title = A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders | journal = Journal of Child and Adolescent Psychopharmacology | volume = 11 | issue = 3 | pages = 267–77 | year = 2001 | pmid = 11642476 | doi = 10.1089/10445460152595586 }}</ref><ref name="pmid19364298">{{cite journal | vauthors = Coskun M, Karakoc S, Kircelli F, Mukaddes NM | title = Effectiveness of mirtazapine in the treatment of inappropriate sexual behaviors in individuals with autistic disorder | journal = Journal of Child and Adolescent Psychopharmacology | volume = 19 | issue = 2 | pages = 203–6 | date = Apr 2009 | pmid = 19364298 | doi = 10.1089/cap.2008.020 }}</ref>
-* [[Antipsychotic]]-induced [[akathisia]]<ref name="pmid19378382">{{cite journal | author = Kumar, R; Sachdev, PS | title = Akathisia and second-generation antipsychotic drugs | journal = Current Opinion in Psychiatry | volume = 22 | issue = 3 | pages = 293–99 |date=May 2009 | pmid = 19378382 | doi = 10.1097/YCO.0b013e32832a16da| url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0951-7367&volume=22&issue=3&spage=293}}</ref><ref name="pmid18460588">{{cite journal | author = Hieber, R; Dellenbaugh, T; Nelson, LA | title = Role of mirtazapine in the treatment of antipsychotic-induced akathisia | journal = Annals of Pharmacotherapy | volume = 42 | issue = 6 | pages = 841–6 |date=June 2008 | pmid = 18460588 | doi = 10.1345/aph.1K672 }}</ref>
+* [[Antipsychotic]]-induced [[akathisia]]<ref name="pmid19378382">{{cite journal | vauthors = Kumar R, Sachdev PS | title = Akathisia and second-generation antipsychotic drugs | journal = Current Opinion in Psychiatry | volume = 22 | issue = 3 | pages = 293–99 | date = May 2009 | pmid = 19378382 | doi = 10.1097/YCO.0b013e32832a16da | url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0951-7367&volume=22&issue=3&spage=293 }}</ref><ref name="pmid18460588">{{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 = 841–6 | date = Jun 2008 | pmid = 18460588 | doi = 10.1345/aph.1K672 }}</ref>
-* [[Drug withdrawal]], [[drug dependence|dependence]] and [[drug detoxification|detoxification]]<ref>{{cite journal|title=Mirtazapine, and mirtazapine-like compounds as possible pharmacotherapy for substance abuse disorders: evidence from the bench and the bedside|journal=Pharmacology & Therapeutics|author=Graves, SM; Rafeyan, R; Watts, J; Napier, TC|date=December 2012|volume=136|issue=3|pages=343–353|doi=10.1016/j.pharmthera.2012.08.013|pmid=22960395|pmc=3483434}}</ref>
+* [[Drug withdrawal]], [[drug dependence|dependence]] and [[drug detoxification|detoxification]]<ref>{{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 = 343–53 | date = Dec 2012 | pmid = 22960395 | pmc = 3483434 | doi = 10.1016/j.pharmthera.2012.08.013 }}</ref>
-* Negative, depressive and cognitive symptoms of [[schizophrenia]] (as an adjunct)<ref>{{cite book | isbn = 9789400758056 | title = Polypharmacy in Psychiatry Practice, Volume I | author = Ritsner, MS | year = 2013 | publisher = Springer Science+Business Media Dordrecht | url = http://link.springer.com/book/10.1007/978-94-007-5805-6/  | pages =  }}</ref><ref>{{cite journal|title=Meta-Analysis of Efficacy of Mirtazapine as an Adjunctive Treatment of Negative Symptoms in Schizophrenia|journal=Clinical Schizophrenia & Related Psychoses|publisher=Walsh Medical Media|issn=1935-1232|doi=10.3371/CSRP.VIRE.030813|date=March 2013|pages=1–24|pmid=23491969|author=Vidal, C; Reese, C; Fischer, BA; Chiapelli, J; Himelhoch, S|volume=1}}</ref>
+* Negative, depressive and cognitive symptoms of [[schizophrenia]] (as an adjunct)<ref>{{cite book | isbn = 9789400758056 | title = Polypharmacy in Psychiatry Practice, Volume I | author = Ritsner, MS | year = 2013 | publisher = Springer Science+Business Media Dordrecht | url = http://link.springer.com/book/10.1007/978-94-007-5805-6/  | pages =  }}</ref><ref>{{cite journal | vauthors = Vidal C, Reese C, Fischer BA, Chiapelli J, Himelhoch S | title = Meta-Analysis of Efficacy of Mirtazapine as an Adjunctive Treatment of Negative Symptoms in Schizophrenia | journal = Clinical Schizophrenia & Related Psychoses | volume = 9 | issue = 2 | pages = 88–95 | date = Jul 2015 | pmid = 23491969 | doi = 10.3371/CSRP.VIRE.030813 | publisher = Walsh Medical Media }}</ref>
-* A case report has been published in which mirtazapine reduced visual hallucinations in a patient with [[Parkinson's disease]] psychosis (PDP).<ref>{{cite journal|title=Mirtazapine improves visual hallucinations in Parkinson's disease: a case report|journal=Psychogeriatrics|year=June 2013|volume=13|issue=2|pages=103–107|doi=10.1111/j.1479-8301.2012.00432.x|pmid=23909968|author=Tagai, K; Nagata, T; Shinagawa, S; Tsuno, N; Ozone, M; Nakayama, K}}</ref> This is in alignment with recent findings that [[inverse agonist]]s at the [[5-HT2A receptor|5-HT<sub>2A</sub> 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 [[Dopamine D2 receptor|D<sub>2</sub> receptor]], but sufficiently high doses to inversely agonise the 5-HT<sub>2A</sub> receptors.<ref>{{cite book | isbn = 978-0-470-97948-8 | title = The Maudsley prescribing guidelines in psychiatry | last1 = Taylor | first1 = D |author2=Paton, C; Shitij, K | year = 2012 | publisher = Wiley-Blackwell | location = West Sussex  | pages =  }}</ref>
+* A case report has been published in which mirtazapine reduced visual hallucinations in a patient with [[Parkinson's disease]] psychosis (PDP).<ref>{{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 = 103–7 | date = Jun 2013 | pmid = 23909968 | doi = 10.1111/j.1479-8301.2012.00432.x }}</ref> This is in alignment with recent findings that [[inverse agonist]]s at the [[5-HT2A receptor|5-HT<sub>2A</sub> 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 [[Dopamine D2 receptor|D<sub>2</sub> receptor]], but sufficiently high doses to inversely agonise the 5-HT<sub>2A</sub> receptors.<ref>{{cite book | isbn = 978-0-470-97948-8 | title = The Maudsley prescribing guidelines in psychiatry | last1 = Taylor | first1 = D |author2=Paton, C; Shitij, K | year = 2012 | publisher = Wiley-Blackwell | location = West Sussex  | pages =  }}</ref>
 {{colend}}
-===Feline and canine===
+=== Feline and canine ===
 Mirtazapine is sometimes prescribed as an appetite stimulant for [[cat]]s or [[dog]]s 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.<ref>{{cite web|title=Remeron for Cats|url=http://www.vetinfo.com/remeron-for-cats.html}}</ref><ref>{{cite web|title=Mirtazapine (Remeron)|url=http://www.veterinarypartner.com/Content.plx?P=A&A=2552}}</ref>
-===Efficacy and tolerability===
+=== Efficacy and tolerability ===
-In clinical studies, mirtazapine has been found to be an effective antidepressant with a generally tolerable [[adverse effect|side-effect]] profile relative to other antidepressants.<ref name="Cipriani_2009">{{cite journal | author = Cipriani, A; Furukawa, TA; Salanti, G; Geddes, JR; Higgins, JP; Churchill, R; Watanabe, N; Nakagawa, A; Omori, IM; McGuire, H; Tansella, M; Barbui, C | title = Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis | journal = Lancet | volume = 373 | issue = 9665 | pages = 746–58 |date=February 2009 | pmid = 19185342 | doi = 10.1016/S0140-6736(09)60046-5 }}</ref>
+In clinical studies, mirtazapine has been found to be an effective antidepressant with a generally tolerable [[adverse effect|side-effect]] profile relative to other antidepressants.<ref name="Cipriani_2009">{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C | title = Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis | journal = Lancet | volume = 373 | issue = 9665 | pages = 746–58 | date = Feb 2009 | pmid = 19185342 | doi = 10.1016/S0140-6736(09)60046-5 }}</ref>
 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 inhibitor]]s (SSRIs), [[serotonin-norepinephrine reuptake inhibitor]]s (SNRIs), [[reboxetine]] and [[bupropion]] in terms of antidepressant efficacy, while it was average in regard to tolerability.<ref name="Cipriani_2009" /> However, its superior efficacy over the other medications in the top four ([[escitalopram]], [[sertraline]] and [[venlafaxine]]) did not reach [[statistical significance]].<ref name = "Cipriani_2009" />
