Mirtazapine

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Mirtazapine
200px
150px
Systematic (IUPAC) name
(±)-1,2,3,4,10,14b-hexahydro-2-[11C]methylpyrazino(2,1-a)pyrido(2,3-c)(2)benzazepine
Clinical data
Pregnancy
category
  • C
Routes of
administration		 Oral
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 50%
Metabolism Liver (enzymes CYP2D6 and CYP3A4)[1]
Biological half-life 20-40 hours
Excretion Urine (75%), Feces (15%)
Identifiers
CAS Number 61337-67-5
ATC code N06AX11 (WHO)
PubChem CID 4205
DrugBank DB00370
ChemSpider 4060
Synonyms 6-Azamianserin, Org 3770
Chemical data
Formula C17H19N3
Molar mass 265.35 g/mol[[Script error: No such module "String".]]
Script error: No such module "collapsible list".
Physical data
Melting point 114 to 116 °C (237 to 241 °F)
Solubility in water Soluble in methanol and chloroform mg/mL (20 °C)
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Mirtazapine (Remeron, Avanza, Zispin) is a tetracyclic antidepressant (TeCA) used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications. Along with its close analogues mianserin and setiptiline, mirtazapine is one of the few noradrenergic and specific serotonergic antidepressants (NaSSAs).

Esmirtazapine, the (S)-(+)-enantiomer of mirtazapine, is currently under development for the treatment of insomnia and menopausal symptoms by the same company that produced mirtazapine.[2]

History

Mirtazapine was introduced by Organon International in the United States in 1990 for the treatment of depression. It quickly spread throughout the world and became a widely used antidepressant.[citation needed]

Indications

Clinical

Mirtazapine's primary use is the treatment of major depressive disorder.[3] Mirtazapine has been found to be useful in the treatment of generalized anxiety disorder,[4][5] social anxiety disorder,[6][7][8][9][10] obsessive-compulsive disorder,[11][12][13] panic disorder,[14][15][16][17][18] post-traumatic stress disorder,[19][20][21][22][23][24] seasonal affective disorder,[25] insomnia,[26][27][28] nausea and vomiting,[27][29][30][31][32][33][34] diminished appetite and associated weight loss,[33][35][36] and itching[37][38][39][40] as well, and it may be prescribed off-label for these conditions.

Experimental

Mirtazapine has had literature published on its efficacy (or lack thereof) in the following areas: for the treatment of sleep apnea/hypopnea syndrome,[41][42][43][44][45] headaches such as migraines,[46][47] tension headaches,[48][49][50] post-dural puncture headaches[51] and cluster headaches,[52] hyperemesis gravidarum,[53][54][55] irritable bowel syndrome,[56][57] gastroparesis,[58] dysgeusia,[citation needed] undifferentiated somatoform disorder,[59] autism and other pervasive developmental disorders,[60][61][62][63][64] and neuroleptic-induced akathisia.[65][66][66][67][68][69][70]

Pharmacology

Pharmacodynamics

Mirtazapine is an antagonist/inverse agonist at the following receptors:[71][72]

As well as an inhibitor of the following transporters:

All affinities listed were assayed using human materials except those for α1-adrenergic and mACh which are for rat tissues, due to human values being unavailable.[71][72] Though not known to have ever been screened, mirtazapine may act on the 5-HT6 and α2B-adrenergic receptors as well. Notably, mianserin (which is 6-desazamirtazapine) has been shown to have high affinity for 5-HT6 and does not produce cAMP accumulation (indicating it is an antagonist).[75]

Antagonization of the α2-adrenergic receptors which function largely as autoreceptors and heteroreceptors enhances adrenergic and serotonergic neurotransmission, notably central 5-HT1A receptor-mediated transmission in the dorsal raphe nucleus and hippocampus.[3][76][77][78][79] Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT1A receptor.[78] Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs.[80] Unlike most conventional antidepressants, however, mirtazapine is not a reuptake inhibitor and has no appreciable affinity for the serotonin, norepinephrine, or dopamine transporters, nor is it an MAOI or have any efficacy at inhibiting/inducing any other enzyme for that matter.

