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6.19.2017 | Logan Blare

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

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

but some studies have shown mixed benefit. Antagonism of the 5-HT 2 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. 5-HT 2C inverse agonists have been shown to inhibit mesoaccumbens dopamine outflow attenuating the rewarding properties of various substances like morphine. 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. 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. Accordingly, it was shown that by blocking the α 2 adrenergic receptors and 5-HT 2C receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats. The newest research however has shown that mirtazapine is actually an inverse agonist of the 5-HT 2C receptor. 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. It is also being investigated to help in substance abuse disorders with withdrawal effects and remission rates. 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.

It may also contribute to weight gain, however. Blockade of the H 1 receptor may improve pre-existing allergies, pruritus, nausea, and insomnia in afflicted individuals. Mirtazapine is a very strong H 1 receptor inverse agonist and, as a result, it can cause powerful sedative and hypnotic effects. After a short period of chronic treatment, however, the H 1 receptor tends to desensitize and the antihistamine effects become more tolerable. In contrast to the H 1 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. Many patients may also dose at night to avoid the effects, and this appears to be an effective strategy for combating them.

Indirect α 1 adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory α 2 heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT. Because of this, mirtazapine has been said to be a functional " indirect agonist " of the 5-HT 1A receptor. Increased activation of the central 5-HT 1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs. Unlike most conventional antidepressants, however, at clinically used doses mirtazapine has no appreciable affinity for the serotonin, norepinephrine, or dopamine transporters and thus lacks any significant effects as a reuptake inhibitor of these neurotransmitters, nor does it have any significant inhibitory effects on monoamine oxidase. Antagonization of the α 2 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.

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

In a meta-analysis published in 2009 that compared the efficacy and tolerability of 12 second-generation antidepressants, mirtazapine was found to be superior to all of the included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), reboxetine and bupropion in terms of antidepressant efficacy, while it was average in regard to tolerability. However, its superior efficacy over the other medications in the top four ( escitalopram, sertraline and venlaine ) did not reach statistical significance.

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The ( S )-(+)-enantiomer has a plasma half-life of 9.9±3 hours and the ( R )-(–)-enantiomer has a plasma half-life of 18±2.5 hours. The overall elimination half-life is 20–40 hours.

This is similar to that observed with SSRIs. The fatal toxicity index (deaths per million prescriptions) for mirtazapine is 3.1 (95% CI: 0.1 to 17.2). Twelve reported fatalities have been attributed to mirtazapine overdose.

A four-step chemical synthesis of mirtazapine has been published.

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

According to information from the manufacturers, mirtazapine should not be started within two weeks of any Monoamine oxidase inhibitor (MAOI) usage; likewise, MAOIs should not be administered within two weeks of discontinuing mirtazapine. However, a single study regarding the combination reported it does not result in any incidence of serotonin-related toxicity. Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is considered to be relatively safe and is often employed therapeutically, with a combination of venlaine and mirtazapine sometimes referred to as “ California rocket fuel ”. In addition, a case report claimed that mirtazapine can actually be used to treat serotonin syndrome.

Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron. Antagonism of the 5-HT 3 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. Blockade of the 5-HT 3 receptors has also shown to improve anxiety and to be effective in the treatment of drug addiction in several studies. As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect. In conjunction with substance abuse counseling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success. In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT 2A, 5-HT 2C, and 5-HT 3 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.

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

Interestingly, while virtually all antidepressants differ little in their maximal effectiveness in the treatment of major depression, mirtazapine and venlaine have demonstrated superior efficacy in treating severe types of depression such as psychotic depression and treatment-resistant depression. This may be due to their unique influence on the opioid system, which is a property that may give them an advantage over other antidepressants in cases of severe depressive symptomatology. However, unlike most other antidepressants, though similarly to venlaine, these effects are mostly mediated through downstream modulation of the endogenous opioid system, of which in the case of mirtazapine the μ opioid and κ 3 opioid receptors are mainly involved. Like many other antidepressants, mirtazapine has been found to have antinociceptive properties in mice.

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

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%

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) developed by Organon International in the Netherlands, and introduced in the United States in 1996, and is used primarily in the treatment of depression. It is also commonly used as an anxiolytic, hypnotic, antiemetic and appetite stimulant. In structure, mirtazapine can also be classified as a tetracyclic antidepressant (TeCA) and is the 6- aza analogue of mianserin.