-Compared to earlier antidepressants, mirtazapine has been found to be significantly superior to [[trazodone]],<ref name="pmid7622801">{{cite journal | author = van Moffaert, M; de Wilde, J; Vereecken, A; Dierick, M; Evrard, JL; Wilmotte, J; Mendlewicz, J | title = Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalised patients with major depression | journal = Int Clin Psychopharmacol | volume = 10 | issue = 1 | pages = 3–9 |date=March 1995 | pmid = 7622801 | doi = 10.1097/00004850-199503000-00001 }}</ref> while it has been shown to be approximately equivalent in efficacy to several of the [[tricyclic antidepressant]]s <!-- (TCAs) --> including [[amitriptyline]], [[doxepin]] and [[clomipramine]], though with a much improved tolerability profile.<ref name="pmid11607047"/><ref name="pmid10333982"/> However, two other studies found mirtazapine to be significantly inferior to [[imipramine]], another TCA.<ref name="pmid8912401">{{cite journal | author = Bruijn, JA; Moleman, P; Mulder, PG; van den Broek, WW; van Hulst, AM; van der Mast, RC; van de Wetering, BJ | title = A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients | journal = Psychopharmacology (Berl.) | volume = 127 | issue = 3 | pages = 231–7 |date=October 1996 | pmid = 8912401 | doi = 10.1007/BF02246131 }}</ref><ref name="pmid10463374">{{cite journal | author = Bruijn, JA; Moleman, P; Mulder, PG; van den Broek, WW | title = Depressed in-patients respond differently to imipramine and mirtazapine | journal = Pharmacopsychiatry | volume = 32 | issue = 3 | pages = 87–92 |date=May 1999 | pmid = 10463374 | doi = 10.1055/s-2007-979200 }}</ref> One study compared the combination of venlafaxine and mirtazapine to the [[monoamine oxidase inhibitor]] (MAOI) [[tranylcypromine]] alone and found them to be similarly effective, though [[tranylcypromine]] was much less tolerable in regard to [[adverse effect|side effect]]s and [[drug interaction]]s.<ref name="pmid16946177"/>
+Compared to earlier antidepressants, mirtazapine has been found to be significantly superior to [[trazodone]],<ref name="pmid7622801">{{cite journal | vauthors = van Moffaert M, de Wilde J, Vereecken A, Dierick M, Evrard JL, Wilmotte J, Mendlewicz J | title = Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalized patients with major depression | journal = International Clinical Psychopharmacology | volume = 10 | issue = 1 | pages = 3–9 | date = Mar 1995 | pmid = 7622801 | doi = 10.1097/00004850-199503000-00001 }}</ref> while it has been shown to be approximately equivalent in efficacy to several of the [[tricyclic antidepressant]]s <!-- (TCAs) --> including [[amitriptyline]], [[doxepin]] and [[clomipramine]], though with a much improved tolerability profile.<ref name="pmid11607047"/><ref name="pmid10333982"/> However, two other studies found mirtazapine to be significantly inferior to [[imipramine]], another TCA.<ref name="pmid8912401">{{cite journal | vauthors = Bruijn JA, Moleman P, Mulder PG, van den Broek WW, van Hulst AM, van der Mast RC, van de Wetering BJ | title = A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients | journal = Psychopharmacology | volume = 127 | issue = 3 | pages = 231–7 | date = Oct 1996 | pmid = 8912401 | doi = 10.1007/BF02246131 }}</ref><ref name="pmid10463374">{{cite journal | vauthors = Bruijn JA, Moleman P, Mulder PG, van den Broek WW | title = Depressed in-patients respond differently to imipramine and mirtazapine | journal = Pharmacopsychiatry | volume = 32 | issue = 3 | pages = 87–92 | date = May 1999 | pmid = 10463374 | doi = 10.1055/s-2007-979200 }}</ref> One study compared the combination of venlafaxine and mirtazapine to the [[monoamine oxidase inhibitor]] (MAOI) [[tranylcypromine]] alone and found them to be similarly effective, though [[tranylcypromine]] was much less tolerable in regard to [[adverse effect|side effect]]s and [[drug interaction]]s.<ref name="pmid16946177"/>
-In general, all antidepressants, including mirtazapine, require at least a week for their therapeutic benefits on depressive and anxious symptoms to become apparent.<ref name="pmid12404667">{{cite journal | author = Thompson, C | title = Onset of action of antidepressants: results of different analyses | journal = Human Psychopharmacology | volume = 17 Suppl 1 | issue = | pages = S27–32 |date=June 2002 | pmid = 12404667 | doi = 10.1002/hup.386 | url = http://dx.doi.org/10.1002/hup.386}}</ref><ref name="Maudsley">{{cite book
+In general, all antidepressants, including mirtazapine, require at least a week for their therapeutic benefits on depressive and anxious symptoms to become apparent.<ref name="pmid12404667">{{cite journal | vauthors = Thompson C | title = Onset of action of antidepressants: results of different analyses | journal = Human Psychopharmacology | volume = 17 Suppl 1 | issue =  | pages = S27-32 | date = Jun 2002 | pmid = 12404667 | doi = 10.1002/hup.386 | url = http://dx.doi.org/10.1002/hup.386 }}</ref><ref name="Maudsley">{{cite book | isbn = 978-0-47-097948-8 | title = Maudsley Prescribing Guidelines in Psychiatry | edition = 11th | author = Taylor, D; Paton, C; Shitij, K | date = 2012 | publisher = Wiley-Blackwell | location = West Sussex }}
+</ref> 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.<ref name="pmid12404667" /><ref name="pmid18568129">{{cite journal | vauthors = Lavergne F, Berlin I, Gamma A, Stassen H, Angst J | title = Onset of improvement and response to mirtazapine in depression: a multicenter naturalistic study of 4771 patients | journal = Neuropsychiatric Disease and Treatment | volume = 1 | issue = 1 | pages = 59–68 | date = Mar 2005 | pmid = 18568129 | pmc = 2426820 | doi = 10.2147/nedt.1.1.59.52296 }}</ref>
- | isbn = 978-0-47-097948-8
- | title = Maudsley Prescribing Guidelines in Psychiatry
+== Adverse reactions ==
- | edition = 11th
- | author = Taylor, D; Paton, C; Shitij, K
- | date = 2012
- | publisher = Wiley-Blackwell
- | location = West Sussex
-}}
-</ref> 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.<ref name="pmid12404667" /><ref name="pmid18568129">{{cite journal | author = Lavergne, F; Berlin, I; Gamma, A; Stassen, H; Angst, J | title = Onset of improvement and response to mirtazapine in depression: a multicenter naturalistic study of 4771 patients | journal = Neuropsychiatric Disease and Treatment | volume = 1 | issue = 1 | pages = 59–68 |date=March 2005 | pmid = 18568129 | pmc = 2426820 | doi =10.2147/nedt.1.1.59.52296 }}</ref>
-==Adverse reactions==
 [[File:Mirtazapine-sandoz.jpg|thumb|right|A box of Mirtazapine-Sandoz]]
-===Side effects===
+=== Side effects ===
 Information sources:<ref name = DM/><ref name = AXIT>{{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|accessdate=15 October 2013|date=25 October 2011}}</ref><ref name = EMC>{{cite web|title=Mirtazapine 30 mg Tablets - Summary of Product Characteristics|date=20 March 2013|accessdate=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}}</ref><ref name = MS>{{cite web|title=mirtazapine (Rx) - Remeron, Remeron SolTab|work=Medscape|publisher=WebMD|accessdate=24 October 2013|url=http://reference.medscape.com/drug/remeron-soltab-mirtazapine-342966}}</ref><ref name = "AMH">{{cite web | title = Australian Medicines Handbook | url = http://www.amh.net.au  | year = 2013 | publisher = Australian Medicines Handbook Pty Ltd }}</ref><ref name = "BNF">{{cite book | title = British National Formulary (BNF) | edition = 65th | publisher = Pharmaceutical Press | pages = 1120  | isbn = 978-0857110848 }}</ref>
@@ Line 209: / Line 207: @@
 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.<ref name="pmid11607047"/><ref name="pmid10333982"/> These adverse effects include [[anorexia (symptom)|decreased appetite]], [[weight loss]], [[insomnia]], [[nausea]] and [[vomiting]], [[diarrhoea]], [[urinary retention]], increased [[body temperature]], [[diaphoresis|excessive sweating]], [[mydriasis|pupil dilation]] and [[sexual dysfunction]].<ref name="pmid11607047"/><ref name="pmid10333982"/>
-In general, some antidepressants, especially SSRIs, can paradoxically exacerbate some peoples' depression or anxiety or cause [[suicidal ideation]].<ref name="pmid17143567">{{cite journal | author = 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 = 476–96 |date=December 2006 | pmid = 17143567 | doi = 10.1007/s00406-006-0689-8 }}</ref> 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 [[boxed warning|black box]] label warning of these potential effects.
+In general, some antidepressants, especially SSRIs, can paradoxically exacerbate some peoples' depression or anxiety or cause [[suicidal ideation]].<ref name="pmid17143567">{{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 = 476–96 | date = Dec 2006 | pmid = 17143567 | doi = 10.1007/s00406-006-0689-8 }}</ref> 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 [[boxed warning|black box]] label warning of these potential effects.