More recent findings suggest that mirtazapine also possesses a second antidepressant property, which is likely to be just as important as its actions at the α2-adrenergic receptor in mitigating depression, mirtazapine's secondary antidepressant properties are likely to be mediated by its blockade of serotonin receptors, notably 5-HT2C.[81][82][83][83] The 5-HT2C receptor normally works to inhibit the release of the neurotransmitters dopamine and norepinephrine in various parts of the brain, notably in the pleasure centers such as the ventral tegmental area (VTA).[84][85] By blocking it, mirtazapine disinhibits dopamine and norepinephrine activity in these areas, causing a pronounced antidepressant and anxiolytic response.[86] Indeed, the novel antidepressant agomelatine acts primarily as a 5-HT2C receptor antagonist and has antidepressant efficacy at least comparable to that of the SSRIs and SNRIs.[87][88]

Antagonism of the 5-HT2A and 5-HT2C receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor.[76][89] Additionally, antagonism of the 5-HT3 receptor, the mechanism of action of antiemetic ondansetron, significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and general irritable bowel syndrome in afflicted individuals.[90] Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron.[30] 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.[91] Mirtazapine appears to enhance memory function as well and reverses scopolamine-induced memory deficits in rodents,[92] effects which may be attributed to 5-HT3 antagonism.[93] In contrast to mirtazapine, the SSRIs, SNRIs, TCAs, and MAOIs all increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors, leading to a host of negative changes and side effects, the most prominent of which include anorexia, insomnia, sexual dysfunction (impaired libido and anorgasmia), nausea, and diarrhea, among others. As a result, mirtazapine is often used in conjunction with these drugs to reduce their side effect profile and to produce a stronger antidepressant effect.[89][94][95][96][97][98]

Mirtazapine is a very strong H1 receptor antagonist and as a result, it can cause powerful sedative and hypnotic effects.[83] After a short period of chronic treatment, however, the H1 receptor tends to sensitize and the antihistamine effects become more tolerable. Many patients may also dose at night to avoid the effects and this appears to be an effective strategy for combating them. Blockade of the H1 receptor may improve pre-existing allergies, pruritus, nausea, and insomnia in afflicted individuals; hence, this may actually be a positive thing for some. It may also contribute to weight gain, however.[citation needed] Mirtazapine has very low affinity for the muscarinic acetylcholine receptors and therefore lacks significant anticholinergic properties at clinically used doses.

File:Mirtazapine30s.jpg
Mirtazapine 30 mg tablets.

Pharmacokinetics

Mirtazapine is typically prescribed in doses ranging from 15 mg to 45 mg. However, in severely depressed individuals, doses as high as 120 mg have been used with success.[citation needed] Mirtazapine has a half-life of approximately 20–40 hours. Like most other antidepressants, because of the "therapeutic lag" mirtazapine may require as long as 2–4 weeks until the therapeutic benefits of the drug become evident.

Chemistry

File:Mirtazapine structure.svg
The racemic mixture of enantiomers

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

A four step chemical synthesis of mirtazapine has been published.[99][100]

Efficacy and tolerability

Mirtazapine has been found to be one of the most effective antidepressants available and has a generally tolerable side effect profile. In a major systematic review published in 2009 which compared the efficacy and tolerability of 12 popular antidepressants, mirtazapine was found to be superior to all of the included SSRIs and SNRIs, reboxetine, bupropion, and mianserin in terms of antidepressant efficacy, while it was average in regards to tolerability.[76][101][102] Mirtazapine has been demonstrated to be superior to trazodone as well.[103] Mirtazapine has also been shown to be equal in efficacy to many of the TCAs, including amitriptyline, doxepin, and clomipramine, but with a much improved tolerability profile.[76][89] However, two other studies found mirtazapine inferior to the TCA imipramine.[104][105] One study compared the combination of venlafaxine and mirtazapine versus the MAOI tranylcypromine and found them to be equally effective, though the MAOI was much less tolerable in terms of side effects and drug interactions.[94]

Side effects

Common side effects of mirtazapine: dizziness, blurred vision, sedation, somnolence, malaise/lassitude, increased appetite and subsequent weight gain,[106] dry mouth, constipation, enhanced libido and sexual function, and vivid, bizarre, lucid dreams or nightmares.[citation needed]

