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Mirtazapine

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Mirtazapine
Clinical data
Trade namesRemeron, Avanza, Zispin
Other names6-Azamianserin, Org 3770
AHFS/Drugs.comMonograph
MedlinePlusa697009
Pregnancy
category
  • AU: B3
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability50%[2]
Protein binding85%[2]
MetabolismLiver (CYP1A2, CYP2D6, and CYP3A4)[2][3]
Elimination half-life20–40 hours[2]
ExcretionUrine (75%)[2]
Feces (15%)[2]
Identifiers
  • (±)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.080.027 Edit this at Wikidata
Chemical and physical data
FormulaC17H19N3
Molar mass265.35 g/mol g·mol−1
3D model (JSmol)
Density1.22 g/cm3
Melting point114 to 116 °C (237 to 241 °F)
Boiling point432 °C (810 °F)
Solubility in waterSoluble in methanol and chloroform mg/mL (20 °C)
  • n1cccc3c1N4C(c2ccccc2C3)CN(C)CC4
  • 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 checkY
  • Key:RONZAEMNMFQXRA-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Mirtazapine (Remeron, Avanza, Zispin) is a noradrenergic and specific serotonergic antidepressant (NaSSA) that was introduced by Organon International in the United States in 1990 and is used primarily in the treatment of depression. It is also commonly used as an anxiolytic, hypnotic, antiemetic, and appetite stimulant. In terms of structure, mirtazapine can also be classified as a tetracyclic antidepressant (TeCA).

It is broadly classified as a centrally acting α2-adrenergic receptor antagonist.

Medical uses

Approved and off-label

Mirtazapine's primary use is the treatment of major depressive disorder and other mood disorders.[4][5]

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 the following conditions:

Feline

Mirtazapine is sometimes prescribed as an appetite stimulant for cats experiencing anorexia due to medical conditions such as chronic kidney disease. It is especially useful for treating combined poor appetite and nausea in cats.[37][38]

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.[39]

In a major systematic review published in 2009 that compared the efficacy and tolerability of 12 popular antidepressants, mirtazapine was found to be superior to all of the included selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and reboxetine, bupropion, and mianserin in terms of antidepressant efficacy, while it was average in regard to tolerability.[39] However, it is important to note that the efficacies of most of the antidepressants in this review differed only slightly. Hence, the apparent superiority of mirtazapine relative to most of the others included may not actually be all that prominent or significant in this case.[citation needed]

Compared to earlier antidepressants, mirtazapine has been found to be significantly superior to trazodone,[40] while it has been shown to be approximately equivalent in efficacy to several of the tricyclic antidepressants (TCAs) including amitriptyline, doxepin, and clomipramine, though with a much improved tolerability profile.[3][41] However, two other studies found mirtazapine to be significantly inferior to imipramine, another TCA.[42][43] 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 regards to side-effects and drug interactions.[44]

In general, all antidepressants, including mirtazapine, require a few weeks for their therapeutic benefits on depressive and anxious symptoms to become apparent.[45] Unlike most antidepressants, however, mirtazapine has demonstrated itself to have a faster onset of antidepressant action with an initial reduction in affective symptoms being seen within the first week of treatment and the maximal change in improvement occurring over the course of the first two weeks.[45][46] Hence, it may be a better choice for patients in whom hastened relief is urgently needed, such as those who are considered to be a suicide risk.

Adverse reactions

Side-effects

Common side-effects of mirtazapine include dizziness, blurred vision, sedation, somnolence, malaise, increased appetite, weight gain (as a result of increased appetite), dry mouth, constipation, and joint and muscle pain. Less common side-effects that tend to occur more often at higher doses include restlessness, irritability, aggression, apathy, anhedonia, difficulty swallowing, shallow breathing, decreased body temperature, pupil constriction, nocturnal emissions, spontaneous orgasms, impaired balance, restless legs syndrome, and vivid dreams.[3][47][48][49] Rare and potentially serious adverse reactions of mirtazapine include allergic reaction, edema, fainting, seizures, bone marrow suppression, myelodysplasia, and agranulocytosis.[15]

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.[3][41] These adverse effects include decreased appetite, weight loss, insomnia, nausea and vomiting, diarrhea, urinary retention, increased body temperature, excessive sweating, pupil dilation, and sexual dysfunction.[3][41]

In general, some antidepressants, especially SSRIs, can paradoxically exacerbate some patients' depression or anxiety or cause suicidal ideation.[50] Despite its sedating action, mirtazapine is also believed to be capable of this, and for this reason in the United States and certain other countries it carries a black box label warning of these potential effects.