-===Discontinuation===
+=== Discontinuation ===
-Mirtazapine and other antidepressants may cause a [[SSRI discontinuation syndrome|withdrawal syndrome]] upon discontinuation.<ref name="pmid11607047"/><ref name="pmid9653542">{{cite journal | author = Benazzi, F | title = Mirtazapine withdrawal symptoms | journal = Can J Psychiatry | volume = 43 | issue = 5 | page = 525 |date=June 1998 | pmid = 9653542 | doi = }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid11444761">{{cite journal | author = Blier, P | title = Pharmacology of rapid-onset antidepressant treatment strategies | journal = J Clin Psychiatry | volume = 62 Suppl 15 | issue = | pages = 12–7 | year = 2001 | pmid = 11444761 | doi = }}</ref>  A gradual and slow reduction in dose is recommended to minimize withdrawal symptoms.<ref name="pmid15819135">{{cite journal | author = Vlaminck, JJ; van Vliet, IM; Zitman, FG | title = [Withdrawal symptoms of antidepressants] | language = Dutch, Flemish | journal = Ned Tijdschr Geneeskd | volume = 149 | issue = 13 | pages = 698–701 |date=March 2005 | pmid = 15819135 | doi = }}</ref> Effects of sudden cessation of treatment with mirtazapine may include depression, [[anxiety]], [[panic attack]]s, [[vertigo (medical)|vertigo]], [[psychomotor agitation|restlessness]], [[irritability]], [[anorexia (symptom)|decreased appetite]], [[insomnia]], [[diarrhoea]], [[nausea]], [[vomiting]], [[flu]]-like symptoms such as [[allergies]] and [[pruritus]], [[headache]]s and sometimes [[hypomania]] or [[mania]].<ref name="pmid9653542"/><ref name="pmid15014614">{{cite journal | author = Berigan, TR | title = Mirtazapine-Associated Withdrawal Symptoms: A Case Report | journal = Prim Care Companion J Clin Psychiatry | volume = 3 | issue = 3 | page = 143 |date=June 2001 | pmid = 15014614 | pmc = 181176 | doi =10.4088/PCC.v03n0307a }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid10986577">{{cite journal | author = Klesmer, J; Sarcevic, A; Fomari, V | title = Panic attacks during discontinuation of mirtazepine | journal = Can J Psychiatry | volume = 45 | issue = 6 | pages = 570–1 |date=August 2000 | pmid = 10986577 | doi = }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid10789310">{{cite journal | author = MacCall, C; Callender, J | title = Mirtazapine withdrawal causing hypomania | journal = Br J Psychiatry | volume = 175 | issue = 4| page = 390 |date=October 1999 | pmid = 10789310 | doi = 10.1192/bjp.175.4.390a}}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid12776393">{{cite journal | author = Ali, S; Milev, R | title = Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review of the literature | journal = Can J Psychiatry | volume = 48 | issue = 4 | pages = 258–64 |date=May 2003 | pmid = 12776393 | doi = }}</ref>
+Mirtazapine and other antidepressants may cause a [[SSRI discontinuation syndrome|withdrawal syndrome]] upon discontinuation.<ref name="pmid11607047"/><ref name="pmid9653542">{{cite journal | vauthors = Benazzi F | title = Mirtazapine withdrawal symptoms | journal = Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie | volume = 43 | issue = 5 | pages = 525 | page = 525 | date = Jun 1998 | pmid = 9653542 | doi =  }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid11444761">{{cite journal | vauthors = Blier P | title = Pharmacology of rapid-onset antidepressant treatment strategies | journal = The Journal of Clinical Psychiatry | volume = 62 Suppl 15 | issue =  | pages = 12–7 | year = 2001 | pmid = 11444761 | doi =  }}</ref>  A gradual and slow reduction in dose is recommended to minimize withdrawal symptoms.<ref name="pmid15819135">{{cite journal | vauthors = Vlaminck JJ, van Vliet IM, Zitman FG | title = [Withdrawal symptoms of antidepressants] | language = Dutch, Flemish | journal = Nederlands Tijdschrift Voor Geneeskunde | volume = 149 | issue = 13 | pages = 698–701 | date = Mar 2005 | pmid = 15819135 | doi =  }}</ref> Effects of sudden cessation of treatment with mirtazapine may include depression, [[anxiety]], [[panic attack]]s, [[vertigo (medical)|vertigo]], [[psychomotor agitation|restlessness]], [[irritability]], [[anorexia (symptom)|decreased appetite]], [[insomnia]], [[diarrhoea]], [[nausea]], [[vomiting]], [[flu]]-like symptoms such as [[allergies]] and [[pruritus]], [[headache]]s and sometimes [[hypomania]] or [[mania]].<ref name="pmid9653542"/><ref name="pmid15014614">{{cite journal | vauthors = Berigan TR | title = Mirtazapine-Associated Withdrawal Symptoms: A Case Report | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 3 | issue = 3 | pages = 143 | page = 143 | date = Jun 2001 | pmid = 15014614 | pmc = 181176 | doi = 10.4088/PCC.v03n0307a }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid10986577">{{cite journal | vauthors = Klesmer J, Sarcevic A, Fomari V | title = Panic attacks during discontinuation of mirtazepine | journal = Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie | volume = 45 | issue = 6 | pages = 570–1 | date = Aug 2000 | pmid = 10986577 | doi =  }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid10789310">{{cite journal | vauthors = MacCall C, Callender J | title = Mirtazapine withdrawal causing hypomania | journal = The British Journal of Psychiatry | volume = 175 | issue = 4 | pages = 390 | page = 390 | date = Oct 1999 | pmid = 10789310 | doi = 10.1192/bjp.175.4.390a }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid12776393">{{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. Revue Canadienne De Psychiatrie | volume = 48 | issue = 4 | pages = 258–64 | date = May 2003 | pmid = 12776393 | doi =  }}</ref>
-===Overdose===
-Mirtazapine is considered to be relatively safe in the event of an [[overdose]],<ref name="Maudsley"/> although it is considered slightly more toxic in overdose than most of the SSRIs (except [[citalopram]]).<ref>{{cite journal|last=White|first=N|author2=Litovitz, T |author3=Clancy, C |title=Suicidal antidepressant overdoses: a comparative analysis by antidepressant type.|journal=Journal of Medical Toxicology|date=December 2008|volume=4|issue=4|pages=238–50|pmid=19031375|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550116/pdf/13181_2009_Article_BF03161207.pdf|format=PDF|pmc=3550116|doi=10.1007/bf03161207}}</ref> Unlike the TCAs, mirtazapine showed no significant [[cardiovascular]] [[adverse reaction|adverse effect]]s at 7 to 22 times the maximum recommended dose.<ref name="pmid10333982"/> Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to TCAs.<ref name="pmid9807651">{{cite journal | author = Holzbach R, Jahn H, Pajonk FG, Mähne C | title = Suicide attempts with mirtazapine overdose without complications | journal = Biol. Psychiatry | volume = 44 | issue = 9 | pages = 925–6 |date=November 1998 | pmid = 9807651 | doi = 10.1016/S0006-3223(98)00081-X }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid9861579">{{cite journal | author = Retz W, Maier S, Maris F, Rösler M | title = Non-fatal mirtazapine overdose | journal = Int Clin Psychopharmacol | volume = 13 | issue = 6 | pages = 277–9 |date=November 1998 | pmid = 9861579 | doi = 10.1097/00004850-199811000-00007 }}{{Unreliable medical source|date=October 2011}}</ref>
+=== Overdose ===
-Twelve reported fatalities have been attributed to mirtazapine overdose.<ref>{{cite journal |author= Nikolaou, P; Dona, A; Papoutsis, I; Spiliopoulou, C; Maravelias, C | title = Death Due to Mirtazapine Overdose}} in {{cite journal |doi=10.1080/15563650902952273 |title=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 }}</ref><ref>{{cite book | author = 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 }}</ref> 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.<ref name="bmj325">{{cite journal | author = 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 = 1332–3 |date=December 2002 | pmid = 12468481 | pmc = 137809 | doi = 10.1136/bmj.325.7376.1332 }}{{Unreliable medical source|date=October 2011}}</ref>
+Mirtazapine is considered to be relatively safe in the event of an [[overdose]],<ref name="Maudsley"/> although it is considered slightly more toxic in overdose than most of the SSRIs (except [[citalopram]]).<ref>{{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 = 238–50 | date = Dec 2008 | pmid = 19031375 | pmc = 3550116 | doi = 10.1007/bf03161207 | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550116/pdf/13181_2009_Article_BF03161207.pdf | format = PDF }}</ref> Unlike the TCAs, mirtazapine showed no significant [[cardiovascular]] [[adverse reaction|adverse effect]]s at 7 to 22 times the maximum recommended dose.<ref name="pmid10333982"/> Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to TCAs.<ref name="pmid9807651">{{cite journal | vauthors = Holzbach R, Jahn H, Pajonk FG, Mähne C | title = Suicide attempts with mirtazapine overdose without complications | journal = Biological Psychiatry | volume = 44 | issue = 9 | pages = 925–6 | date = Nov 1998 | pmid = 9807651 | doi = 10.1016/S0006-3223(98)00081-X }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid9861579">{{cite journal | vauthors = Retz W, Maier S, Maris F, Rösler M | title = Non-fatal mirtazapine overdose | journal = International Clinical Psychopharmacology | volume = 13 | issue = 6 | pages = 277–9 | date = Nov 1998 | pmid = 9861579 | doi = 10.1097/00004850-199811000-00007 }}{{Unreliable medical source|date=October 2011}}</ref>
-==Pharmacology==
+Twelve reported fatalities have been attributed to mirtazapine overdose.<ref>{{cite journal |author= Nikolaou, P; Dona, A; Papoutsis, I; Spiliopoulou, C; Maravelias, C | title = Death Due to Mirtazapine Overdose}} in {{cite journal |doi=10.1080/15563650902952273 |title=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 }}</ref><ref>{{cite book | author = 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 }}</ref> 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.<ref name="bmj325">{{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 = 1332–3 | date = Dec 2002 | pmid = 12468481 | pmc = 137809 | doi = 10.1136/bmj.325.7376.1332 }}{{Unreliable medical source|date=October 2011}}</ref>
-===Binding profile===
-Mirtazapine is an [[receptor antagonist|antagonist]]/[[inverse agonist]] at the following [[receptor (biochemistry)|receptor]]s:<ref name="pmid15771415">{{cite journal | author = Fernández, J; Alonso, JM; Andrés, JI; Cid, JM; Díaz, A; Iturrino, L; Gil, P; Megens, A; Sipido, VK; Trabanco, AA | title = Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 6 | pages = 1709–12 |date=March 2005 | pmid = 15771415 | doi = 10.1021/jm049632c }}</ref><ref name="pmid3419539">{{cite journal | author = de Boer, TH; Maura, G; Raiteri, M; de Vos, CJ; Wieringa, J; Pinder, RM | title = Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers | journal = Neuropharmacology | volume = 27 | issue = 4 | pages = 399–408 |date=April 1988 | pmid = 3419539 | doi = 10.1016/0028-3908(88)90149-9 }}</ref>