Mirtazapine is an antagonist / inverse agonist at the following receptors :

Mirtazapine has recently been found to act as a weak ( EC 50 7.2 μM) κ-opioid receptor partial agonist.

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

In clinical studies, mirtazapine has been found to be an effective antidepressant with a generally tolerable side-effect profile relative to other antidepressants.

A case report published in 2000 noted an instance in which mirtazapine counteracted the action of clonidine, causing a dangerous rise in blood pressure.

However, two other studies found mirtazapine to be significantly inferior to imipramine, another TCA. Compared to earlier antidepressants, mirtazapine has been found to be significantly superior to trazodone, while it has been shown to be approximay equivalent in efficacy to several of the tricyclic antidepressants including amitriptyline, doxepin and clomipramine.

In general, all antidepressants, including mirtazapine, require at least a week for their therapeutic benefits on depressive and anxious symptoms to become apparent. Mirtazapine has a faster onset of antidepressant action when compared to SSRIs, with an initial reduction in affective symptoms being seen within the first week of treatment, and the maximal change in improvement occurring over the course of the first two weeks, however ingesting small doses sporadically can cause some of the same short term side effects as opiates such as minor pain relief as well as constricting of the pupils.

Its patent expired in 2004, so generic versions are available.

Mirtazapine is marketed under many brand names worldwide, including Adco-Mirteron, Afloyan, Amirel, Arintapin Smelt, Avanza, Azapin, Beron, Bilanz, Calixta, Ciblex, Combar, Comenter, Depreram, Divaril, Esprital, Maz, Menelat, Mepirzapine, Merdaten, Meronin, Mi Er Ning, Milivin, Minelza, Minivane, Mirastad, Mirazep, Miro, Miron, Mirrador, Mirt, Mirta, Mirtabene, Mirtadepi, Mirtagamma, Mirtagen, Mirtalan, Mirtamor, Mirtamylan, Mirtan, Mirtaneo, Mirtapax, Mirtapil, Mirtapine, Mirtaron, Mirtastad, Mirtax, Mirtaz, Mirtazap, Mirtazapin, Mirtazapina, Mirtazapine, Mirtazapinum, Mirtazelon, Mirtazon, Mirtazonal, Mir, Mirtimash, Mirtin, Mirtine, Mirzapine, Mirzaten, Mirzaten, Mirzest, Mitaprex, Mitaxind, Mitocent, Mitrazin, Mizapin, Motofen, Mytra, Norset, Noxibel, Pharmataz, Promyrtil, Ramure, Redepra, Reflex, Remergil, Remergon, Remeron, Remirta, Rexer, Saxib, Sinmaron, Smilon, Tazepin, Tazimed, Tetrazic, Tifona, U-Mirtaron, U-zepine, Valdren, Vastat, Velorin, Yarocen, Zania, Zapex, Zestat, Zismirt, Zispin, Zuleptan, and Zulin.

Another case report described mirtazapine as inducing hypertension in a clonidine -treated patient, likely due to occupancy of α 2 autoreceptors by mirtazapine limiting the efficacy of concurrent clonidine therapy.

Mirtazapine was first synthesized at Organon and published in 1989, was first approved for use in major depressive disorder in the Netherlands in 1994, and was introduced in the United States in 1996 under the brand name Remeron.

Mirtazapine is not considered to have a risk of many of the side effects often associated with other antidepressants like the SSRIs, and may actually improve certain ones when taken in conjunction with them. ). (Those adverse effects include decreased appetite, weight loss, insomnia, nausea and vomiting, diarrhoea, urinary retention, increased body temperature, excessive sweating, pupil dilation and sexual dysfunction.

A 2010 study comparing 14 most common antidepressants ranked Mirtazapine as the most efficacious and cost-effective treatment for moderate to severe depression.

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

Mirtazapine, originally branded Remeron, is an atypical antidepressant with noradrenergic and specific serotonergic activity. Mirtazapine is not a serotonin or norepinephrine reuptake inhibitor but increases serotonin and norepinephrine action by other mechanisms. It also enhances serotonin neurotransmission at the 5-HT 1 receptor and blocks the histaminergic ( H 1 ). It blocks the α 2 adrenergic auto- and heteroreceptors (enhancing norepinephrine and serotonin release), and selectively antagonizes the 5-HT 2 serotonin receptors in the central and peripheral nervous system.

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

All affinities listed were assayed using human materials except those for α 1 adrenergic and mACh that are for rat tissues, due to human values being unavailable.

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.