Rarer side effects: agitation/restlessness, irritability, aggression, apathy and/or anhedonia (emotional blunting), excessive mellowness or calmness, difficulty swallowing, shallow breathing, decreased body temperature, miosis, nocturnal emissions, spontaneous orgasm, loss of balance, and restless legs syndrome.[76][107][108][109] Mirtazapine has also occasionally been reported to cause mild hallucinogenic effects in some patients, including mental imagery, auditory and visual hallucinations. Most of these side effects are generally mild and become less prominent over time.[76]

Very rare, potentially serious adverse reactions may include allergic reaction, edema, fainting, seizures, bone marrow suppression, myelodysplasia,[109] and agranulocytosis (occurs in 1/1,000 patients)[citation needed].

Mirtazapine has a lower risk to cause many of the side effects encountered with other antidepressants, such as decreased appetite, insomnia, nausea and vomiting, diarrhea, urinary retention, increased body temperature, increased perspiration/sweating, mydriasis, and sexual dysfunction (consisting of loss of libido and anorgasmia).[76][89]

In general, some antidepressants may have the capacity to exacerbate some patients' depression or anxiety or cause suicidal ideation, particularly early in the treatment. It has been proven that mirtazapine has a faster onset of antidepressant action compared to SSRIs.[110]

Discontinuation

Mirtazapine and other antidepressants may cause a withdrawal upon discontinuation.[76][111][112][113] It should be noted that withdrawal effects from psychoactive drugs such as antidepressants are not uncommon; but are typically less severe than seen with benzodiazepines.[114] A gradual and slow reduction in dose is recommended in order to minimize withdrawal symptoms.[115] Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety, panic attacks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhea, nausea and vomiting, flu-like symptoms such as allergies and pruritus, headache, and sometimes hypomania/mania.[111][112][116][117][118]

Interactions

The potential for dangerous drug interactions with mirtazapine is considered to be very low, if not completely negligible. As a serotonin receptor antagonist, mirtazapine will not cause serotonin syndrome at any dose, nor is it capable of causing tyramine-induced hypertensive crisis, unlike the SSRIs and MAOIs, respectively. In fact, mirtazapine can actually be used to treat serotonin syndrome.[119]

Mirtazapine may, however, increase the effects of warfarin and sedative drugs, such as alcohol, benzodiazepines, and barbiturates,[citation needed] and it has also been reported to reduce or block the effects of some street drugs including hallucinogens such as MDMA, LSD and magic mushrooms.[citation needed] Carbamazepine and phenytoin decrease effects of mirtazapine.[citation needed] Cimetidine, azole-antifungals, HIV protease inhibitors, erythromycin and nefazodone may increase effects of mirtazapine.[citation needed]

Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is safe and is often used therapeutically.[89][94][95][96][98] Mirtazapine and MAOIs are said to be contraindicated by some sources; however, there is no true indication that this is actually the case, and there is no proper literature on the subject warning against the combination whatsoever. Only a single study has mentioned anything significantly important regarding the combination, and they reported that it does not result in any incidence of serotonin-related toxicity.[120] However, mirtazapine has been associated with inducing hypertension in clonidine-treated patients.[121]

Overdose

Mirtazapine is relatively safe if an overdose is taken.[122] Unlike the TCAs, mirtazapine shows no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose.[89] Overdose with as much as 30 to 50 times the standard dose has shown to be relatively non-toxic.[123] One case in which 1,200 mg was ingested proved non-fatal.[124]

12 fatalities have been attributed to mirtazapine overdose in literature.[125][126] However, the fatal toxicity index (FTI: deaths per million prescriptions) for mirtazapine is only 3.1 (95% CI: 0.1 to 17.2). This is similar to that observed with SSRIs.[127]

See also

References

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Further reading

External links

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af:Mirtazapien

de:Mirtazapin es:Mirtazapina fr:Mirtazapine it:Mirtazapina hu:Mirtazapin ja:ミルタザピン pl:Mirtazapina pt:Mirtazapina ru:Миртазапин fi:Mirtatsapiini sv:Mirtazapin

tr:Mirtazapin
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