+== Pharmacology ==
+=== Binding profile ===
+Mirtazapine is an [[receptor antagonist|antagonist]]/[[inverse agonist]] at the following [[receptor (biochemistry)|receptor]]s:<ref name="pmid15771415">{{cite journal | vauthors = Fernández J, Alonso JM, Andrés JI, Cid JM, Díaz A, Iturrino L, Gil P, Megens A, Sipido VK, Trabanco AA | title = Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 6 | pages = 1709–12 | date = Mar 2005 | pmid = 15771415 | doi = 10.1021/jm049632c }}</ref><ref name="pmid3419539">{{cite journal | vauthors = de Boer TH, Maura G, Raiteri M, de Vos CJ, Wieringa J, Pinder RM | title = Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers | journal = Neuropharmacology | volume = 27 | issue = 4 | pages = 399–408 | date = Apr 1988 | pmid = 3419539 | doi = 10.1016/0028-3908(88)90149-9 }}</ref>
 {| class="wikitable"
 |-
@@ Line 231: / Line 232: @@
 | [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] || 69 || The (''S'')-(+) enantiomer is responsible for this antagonism.<ref name = MD/>
 |-
-| [[5-HT2B receptor|5-HT<sub>2B</sub> receptor]] || ? || ~20-fold lower than for 5-HT<sub>2A</sub>/5-HT<sub>2C</sub><ref name="pmid8636062">{{cite journal | author = de Boer, T | title = The pharmacologic profile of mirtazapine | journal = J Clin Psychiatry | volume = 57 Suppl 4 | issue = | pages = 19–25 | year = 1996 | pmid = 8636062 | doi = }}</ref>
+| [[5-HT2B receptor|5-HT<sub>2B</sub> receptor]] || ? || ~20-fold lower than for 5-HT<sub>2A</sub>/5-HT<sub>2C</sub><ref name="pmid8636062">{{cite journal | vauthors = de Boer T | title = The pharmacologic profile of mirtazapine | journal = The Journal of Clinical Psychiatry | volume = 57 Suppl 4 | issue =  | pages = 19–25 | year = 1996 | pmid = 8636062 | doi =  }}</ref>
 |-
-| [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]] || 39 || Inverse agonist<ref name="Graves_2012">{{cite journal|last1=Graves|first1=Steven M|last2=Napier|first2=T|title=SB 206553, a putative 5-HT2C inverse agonist, attenuates methamphetamine-seeking in rats|journal=BMC Neuroscience|date=2012|volume=13|issue=1|pages=65|doi=10.1186/1471-2202-13-65}}</ref> The (''S'')-(+) enantiomer is responsible for this action.<ref name = MD/>
+| [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]] || 39 || Inverse agonist<ref name="Graves_2012">{{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 = 2012 | pmid = 22697313 | doi = 10.1186/1471-2202-13-65 }}</ref> The (''S'')-(+) enantiomer is responsible for this action.<ref name = MD/>
 |-
-| [[5-HT3 receptor|5-HT<sub>3</sub> receptor]] || ? || Similar to 5-HT<sub>2A</sub>/5-HT<sub>2C</sub> (mouse neuroblastoma cell)<ref name="pmid7984289">{{cite journal | author = Kooyman, AR; Zwart, R; Vanderheijden, PM; Van Hooft, JA; Vijverberg, HP | title = Interaction between enantiomers of mianserin and ORG3770 at 5-HT3 receptors in cultured mouse neuroblastoma cells | journal = Neuropharmacology | volume = 33 | issue = 3–4 | pages = 501–7 | year = 1994 | pmid = 7984289 | doi = 10.1016/0028-3908(94)90081-7 }}</ref> ''R''-(–) enantiomer antagonises the 5-HT<sub>3</sub> receptor.<ref name = MD>{{cite book|editor=Brayfield, A|title=Mirtazapine|work=Martindale: The Complete Drug Reference|publisher=The Royal Pharmaceutical Society of Great Britain|accessdate=3 November 2013|date=30 January 2013|url=http://www.medicinescomplete.com/mc/martindale/current/11022-r.htm}}</ref>
+| [[5-HT3 receptor|5-HT<sub>3</sub> receptor]] || ? || Similar to 5-HT<sub>2A</sub>/5-HT<sub>2C</sub> (mouse neuroblastoma cell)<ref name="pmid7984289">{{cite journal | vauthors = Kooyman AR, Zwart R, Vanderheijden PM, Van Hooft JA, Vijverberg HP | title = Interaction between enantiomers of mianserin and ORG3770 at 5-HT3 receptors in cultured mouse neuroblastoma cells | journal = Neuropharmacology | volume = 33 | issue = 3-4 | pages = 501–7 | year = 1994 | pmid = 7984289 | doi = 10.1016/0028-3908(94)90081-7 }}</ref> ''R''-(–) enantiomer antagonises the 5-HT<sub>3</sub> receptor.<ref name = MD>{{cite book|editor=Brayfield, A|title=Mirtazapine|work=Martindale: The Complete Drug Reference|publisher=The Royal Pharmaceutical Society of Great Britain|accessdate=3 November 2013|date=30 January 2013|url=http://www.medicinescomplete.com/mc/martindale/current/11022-r.htm}}</ref>
 |-
 | [[5-HT7 receptor|5-HT<sub>7</sub> receptor]] || 265 ||
@@ Line 251: / Line 252: @@
 | [[Dopamine D3 receptor|D<sub>3</sub> receptor]] || 5723 ||
 |-
-|  [[Histamine H1 receptor|H<sub>1</sub> receptor]] || 1.6 || <ref name="pmid12109911">{{cite journal | author = Wikström, HV; Mensonides-Harsema, MM; Cremers, TI; Moltzen, EK; Arnt, J | title = 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 = Journal of Medicinal Chemistry | volume = 45 | issue = 15 | pages = 3280–5 |date=July 2002 | pmid = 12109911 | doi = 10.1021/jm010566d }}</ref>
+|  [[Histamine H1 receptor|H<sub>1</sub> receptor]] || 1.6 || <ref name="pmid12109911">{{cite journal | vauthors = Wikström HV, Mensonides-Harsema MM, Cremers TI, Moltzen EK, Arnt J | title = 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 = Journal of Medicinal Chemistry | volume = 45 | issue = 15 | pages = 3280–5 | date = Jul 2002 | pmid = 12109911 | doi = 10.1021/jm010566d }}</ref>
 |-
 | [[Muscarinic acetylcholine receptor|mACh receptors]] || 670 || <ref name="GG">{{cite book | isbn = 978-0-07-162442-8 | title = [[Goodman and Gilman's The Pharmacological Basis of Therapeutics]] | edition = 12th | author = Brunton, L; Chabner, B; Knollman, B | year = 2010 | publisher = McGraw-Hill Professional | location = New York }}</ref>
@@ Line 258: / Line 259: @@
 All [[affinity (pharmacology)|affinities]] listed were assayed using human materials except those for α<sub>1</sub>-adrenergic and mACh that are for [[rat]] tissues, due to human values being unavailable.<ref name="pmid15771415"/><ref name="pmid3419539"/>
-Mirtazapine has recently been found to act as a weak ([[EC50|EC<sub>50</sub>]] 7.2 μM) [[κ-opioid receptor]] [[partial agonist]].<ref name="pmid22708686">{{cite journal | author = Olianas MC, Dedoni S, Onali P | title = The atypical antidepressant mianserin exhibits agonist activity at κ-opioid receptors | journal = Br. J. Pharmacol. | volume = 167 | issue = 6 | pages = 1329–41 |date=November 2012 | pmid = 22708686 | doi = 10.1111/j.1476-5381.2012.02078.x }}</ref>
+Mirtazapine has recently been found to act as a weak ([[EC50|EC<sub>50</sub>]] 7.2 μM) [[κ-opioid receptor]] [[partial agonist]].<ref name="pmid22708686">{{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 = 1329–41 | date = Nov 2012 | pmid = 22708686 | doi = 10.1111/j.1476-5381.2012.02078.x }}</ref>
-===Correspondence to clinical effects===
+=== Correspondence to clinical effects ===
-Antagonization of the α<sub>2</sub>-adrenergic receptors, which function largely as [[autoreceptor]]s and [[heteroreceptor]]s enhances [[adrenergic]] and [[serotonergic]] [[neurotransmission]], the notable ones being [[Central nervous system|central]] [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]]-mediated transmission in the [[dorsal raphe nucleus]] and [[hippocampus]]; hence, mirtazapine's classification as a NaSSA. Indirect α<sub>1</sub>-adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory α<sub>2</sub>-heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT.<ref name="pmid11607047"/><ref name="pmid10446735"/><ref name="pmid7912194">{{cite journal | author = De Boer, T; Nefkens, F; Van Helvoirt, A | title = The alpha 2-adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo | journal = Eur. J. Pharmacol. | volume = 253 | issue = 1–2 | pages = R5–6 |date=February 1994 | pmid = 7912194 | doi = 10.1016/0014-2999(94)90778-1 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid9361334">{{cite journal | author = Berendsen, HH; Broekkamp, CL | title = Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine | journal = Psychopharmacology (Berl.) | volume = 133 | issue = 3 | pages = 275–82 |date=October 1997 | pmid = 9361334 | doi = 10.1007/s002130050402 }}</ref><ref name="pmid15145142">{{cite journal | author = Nakayama, K; Sakurai, T; Katsu, H | title = Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation | journal = Brain Res. Bull. | volume = 63 | issue = 3 | pages = 237–41 |date=April 2004 | pmid = 15145142 | doi = 10.1016/j.brainresbull.2004.02.007 }}{{Unreliable medical source|date=October 2011}}</ref> Because of this, mirtazapine has been said to be a functional "[[indirect agonist]]" of the 5-HT<sub>1A</sub> receptor.<ref name="pmid9361334"/> Increased activation of the central 5-HT<sub>1A</sub> receptor is thought to be a major mediator of efficacy of most antidepressant drugs.<ref name="pmid11212592">{{cite journal | author = Blier, P; Abbott, FV | title = Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain | journal = J Psychiatry Neurosci | volume = 26 | issue = 1 | pages = 37–43 |date=January 2001 | pmid = 11212592 | pmc = 1408043 | doi = | url = http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-26/issue-1/pdf/pg37.pdf }}</ref> Unlike most conventional antidepressants, however, at clinically used doses mirtazapine has no appreciable affinity for the [[Serotonin transporter|serotonin]], [[Norepinephrine transporter|norepinephrine]], or [[dopamine transporter]]s and thus lacks any significant effects as a [[reuptake inhibitor]] of these  [[neurotransmitter]]s,<ref name="pmid9537821">{{cite journal | author = Tatsumi, M; Groshan, K; Blakely, RD; Richelson, E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = European Journal of Pharmacology | volume = 340 | issue = 2–3 | pages = 249–58 |date=December 1997 | pmid = 9537821 | doi = 10.1016/S0014-2999(97)01393-9| url = http://linkinghub.elsevier.com/retrieve/pii/S0014-2999(97)01393-9}}</ref> nor does it have any significant inhibitory effects on [[monoamine oxidase]].<ref name="pmid21200377">{{cite journal | author = 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 = 645–56 | year = 2010 | pmid = 21200377 | doi = | url = }}</ref>