Discontinuation

Mirtazapine and other antidepressants may cause a withdrawal syndrome upon discontinuation.[3][51][52][53] A gradual and slow reduction in dose is recommended in order to minimize withdrawal symptoms.[54] Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety, panic attacks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhea, nausea, vomiting, flu-like symptoms such as allergies and pruritus, headaches, and sometimes hypomania or mania.[51][52][55][56][57]

Overdose

Mirtazapine is considered to be relatively safe in the event of an overdose.[58] Unlike the TCAs, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose.[41] Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to TCAs.[59][60]

Twelve reported fatalities have been attributed to mirtazapine overdose in literature.[61][62] 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.[63]

On 10 June 2013 Lee Webster was convicted of the manslaughter of Jason Wood at Maidstone Crown Court. He had added 27 mirtazapine tablets to Wood's drink while both were drunk.[64] Wood was a dwarf with a body weight of 6 stone (38 kilogram).[65]

Pharmacology

Binding profile

Mirtazapine is an antagonist/inverse agonist at the following receptors:[66][67][68]

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.[66][67]

Taking the affinity and ED50 value of the 5HT1a receptor into consideration, the results would indicate that Mirtizapine acts as a partial agonist at that specific receptor. While it potently displaces serotonin at very low concentrations, it is not until the concentration raises to 1000 nM that the intracellular activity decreases by 50%.

Though not known to have ever been screened at this site, it is possible that mirtazapine may act on the 5-HT6 receptor as well. Supporting this speculation is the fact that its analogue mianserin (which, regarding structure, can also be called 6-desazamirtazapine) has been shown to have high affinity for 5-HT6 and does not produce cAMP accumulation (indicating it is an antagonist).[74]

Correspondence to clinical effects

Antagonization of the α2-adrenergic receptors, which function largely as autoreceptors and heteroreceptors enhances adrenergic and serotonergic neurotransmission, the notable ones being central 5-HT1A receptor-mediated transmission in the dorsal raphe nucleus and hippocampus; hence, mirtazapine's classification as a NaSSA. Indirect α1-adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory α2-heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT.[3][4][75][76][77] Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT1A receptor.[76] Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs.[78] 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,[79] nor does it have any significant inhibitory effects on monoamine oxidase.[80]

Antagonism of the 5-HT2 subfamily of receptors and inverse agonisim of the 5-HT2C receptor appears to be in part responsible for mirtazapine's efficacy in the treatment of depressive states.[81][82] The 5-HT2C receptor is known to inhibit the release of the neurotransmitters dopamine and norepinephrine in various parts of the brains of rodents, notably in reward pathways such as the ventral tegmental area.[83][84] Accordingly, it was shown that by blocking the α2-adrenergic receptors and 5-HT2C receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats.[85] In addition, mirtazapine's antagonism of 5-HT2A receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor.[3][41] The newest research however has shown that mitrazapine is actually an inverse agonist of the 5-HT2C receptor. 5-HT2C inverse agonists have been shown to inhibit mesoaccumbens dopamine outflow[86] attenuating the rewarding properties of various substances like morphine. This inhibition of dopamine may be stronger then thought as substances with 5-HT2C inverse agonist properties may have more activity to regulate dopamine neurotransmission than ones with competitive antagonism.[87] With its newly understood properties of 5-HT2C inverse agonisim, it is being investigated and shown to lower drug seeking behavior, conditioned place preference and the rewarding effects of substances such as methamphetamine in various human and animal studies.[71][88][89][90] It is also being investigated to help in substance abuse disorders with withdrawal effects and remission rates [88][91] but some studies have shown mixed benefit.[88][92][93]

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.[94] Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron.[19] 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.[95] In conjunction with substance abuse counseling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success.[36] In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors leading to a host of negative changes and side-effects, the most prominent of which including anorexia, insomnia, sexual dysfunction (loss of libido and anorgasmia), nausea, and diarrhea, among others. As a result, mirtazapine is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.[41][44][96][97][98][99]

Mirtazapine is a very strong H1 receptor inverse agonist and, as a result, it can cause powerful sedative and hypnotic effects.[3] 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.[100] In contrast to the H1 receptor, mirtazapine has very low affinity for the mACh receptors, and thus is virtually devoid of any anticholinergic properties at clinical doses.[101]

Like many other antidepressants, mirtazapine has been found to have antinociceptive properties in mice.[102] 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.[102] 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.[102] It has been suggested that this may be due to their unique influence on the opioid system, which is a property that has been hypothesized to somehow give them an advantage over other antidepressants in cases of severe depressive symptomatology.[102]

Pharmacokinetics

Dosage

Mirtazapine is typically prescribed in doses 15 mg, 30 mg and 45 mg. However, clinical doses as high as 120 mg have been reported in the medical literature.[103]

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][3] 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.[104] However, a single study regarding the combination reported that it does not result in any incidence of serotonin-related toxicity.[105] In addition, a case report claimed that mirtazapine can actually be used to treat serotonin syndrome.[106] Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is considered to be relatively safe and is often employed therapeutically,[41][44][96][97][98] with a combination of venlafaxine and mirtazapine sometimes referred to as “California rocket fuel”.[107]

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.[108]

Liver and moderate renal impairment has been reported to decrease the oral clearance of mirtazapine by approximately 30%; severe renal impairment decreases it by 50%.[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.[109][110]

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Further reading

  • Stimmel GL, Dopheide JA, Stahl SM (1997). "Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects". Pharmacotherapy. 17 (1): 10–21. PMID 9017762.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Anttila SA, Leinonen EV (2001). "A review of the pharmacological and clinical profile of mirtazapine". CNS Drug Rev. 7 (3): 249–64. doi:10.1111/j.1527-3458.2001.tb00198.x. PMID 11607047.
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