+Antagonization of the α<sub>2</sub>-adrenergic receptors, which function largely as [[autoreceptor]]s and [[heteroreceptor]]s enhances [[adrenergic]] and [[serotonergic]] [[neurotransmission]], the notable ones being [[Central nervous system|central]] [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]]-mediated transmission in the [[dorsal raphe nucleus]] and [[hippocampus]]; hence, mirtazapine's classification as a NaSSA. Indirect α<sub>1</sub>-adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory α<sub>2</sub>-heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT.<ref name="pmid11607047"/><ref name="pmid10446735"/><ref name="pmid7912194">{{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 = R5-6 | date = Feb 1994 | pmid = 7912194 | doi = 10.1016/0014-2999(94)90778-1 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid9361334">{{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 = 275–82 | date = Oct 1997 | pmid = 9361334 | doi = 10.1007/s002130050402 }}</ref><ref name="pmid15145142">{{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 = 237–41 | date = Apr 2004 | pmid = 15145142 | doi = 10.1016/j.brainresbull.2004.02.007 }}{{Unreliable medical source|date=October 2011}}</ref> Because of this, mirtazapine has been said to be a functional "[[indirect agonist]]" of the 5-HT<sub>1A</sub> receptor.<ref name="pmid9361334"/> Increased activation of the central 5-HT<sub>1A</sub> receptor is thought to be a major mediator of efficacy of most antidepressant drugs.<ref name="pmid11212592">{{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 = Jan 2001 | pmid = 11212592 | pmc = 1408043 | doi =  | url = http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-26/issue-1/pdf/pg37.pdf }}</ref> Unlike most conventional antidepressants, however, at clinically used doses mirtazapine has no appreciable affinity for the [[Serotonin transporter|serotonin]], [[Norepinephrine transporter|norepinephrine]], or [[dopamine transporter]]s and thus lacks any significant effects as a [[reuptake inhibitor]] of these  [[neurotransmitter]]s,<ref name="pmid9537821">{{cite journal | vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = European Journal of Pharmacology | volume = 340 | issue = 2-3 | pages = 249–58 | date = Dec 1997 | pmid = 9537821 | doi = 10.1016/S0014-2999(97)01393-9 | url = http://linkinghub.elsevier.com/retrieve/pii/S0014-2999(97)01393-9 }}</ref> nor does it have any significant inhibitory effects on [[monoamine oxidase]].<ref name="pmid21200377">{{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 = 645–56 | year = 2010 | pmid = 21200377 | doi =  }}</ref>
-Antagonism of the 5-HT<sub>2</sub> subfamily of receptors and inverse agonism of the 5-HT<sub>2C</sub> receptor appears to be in part responsible for mirtazapine's efficacy in the treatment of depressive states.<ref name="pmid16433010">{{cite journal | author = 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 = 441–60 | year = 2005 | pmid = 16433010 | doi = 10.2515/therapie:2005065 }}</ref><ref name="pmid18709360">{{cite journal | author = Dekeyne, A; Millan, MJ | title = Discriminative stimulus properties of the atypical antidepressant, mirtazapine, in rats: a pharmacological characterization | journal = Psychopharmacology (Berl.) | volume = 203 | issue = 2 | pages = 329–41 |date=April 2009 | pmid = 18709360 | doi = 10.1007/s00213-008-1259-8 }}</ref> The 5-HT<sub>2C</sub> receptor is known to inhibit the release of the neurotransmitters [[dopamine]] and [[norepinephrine]] in various parts of the brains of rodents, notably in [[pleasure center|reward pathways]] such as the [[ventral tegmental area]].<ref name="pmid15056702">{{cite journal | author = De Deurwaerdère, P; Navailles, S; Berg, KA; Clarke, WP; Spampinato, U | title = Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens | journal = J. Neurosci. | volume = 24 | issue = 13 | pages = 3235–41 |date=March 2004 | pmid = 15056702 | doi = 10.1523/JNEUROSCI.0112-04.2004 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid17367945">{{cite journal | author = Bubar, MJ; Cunningham, KA | title = Distribution of serotonin 5-HT2C receptors in the ventral tegmental area | journal = Neuroscience | volume = 146 | issue = 1 | pages = 286–97 |date=April 2007 | pmid = 17367945 | pmc = 1939890 | doi = 10.1016/j.neuroscience.2006.12.071 }}{{Unreliable medical source|date=October 2011}}</ref> Accordingly, it was shown that by blocking the α<sub>2</sub>-adrenergic receptors and 5-HT<sub>2C</sub> receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats.<ref name="pmid10762339">{{cite journal | author = 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 α<sub>2</sub>-adrenergic and serotonin<sub>2C</sub> receptors: a comparison with citalopram | journal = Eur. J. Neurosci. | volume = 12 | issue = 3 | pages = 1079–95 |date=March 2000 | pmid = 10762339 | doi = 10.1046/j.1460-9568.2000.00982.x }}</ref> In addition, mirtazapine's antagonism of 5-HT<sub>2A</sub> receptors has beneficial effects on [[anxiety]], [[sleep]] and [[appetite]], as well as sexual function regarding the latter receptor.<ref name="pmid11607047"/><ref name="pmid10333982">{{cite journal | author = 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 = J Affect Disord | volume = 51 | issue = 3 | pages = 267–85 |date=December 1998 | pmid = 10333982 | doi = 10.1016/S0165-0327(98)00224-9 }}</ref> The newest research however has shown that mirtazapine is actually an inverse agonist of the 5-HT<sub>2C</sub> receptor. 5-HT<sub>2C</sub> inverse agonists have been shown to inhibit mesoaccumbens dopamine outflow<ref name="pmid19702657">{{cite journal | author = Leggio, GM; Cathala, A; Neny, M; Rouge-Pont, F; Drago, F; Piazza, PV; Spampinato, U | title = 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 = J. Neurochem. | volume = 111 | issue = 2 | pages = 614–23 |date=October 2009 | pmid = 19702657 | doi = 10.1111/j.1471-4159.2009.06356.x }}</ref> attenuating the rewarding properties of various substances like morphine. This inhibition of dopamine may be stronger than thought as substances with 5-HT<sub>2C</sub> inverse agonist properties may have more activity to regulate dopamine neurotransmission than ones with competitive antagonism.<ref name="pmid18772038">{{cite journal | author = Berg, KA; Harvey, JA; Spampinato, U; Clarke, WP | title = Physiological and therapeutic relevance of constitutive activity of 5-HT 2A and 5-HT 2C receptors for the treatment of depression | journal = Prog. Brain Res. | volume = 172 | issue = | pages = 287–305 | year = 2008 | pmid = 18772038 | doi = 10.1016/S0079-6123(08)00914-X+= }}</ref> With its newly understood properties of 5-HT<sub>2C</sub> 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.<ref name="Graves_2012"/><ref name="pmid22065532">{{cite journal | author = 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 = Arch. Gen. Psychiatry | volume = 68 | issue = 11 | pages = 1168–75 |date=November 2011 | pmid = 22065532 | pmc = 3437988 | doi = 10.1001/archgenpsychiatry.2011.124 }}</ref><ref name="pmid18945553">{{cite journal | author = 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 Alcohol Depend | volume = 99 | issue = 1–3 | pages = 231–9 |date=January 2009 | pmid = 18945553 | doi = 10.1016/j.drugalcdep.2008.08.005 }}</ref> It is also being investigated to help in substance abuse disorders with withdrawal effects and remission rates.<ref name="Graves_2012"/><ref name="pmid18633741">{{cite journal | author = 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 = Ann Clin Psychiatry | volume = 20 | issue = 3 | pages = 145–55 | year = 2008 | pmid = 18633741 | doi = 10.1080/10401230802177656 }}</ref> but some studies have shown mixed benefit.<ref name="Graves_2012"/><ref name="pmid22095579">{{cite journal | author = Brackins, T; Brahm, NC; Kissack, JC | title = Treatments for methamphetamine abuse: a literature review for the clinician | journal = J Pharm Pract | volume = 24 | issue = 6 | pages = 541–50 |date=December 2011 | pmid = 22095579 | doi = 10.1177/0897190011426557 }}</ref><ref name="pmid23617468">{{cite journal | author = Brensilver, M; Heinzerling, KG; Shoptaw, S | title = Pharmacotherapy of amphetamine-type stimulant dependence: An update | journal = Drug Alcohol Rev | volume = 32 | issue = 5 | pages = 449–60 |date=September 2013 | pmid = 23617468 | doi = 10.1111/dar.12048 }}</ref>
+Antagonism of the 5-HT<sub>2</sub> subfamily of receptors and inverse agonism of the 5-HT<sub>2C</sub> receptor appears to be in part responsible for mirtazapine's efficacy in the treatment of depressive states.<ref name="pmid16433010">{{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 = Thérapie | volume = 60 | issue = 5 | pages = 441–60 | year = 2005 | pmid = 16433010 | doi = 10.2515/therapie:2005065 }}</ref><ref name="pmid18709360">{{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 = 329–41 | date = Apr 2009 | pmid = 18709360 | doi = 10.1007/s00213-008-1259-8 }}</ref> The 5-HT<sub>2C</sub> receptor is known to inhibit the release of the neurotransmitters [[dopamine]] and [[norepinephrine]] in various parts of the brains of rodents, notably in [[pleasure center|reward pathways]] such as the [[ventral tegmental area]].<ref name="pmid15056702">{{cite journal | vauthors = De Deurwaerdère P, Navailles S, Berg KA, Clarke WP, Spampinato U | title = Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens | journal = The Journal of Neuroscience | volume = 24 | issue = 13 | pages = 3235–41 | date = Mar 2004 | pmid = 15056702 | doi = 10.1523/JNEUROSCI.0112-04.2004 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid17367945">{{cite journal | vauthors = Bubar MJ, Cunningham KA | title = Distribution of serotonin 5-HT2C receptors in the ventral tegmental area | journal = Neuroscience | volume = 146 | issue = 1 | pages = 286–97 | date = Apr 2007 | pmid = 17367945 | pmc = 1939890 | doi = 10.1016/j.neuroscience.2006.12.071 }}{{Unreliable medical source|date=October 2011}}</ref> Accordingly, it was shown that by blocking the α<sub>2</sub>-adrenergic receptors and 5-HT<sub>2C</sub> receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats.<ref name="pmid10762339">{{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 = 1079–95 | date = Mar 2000 | pmid = 10762339 | doi = 10.1046/j.1460-9568.2000.00982.x }}</ref> In addition, mirtazapine's antagonism of 5-HT<sub>2A</sub> receptors has beneficial effects on [[anxiety]], [[sleep]] and [[appetite]], as well as sexual function regarding the latter receptor.<ref name="pmid11607047"/><ref name="pmid10333982">{{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 = 267–85 | date = Dec 1998 | pmid = 10333982 | doi = 10.1016/S0165-0327(98)00224-9 }}</ref> The newest research however has shown that mirtazapine is actually an inverse agonist of the 5-HT<sub>2C</sub> receptor. 5-HT<sub>2C</sub> inverse agonists have been shown to inhibit mesoaccumbens dopamine outflow<ref name="pmid19702657">{{cite journal | vauthors = Leggio GM, Cathala A, Neny M, Rouge-Pont F, Drago F, Piazza PV, Spampinato U | title = 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 = Journal of Neurochemistry | volume = 111 | issue = 2 | pages = 614–23 | date = Oct 2009 | pmid = 19702657 | doi = 10.1111/j.1471-4159.2009.06356.x }}</ref> attenuating the rewarding properties of various substances like morphine. This inhibition of dopamine may be stronger than thought as substances with 5-HT<sub>2C</sub> inverse agonist properties may have more activity to regulate dopamine neurotransmission than ones with competitive antagonism.<ref name="pmid18772038">{{cite journal | vauthors = Berg KA, Harvey JA, Spampinato U, Clarke WP | title = Physiological and therapeutic relevance of constitutive activity of 5-HT 2A and 5-HT 2C receptors for the treatment of depression | journal = Progress in Brain Research | volume = 172 | issue =  | pages = 287–305 | year = 2008 | pmid = 18772038 | doi = 10.1016/S0079-6123(08)00914-X+= }}</ref> With its newly understood properties of 5-HT<sub>2C</sub> 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.<ref name="Graves_2012"/><ref name="pmid22065532">{{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 = 1168–75 | date = Nov 2011 | pmid = 22065532 | pmc = 3437988 | doi = 10.1001/archgenpsychiatry.2011.124 }}</ref><ref name="pmid18945553">{{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 = 231–9 | date = Jan 2009 | pmid = 18945553 | doi = 10.1016/j.drugalcdep.2008.08.005 }}</ref> It is also being investigated to help in substance abuse disorders with withdrawal effects and remission rates.<ref name="Graves_2012"/><ref name="pmid18633741">{{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 = 145–55 | year = 2008 | pmid = 18633741 | doi = 10.1080/10401230802177656 }}</ref> but some studies have shown mixed benefit.<ref name="Graves_2012"/><ref name="pmid22095579">{{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 = 541–50 | date = Dec 2011 | pmid = 22095579 | doi = 10.1177/0897190011426557 }}</ref><ref name="pmid23617468">{{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 = 449–60 | date = Sep 2013 | pmid = 23617468 | doi = 10.1111/dar.12048 }}</ref>
-Antagonism of the 5-HT<sub>3</sub> receptor, an action mirtazapine shares with the approved antiemetic [[ondansetron]], significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and [[irritable bowel syndrome]] in afflicted individuals.<ref name="pmid11585276">{{cite journal | author = Kast, RE | title = Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy | journal = Support Care Cancer | volume = 9 | issue = 6 | pages = 469–70 |date=September 2001 | pmid = 11585276 | doi = 10.1007/s005200000215 }}</ref> Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron.<ref name="pmid17587360"/> Blockade of the 5-HT<sub>3</sub> receptors has also shown to improve anxiety and to be effective in the treatment of [[drug addiction]] in several studies.<ref name="urlThe psychopharmacology of 5-HT3 receptors">{{cite journal |doi=10.1016/0163-7258(90)90086-H | title = The psychopharmacology of 5-HT3 receptors | year = 1990 | author = Costall, B; Naylor, RJ; Tyers, MB | journal = Pharmacology & Therapeutics | volume = 47 | issue = 2 | pages = 181–202 }}</ref> In conjunction with [[drug rehabilitation|substance abuse counseling]], mirtazapine has been investigated for the purpose of reducing [[methamphetamine]] use in dependent individuals with success.<ref name="pmid22065532" /> In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT<sub>2A</sub>, 5-HT<sub>2C</sub>, and 5-HT<sub>3</sub> receptors leading to a host of negative changes and side-effects, the most prominent of which including anorexia, insomnia, sexual dysfunction (loss of [[libido]] and [[anorgasmia]]), nausea, and 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.<ref name="pmid10333982"/><ref name="pmid16946177">{{cite journal | author = McGrath, PJ; Stewart, JW; Fava, M; Trivedi, MH; Wisniewski, SR; Nierenberg, AA; Thase, ME; Davis, L; Biggs, MM; Shores-Wilson, K; Luther, JF; Niederehe, G; Warden, D; Rush, AJ | title = Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report | journal = Am J Psychiatry | volume = 163 | issue = 9 | pages = 1531–41; quiz 1666 |date=September 2006 | pmid = 16946177 | doi = 10.1176/appi.ajp.163.9.1531 }}</ref><ref name="pmid12590402">{{cite journal | author = Sennef, C; Timmer, CJ; Sitsen, JM | title = Mirtazapine in combination with amitriptyline: a drug-drug interaction study in healthy subjects | journal = Hum Psychopharmacol | volume = 18 | issue = 2 | pages = 91–101 |date=March 2003 | pmid = 12590402 | doi = 10.1002/hup.441 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid12028939">{{cite journal | author = Gándara Martín Jde, L; Agüera Ortiz, L; Ferre Navarrete, F; Rojo Rodés, E; Ros Montalbán, S | title = [Tolerability and efficacy of combined antidepressant therapy] | language = Spanish| journal = Actas Esp Psiquiatr | volume = 30 | issue = 2 | pages = 75–84 | year = 2002 | pmid = 12028939 | doi = | url = http://www.psiquiatria.com/articulos/atprimaria_y_sm/15413/ }}</ref><ref name="pmid18204355">{{cite journal | author = Ravindran, LN; Eisfeld, BS; Kennedy, SH | title = Combining mirtazapine and duloxetine in treatment-resistant depression improves outcomes and sexual function | journal = J Clin Psychopharmacol | volume = 28 | issue = 1 | pages = 107–8 |date=February 2008 | pmid = 18204355 | doi = 10.1097/JCP.0b013e318160d609 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid15560319">{{cite journal | author = Caldis, EV; Gair, RD | title = Mirtazapine for treatment of nausea induced by selective serotonin reuptake inhibitors | journal = Can J Psychiatry | volume = 49 | issue = 10 | page = 707 |date=October 2004 | pmid = 15560319 | doi = }}</ref>
+Antagonism of the 5-HT<sub>3</sub> receptor, an action mirtazapine shares with the approved antiemetic [[ondansetron]], significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and [[irritable bowel syndrome]] in afflicted individuals.<ref name="pmid11585276">{{cite journal | vauthors = Kast RE | title = Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy | journal = Supportive Care in Cancer | volume = 9 | issue = 6 | pages = 469–70 | date = Sep 2001 | pmid = 11585276 | doi = 10.1007/s005200000215 }}</ref> Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron.<ref name="pmid17587360"/> Blockade of the 5-HT<sub>3</sub> receptors has also shown to improve anxiety and to be effective in the treatment of [[drug addiction]] in several studies.<ref name="urlThe psychopharmacology of 5-HT3 receptors">{{cite journal |doi=10.1016/0163-7258(90)90086-H | title = The psychopharmacology of 5-HT3 receptors | year = 1990 | author = Costall, B; Naylor, RJ; Tyers, MB | journal = Pharmacology & Therapeutics | volume = 47 | issue = 2 | pages = 181–202 }}</ref> In conjunction with [[drug rehabilitation|substance abuse counseling]], mirtazapine has been investigated for the purpose of reducing [[methamphetamine]] use in dependent individuals with success.<ref name="pmid22065532" /> In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT<sub>2A</sub>, 5-HT<sub>2C</sub>, and 5-HT<sub>3</sub> receptors leading to a host of negative changes and side-effects, the most prominent of which including anorexia, insomnia, sexual dysfunction (loss of [[libido]] and [[anorgasmia]]), nausea, and 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.<ref name="pmid10333982"/><ref name="pmid16946177">{{cite journal | vauthors = McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ | title = Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report | journal = The American Journal of Psychiatry | volume = 163 | issue = 9 | pages = 1531–41; quiz 1666 | date = Sep 2006 | pmid = 16946177 | doi = 10.1176/appi.ajp.163.9.1531 }}</ref><ref name="pmid12590402">{{cite journal | vauthors = Sennef C, Timmer CJ, Sitsen JM | title = Mirtazapine in combination with amitriptyline: a drug-drug interaction study in healthy subjects | journal = Human Psychopharmacology | volume = 18 | issue = 2 | pages = 91–101 | date = Mar 2003 | pmid = 12590402 | doi = 10.1002/hup.441 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid12028939">{{cite journal | vauthors = Gándara Martín Jde L, Agüera Ortiz L, Ferre Navarrete F, Rojo Rodés E, Ros Montalbán S | title = [Tolerability and efficacy of combined antidepressant therapy] | language = Spanish | journal = Actas Españolas De PsiquiatríA | volume = 30 | issue = 2 | pages = 75–84 | year = 2002 | pmid = 12028939 | doi =  | url = http://www.psiquiatria.com/articulos/atprimaria_y_sm/15413/ }}</ref><ref name="pmid18204355">{{cite journal | vauthors = Ravindran LN, Eisfeld BS, Kennedy SH | title = Combining mirtazapine and duloxetine in treatment-resistant depression improves outcomes and sexual function | journal = Journal of Clinical Psychopharmacology | volume = 28 | issue = 1 | pages = 107–8 | date = Feb 2008 | pmid = 18204355 | doi = 10.1097/JCP.0b013e318160d609 }}{{Unreliable medical source|date=October 2011}}</ref><ref name="pmid15560319">{{cite journal | vauthors = Caldis EV, Gair RD | title = Mirtazapine for treatment of nausea induced by selective serotonin reuptake inhibitors | journal = Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie | volume = 49 | issue = 10 | pages = 707 | page = 707 | date = Oct 2004 | pmid = 15560319 | doi =  }}</ref>
-Mirtazapine is a very strong H<sub>1</sub> receptor inverse agonist and, as a result, it can cause powerful [[sedative]] and [[hypnotic]] effects.<ref name="pmid11607047" /> After a short period of chronic treatment, however, the H<sub>1</sub> receptor tends to [[Downregulation and upregulation|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 H<sub>1</sub> receptor may improve pre-existing [[allergy|allergies]], [[pruritus]], nausea, and insomnia in afflicted individuals. It may also contribute to weight gain, however.<ref name="pmid21304130">{{cite journal | author = Chiu, HW; Li, TC | title = Rapid weight gain during mirtazapine treatment | journal = The Journal of Neuropsychiatry and Clinical Neurosciences | volume = 23 | issue = 1 | pages = E7 | year = 2011 | pmid = 21304130 | doi = 10.1176/appi.neuropsych.23.1.E7 | url = http://neuro.psychiatryonline.org/article.aspx?volume=23&page=E7}}</ref> In contrast to the H<sub>1</sub> receptor, mirtazapine has very low affinity for the [[muscarinic acetylcholine receptor|mACh receptor]]s, although anticholinergic side effects like dry mouth, constipation, and mydriasis are still commonly seen in clinical practise.<ref name="pmid9090576">{{cite journal | author = Burrows, GD; Kremer, CM | title = Mirtazapine: clinical advantages in the treatment of depression | journal = Journal of Clinical Psychopharmacology | volume = 17 Suppl 1 | issue = | pages = 34S–39S |date=April 1997 | pmid = 9090576 | doi = 10.1097/00004714-199704001-00005| url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0271-0749&volume=17&issue=&spage=34S}}</ref>
+Mirtazapine is a very strong H<sub>1</sub> receptor inverse agonist and, as a result, it can cause powerful [[sedative]] and [[hypnotic]] effects.<ref name="pmid11607047" /> After a short period of chronic treatment, however, the H<sub>1</sub> receptor tends to [[Downregulation and upregulation|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 H<sub>1</sub> receptor may improve pre-existing [[allergy|allergies]], [[pruritus]], nausea, and insomnia in afflicted individuals. It may also contribute to weight gain, however.<ref name="pmid21304130">{{cite journal | vauthors = Chiu HW, Li TC | title = Rapid weight gain during mirtazapine treatment | journal = The Journal of Neuropsychiatry and Clinical Neurosciences | volume = 23 | issue = 1 | pages = E7 | year = 2011 | pmid = 21304130 | doi = 10.1176/appi.neuropsych.23.1.E7 | url = http://neuro.psychiatryonline.org/article.aspx?volume=23&page=E7 }}</ref> In contrast to the H<sub>1</sub> receptor, mirtazapine has very low affinity for the [[muscarinic acetylcholine receptor|mACh receptor]]s, although anticholinergic side effects like dry mouth, constipation, and mydriasis are still commonly seen in clinical practise.<ref name="pmid9090576">{{cite journal | vauthors = Burrows GD, Kremer CM | title = Mirtazapine: clinical advantages in the treatment of depression | journal = Journal of Clinical Psychopharmacology | volume = 17 Suppl 1 | issue =  | pages = 34S-39S | date = Apr 1997 | pmid = 9090576 | doi = 10.1097/00004714-199704001-00005 | url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0271-0749&volume=17&issue=&spage=34S }}</ref>
-Like many other antidepressants, mirtazapine has been found to have [[antinociceptive]] properties in mice.<ref name="pmid11931344">{{cite journal | author = Schreiber, S; Bleich, A; Pick, CG | title = Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression? | journal = J. Mol. Neurosci. | volume = 18 | issue = 1–2 | pages = 143–9 | year = 2002 | pmid = 11931344 | doi = 10.1385/JMN:18:1-2:143 }}</ref> 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 [[mu-opioid receptor|μ-opioid]] and [[kappa-opioid receptor|κ<sub>3</sub>-opioid receptor]]s are mainly involved.<ref name="pmid11931344" /> 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]].<ref name="pmid11931344" /> 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.<ref name="pmid11931344" />
+Like many other antidepressants, mirtazapine has been found to have [[antinociceptive]] properties in mice.<ref name="pmid11931344">{{cite journal | vauthors = Schreiber S, Bleich A, Pick CG | title = Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression? | journal = Journal of Molecular Neuroscience | volume = 18 | issue = 1-2 | pages = 143–9 | year = 2002 | pmid = 11931344 | doi = 10.1385/JMN:18:1-2:143 }}</ref> 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 [[mu-opioid receptor|μ-opioid]] and [[kappa-opioid receptor|κ<sub>3</sub>-opioid receptor]]s are mainly involved.<ref name="pmid11931344" /> 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]].<ref name="pmid11931344" /> 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.<ref name="pmid11931344" />
+== Pharmacokinetics ==
-==Pharmacokinetics==
 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.<ref name="pmid10885584"/>  The overall elimination half-life is 20–40 hours.
-===Dosage===
+=== Dosage ===
-Mirtazapine is typically prescribed in doses for humans of 15, 30 and 45&nbsp;mg. However, clinical doses as high as 120&nbsp;mg have been reported in the medical literature.<ref name="pmid16970569">{{cite journal | author = Kristensen, JH; Ilett, KF; Rampono, J; Kohan, R; Hackett, LP | title = Transfer of the antidepressant mirtazapine into breast milk | journal = British Journal of Clinical Pharmacology | volume = 63 | issue = 3 | pages = 322–7 |date=March 2007 | pmid = 16970569 | pmc = 2000733 | doi = 10.1111/j.1365-2125.2006.02773.x }}</ref>
+Mirtazapine is typically prescribed in doses for humans of 15, 30 and 45&nbsp;mg. However, clinical doses as high as 120&nbsp;mg have been reported in the medical literature.<ref name="pmid16970569">{{cite journal | vauthors = Kristensen JH, Ilett KF, Rampono J, Kohan R, Hackett LP | title = Transfer of the antidepressant mirtazapine into breast milk | journal = British Journal of Clinical Pharmacology | volume = 63 | issue = 3 | pages = 322–7 | date = Mar 2007 | pmid = 16970569 | pmc = 2000733 | doi = 10.1111/j.1365-2125.2006.02773.x }}</ref>
+=== Interactions ===
-===Interactions===
 Concurrent use with inhibitors or inducers of the [[cytochrome P450|cytochrome (CYP) P450]] [[isoenzyme]]s [[CYP1A2]], [[CYP2D6]], and/or [[CYP3A4]] can result in altered concentrations of mirtazapine, as these are the main [[enzyme]]s responsible for its metabolism.<ref name="pmid10885584" /><ref name="pmid11607047" /> As examples, [[fluoxetine]] and [[paroxetine]], inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while [[carbamazepine]], an inducer, considerably decreases them.<ref name="pmid10885584" />
-According to information from the manufacturers, mirtazapine should not be started within two weeks of any MAOI usage; likewise, MAOIs should not be administered within two weeks of discontinuing mirtazapine.<ref>[http://www.drugs.com/monograph/mirtazapine.html Mirtazapine monograph]</ref> However, a single study regarding the combination reported it does not result in any incidence of serotonin-related toxicity.<ref name="pmid16460699">{{cite journal | author = Gillman, PK | title = A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action | journal = Biol. Psychiatry | volume = 59 | issue = 11 | pages = 1046–51 |date=June 2006 | pmid = 16460699 | doi = 10.1016/j.biopsych.2005.11.016 }}</ref> In addition, a case report claimed that mirtazapine can actually be used to treat serotonin syndrome.<ref name="pmid8741027">{{cite journal | author = Hoes, MJ; Zeijpveld, JH | title = Mirtazapine as treatment for serotonin syndrome | journal = Pharmacopsychiatry | volume = 29 | issue = 2 | page = 81 |date=March 1996 | pmid = 8741027 | doi = 10.1055/s-2007-979550 }}{{Unreliable medical source|date=October 2011}}</ref> Mirtazapine in combination with an SSRI, SNRI, or TCA as an [[Augmentation (psychiatry)|augmentation]] strategy is considered to be relatively safe and is often employed therapeutically,<ref name="pmid10333982"/><ref name="pmid16946177"/><ref name="pmid12590402"/><ref name="pmid12028939"/><ref name="pmid18204355"/> with a combination of [[venlafaxine]] and mirtazapine sometimes referred to as “[[California rocket fuel]]”.<ref name="isbn0-521-74609-4">{{cite book | author = Stahl, SM | title = Stahl's Essential Psychopharmacology Online: Print and Online | publisher = Cambridge University Press | location = Cambridge, UK | year = 2008 | pages = | isbn = 0-521-74609-4 | url = http://stahlonline.cambridge.org/prescribers_drug.jsf?page=0521683505c57_p325-330.html.therapeutics&name=Mirtazapine&title=Therapeutics }}</ref>
+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.<ref>[http://www.drugs.com/monograph/mirtazapine.html Mirtazapine monograph]</ref> However, a single study regarding the combination reported it does not result in any incidence of serotonin-related toxicity.<ref name="pmid16460699">{{cite journal | vauthors = Gillman PK | title = A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action | journal = Biological Psychiatry | volume = 59 | issue = 11 | pages = 1046–51 | date = Jun 2006 | pmid = 16460699 | doi = 10.1016/j.biopsych.2005.11.016 }}</ref> In addition, a case report claimed that mirtazapine can actually be used to treat serotonin syndrome.<ref name="pmid8741027">{{cite journal | vauthors = Hoes MJ, Zeijpveld JH | title = Mirtazapine as treatment for serotonin syndrome | journal = Pharmacopsychiatry | volume = 29 | issue = 2 | pages = 81 | page = 81 | date = Mar 1996 | pmid = 8741027 | doi = 10.1055/s-2007-979550 }}{{Unreliable medical source|date=October 2011}}</ref> Mirtazapine in combination with an SSRI, SNRI, or TCA as an [[Augmentation (psychiatry)|augmentation]] strategy is considered to be relatively safe and is often employed therapeutically,<ref name="pmid10333982"/><ref name="pmid16946177"/><ref name="pmid12590402"/><ref name="pmid12028939"/><ref name="pmid18204355"/> with a combination of [[venlafaxine]] and mirtazapine sometimes referred to as “[[California rocket fuel]]”.<ref name="isbn0-521-74609-4">{{cite book | author = Stahl, SM | title = Stahl's Essential Psychopharmacology Online: Print and Online | publisher = Cambridge University Press | location = Cambridge, UK | year = 2008 | pages = | isbn = 0-521-74609-4 | url = http://stahlonline.cambridge.org/prescribers_drug.jsf?page=0521683505c57_p325-330.html.therapeutics&name=Mirtazapine&title=Therapeutics }}</ref>
-Another case report described mirtazapine as inducing [[hypertension]] in a [[clonidine]]-treated patient, likely due to occupancy of α<sub>2</sub>-autoreceptors by mirtazapine limiting the efficacy of concurrent clonidine therapy.<ref name="pmid10772378">{{cite journal | author = 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 = 476–8 |date=April 2000 | pmid = 10772378 | doi = 10.1592/phco.20.5.476.35061 }}{{Unreliable medical source|date=October 2011}}</ref>
+Another case report described mirtazapine as inducing [[hypertension]] in a [[clonidine]]-treated patient, likely due to occupancy of α<sub>2</sub>-autoreceptors by mirtazapine limiting the efficacy of concurrent clonidine therapy.<ref name="pmid10772378">{{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 = 476–8 | date = Apr 2000 | pmid = 10772378 | doi = 10.1592/phco.20.5.476.35061 }}{{Unreliable medical source|date=October 2011}}</ref>
 [[Liver failure|Liver]] and moderate [[renal failure|renal impairment]] have been reported to decrease the oral clearance of mirtazapine by about 30%; severe renal impairment decreases it by 50%.<ref name="pmid10885584" />
-==Chemistry==
+== Chemistry ==
 Mirtazapine is a [[racemate|racemic mixture]] of [[enantiomer]]s. The (''S'')-(+)-enantiomer is known as [[esmirtazapine]].
-A four-step [[chemical synthesis]] of mirtazapine has been published.<ref name="Rao_2006">{{cite journal | author = Rao, DVNS; Dandala, R; Bharathi, C; Handa, VK; Sivakumaran, M; Naidub, A | title = Synthesis of potential related substances of mirtazapine | journal = Arkivoc | volume = 2006 | issue = 15 | pages = 127–32 | year = 2006 | url = http://www.arkat-usa.org/get-file/22868/ | doi = 10.3998/ark.5550190.0007.f15}}</ref><ref name="pmid123455">{{Ref patent | country = US | number = 4062848 | status = patent | title = Tetracyclic compounds | gdate = 1977-12-13 | pubdate = 1977-12-13 | pridate = 1976-03-23 | inventor = Van der Burg WJ }}</ref>
+A four-step [[chemical synthesis]] of mirtazapine has been published.<ref name="Rao_2006">{{cite journal | vauthors = Rao, DVNS; Dandala, R; Bharathi, C; Handa, VK; Sivakumaran, M; Naidub, A | title = Synthesis of potential related substances of mirtazapine | journal = Arkivoc | volume = 2006 | issue = 15 | pages = 127–32 | year = 2006 | url = http://www.arkat-usa.org/get-file/22868/ | doi = 10.3998/ark.5550190.0007.f15}}</ref><ref name="pmid123455">{{Ref patent | country = US | number = 4062848 | status = patent | title = Tetracyclic compounds | gdate = 1977-12-13 | pubdate = 1977-12-13 | pridate = 1976-03-23 | inventor = Van der Burg WJ }}</ref>
-{{clear}}
-==See also==
+== See also ==
 * [[Aptazapine]]
 * [[Mianserin]]
 * [[Setiptiline]]
-==References==
+== References ==
-{{Reflist|2}}
+{{Reflist|33em}}
-==Further reading==
+== Further reading ==
 {{Refbegin}}
-* {{cite journal | author = Stimmel, GL; Dopheide, JA; Stahl, SM | title = Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects | journal = Pharmacotherapy | volume = 17 | issue = 1 | pages = 10–21 | year = 1997 | pmid = 9017762 | doi = 10.1002/j.1875-9114.1997.tb03674.x}}
+* {{cite journal | vauthors = Stimmel GL, Dopheide JA, Stahl SM | title = Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects | journal = Pharmacotherapy | volume = 17 | issue = 1 | pages = 10–21 | year = 1997 | pmid = 9017762 | doi = 10.1002/j.1875-9114.1997.tb03674.x }}
-* {{cite journal | author = Anttila, SA; Leinonen, EV | title = A review of the pharmacological and clinical profile of mirtazapine | journal = CNS Drug Rev | volume = 7 | issue = 3 | pages = 249–64 | year = 2001 | pmid = 11607047 | doi = 10.1111/j.1527-3458.2001.tb00198.x }}
+* {{cite journal | vauthors = Anttila SA, Leinonen EV | title = A review of the pharmacological and clinical profile of mirtazapine | journal = CNS Drug Reviews | volume = 7 | issue = 3 | pages = 249–64 | year = 2001 | pmid = 11607047 | doi = 10.1111/j.1527-3458.2001.tb00198.x }}
 {{Refend}}
-==External links==
+== External links ==
 * [http://www.drugs.com/cdi/mirtazapine.html Mirtazapine - Drugs.com]
 * [http://www.rxlist.com/remeron-drug.htm Remeron - Rxlist.com]

v t e Antiemetics (A04)
5-HT₃ serotonin ion channel antagonists	Alosetron Azasetron Bemesetron Cilansetron Clozapine Dazopride Dolasetron Granisetron Lerisetron Mianserin Mirtazapine Olanzapine Ondansetron Palonosetron (+netupitant) Quetiapine Ramosetron Ricasetron Tropisetron Zatosetron
5-HT serotonin G-protein receptor antagonists	Clozapine Cyproheptadine Hydroxyzine Olanzapine Risperidone Ziprasidone
CB₁ agonists (cannabinoids)	Dronabinol Nabilone Tetrahydrocannabinol (cannabis)
D₂/D₃ antagonists	Chlorpromazine Haloperidol Hydroxyzine Metoclopramide Metopimazine Prochlorperazine Thiethylperazine Trimethobenzamide
H₁ antagonists (antihistamines)	Cyclizine Dimenhydrinate Diphenhydramine Hydroxyzine Meclizine Promethazine
mACh antagonists (anticholinergics)	Atropine Diphenhydramine Hydroxyzine (very mild) Hyoscyamine Scopolamine
NK₁ antagonists	Aprepitant Fosaprepitant Maropitant Netupitant Rolapitant
Others	Amisulpride Cerium oxalate Dexamethasone Lorazepam Midazolam Propofol

v t e Tricyclics
Classes	Acridine Anthracene Dibenzazepine Dibenzocycloheptene Dibenzodiazepine Dibenzothiazepine Dibenzothiepin Dibenzoxazepine Dibenzoxepin Phenothiazine Pyridazinobenzoxazine Pyridinobenzodiazepine Thioxanthene
Antidepressants (Tricyclic antidepressants (TCAs))	Amoxapine Amezepine Amineptine Amitriptyline Amitriptylinoxide Amoxapine Aptazapine Azepindole Batelapine Beloxepin Butriptyline Cianopramine Ciclazindol Cidoxepin Clomipramine Cotriptyline Cyanodothiepin Demexiptiline Depramine (balipramine) Desipramine (desmethylimipramine) Desmethylclomipramine Desmethyltrimipramine Dibenzepin Dimetacrine Dosulepin (dothiepin) Doxepin Enprazepine Fantridone Fluotracen Hepzidine Homopipramol Imipramine Imipraminoxide Intriptyline Iprindole Ketipramine Litracen Lofepramine Losindole Loxapine Maprotiline Mariptiline Mazindol Melitracen Metapramine Mezepine Mirtazapine Monometacrine Nitroxazepine Norbutriptyline Nordoxepin Northiaden (nordosulepin) Nortriptyline (noramitriptyline) Noxiptiline Octriptyline Opipramol Pipofezine Pirandamine Propizepine Protriptyline Quinupramine Spiroxepin Tandamine Tampramine Tianeptine Tienopramine Trimipramine
Antihistamines	Azatadine Bisulepin Cidoxepin Clobenzepam Cyproheptadine Dacemazine Deptropine Desloratadine Epinastine Etymemazine Fenethazine Hydroxyethylpromethazine Isopromethazine Isothipendyl Ketotifen Latrepirdine Loratadine Mebhydrolin Mequitazine Methdilazine Olopatadine Oxomemazine Perlapine Phenindamine Pimethixene Pirolate Promethazine Propiomazine Rupatadine Thiazinamium
Antipsychotics	Acetophenazine Alimemazine Amoxapine Asenapine Butaclamol Butaperazine Carfenazine (carphenazine) Carpipramine Chlorpromazine Chlorprothixene Ciclindole Citatepine Clocapramine Clomacran Clorotepine Clotiapine Clozapine Cyanothepin Doclothepin Docloxythepin Erizepine Flucindole Flumezapine Fluotracen Flupentixol Fluphenazine Gevotroline Homopipramol Isofloxythepin Levomepromazine/Methotrimeprazine Loxapine Maroxepin Meperathiepin Mesoridazine Metiapine Metitepine Metoxepin Mosapramine Naranol Octomethothepin Olanzapine Oxyclothepin Oxyprothepin Pentiapine Peradithiepin Perathiepin Perazine Perphenazine Periciazine Pinoxepin Piperacetazine Pipotiazine Piquindone Prochlorperazine Promazine Prothipendyl Quetiapine Savoxepin/Cipazoxapine Sulforidazine Tenilapine Thiethylperazine Thiopropazate Thioridazine Thiothixene Tilozepine Traboxopine Trifluoperazine Triflupromazine Trifluthepin Zotepine Zuclopenthixol
Anticonvulsants	Carbamazepine Dizocilpine Eslicarbazepine Eslicarbazepine acetate Etazepine Licarbazepine Oxcarbazepine Oxitriptyline
Anticholinergics	Darenzepine Dipitramine Nuvenzepine Pirenzepine Profenamine Rispenzepine Siltenzepine Telenzepine Tripitramine Tropatepine Zolenzepine
Others	Adosopine Aminopromazine Atiprosin Benzoctamine Botiacrine Carvedilol Cyclobenzaprine Damotepine Elanzepine Fluradoline Methylene blue Monatepil Oxetorone Pipazethate P7C3 Pinadoline Pitrazepin Pizotifen Serazapine Tipindole