Mirtazapine (originally branded Remeron, many generics) is an atypical antidepressant with noradrenergic and specific serotonergic activity. It blocks the α2 adrenergic auto- and heteroreceptors (enhancing serotonin release), and selectively antagonizes the 5-HT2 serotonin receptors in the central and peripheral nervous system. It also enhances serotonin neurotransmission at the 5-HT1 receptor and blocks the histaminergic (H1) and muscarinic receptors. Mirtazapine is not a serotonin or norepinephrine reuptake inhibitor but may increase serotonin and norepinephrine by other mechanisms of action.
Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) introduced by Organon International 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. It is also racemic—occurs as a combination of both (R)-(−)- and (S)-(+)-stereoisomers, both of which are active.
Its patent expired in 2004, so generic versions are available.
- 1 Medical uses
- 2 Adverse reactions
- 3 Pharmacology
- 4 Pharmacokinetics
- 5 Chemistry
- 6 History
- 7 Brands
- 8 See also
- 9 References
- 10 Further reading
- 11 External links
Approved and off-label
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 venlafaxine) did not reach statistical significance.
However, it has also been found useful in alleviating the following conditions and may be prescribed off-label for their treatment:
- Generalized anxiety disorder
- Social anxiety disorder
- Obsessive-compulsive disorder
- Panic disorder
- Post-traumatic stress disorder
- Low appetite/underweight
- Nausea and vomiting
- Headaches and migraine
Mirtazapine has had literature published on its efficacy in the experimental treatment of these conditions:
- Sleep apnea/hypopnea
- Inappropriate sexual behaviour and other secondary symptoms of autistic spectrum conditions and other pervasive developmental disorders
- Antipsychotic-induced akathisia.
- Drug withdrawal, dependence and detoxification
- Negative, depressive and cognitive symptoms of schizophrenia (as an adjunct)
- A case report has been published in which mirtazapine reduced visual hallucinations in a patient with Parkinson's disease psychosis (PDP). This is in alignment with recent findings that inverse agonists at the 5-HT2A receptors are efficacious in 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-HT2A receptors.
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.
Efficacy and tolerability
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.
Compared to earlier antidepressants, mirtazapine has been found to be significantly superior to trazodone, while it has been shown to be approximately equivalent in efficacy to several of the tricyclic antidepressants including amitriptyline, doxepin and clomipramine. However, two other studies found mirtazapine to be significantly inferior to imipramine, another TCA.
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.
- Very common (≥10% incidence) adverse effects
- Weight gain (≥7% weight gain, in 8% of adult trial participants)
- Common (1%≤ incidence <10%) adverse effects
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.)
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.
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.
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). Unlike the TCAs, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose. Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to TCAs.
Twelve reported fatalities have been attributed to mirtazapine overdose. 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.
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.
According to information from the manufacturers, mirtazapine should not be started within two weeks of any MAOI usage; likewise, MAOIs should not be administered within two weeks of discontinuing mirtazapine. However, a single study regarding the combination reported it does not result in any incidence of serotonin-related toxicity. In addition, a case report claimed that mirtazapine can actually be used to treat serotonin syndrome. Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is considered to be relatively safe and is often employed therapeutically, with a combination of venlafaxine and mirtazapine sometimes referred to as “California rocket fuel”.
Another case report described mirtazapine as inducing hypertension in a clonidine-treated patient, likely due to occupancy of α2 autoreceptors by mirtazapine limiting the efficacy of concurrent clonidine therapy.
|Molecular target||Binding affinity, Ki (nM)||Notes|
|5-HT2A receptor||69||The (S)-(+)-enantiomer is responsible for this antagonism.|
|5-HT2B receptor||?||~20-fold lower than for 5-HT2A/5-HT2C|
|5-HT2C receptor||39||Inverse agonist The (S)-(+)-enantiomer is responsible for this action.|
|5-HT3 receptor||?||Similar to 5-HT2A/5-HT2C (mouse neuroblastoma cell) (R)-(–)-enantiomer antagonises the 5-HT3 receptor.|
|α1 adrenergic receptor||500|||
|α2A adrenergic receptor||20||The (S)-(+)-enantiomer is responsible for this antagonism at autoreceptors. Heteroreceptors are blocked by both the (S)-(+)- and (R)-(–)-enantiomers.|
|α2C adrenergic receptor||18||The (S)-(+)-enantiomer is responsible for this antagonism at autoreceptors. Heteroreceptors are blocked by both the (S)-(+)- and (R)-(–)-enantiomers.|
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. Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT1A receptor. Increased activation of the central 5-HT1A 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.
Antagonism of the 5-HT2 subfamily of receptors and inverse agonism of the 5-HT2C receptor appears to be in part responsible for mirtazapine's efficacy in the treatment of depressive states. The 5-HT2C receptor is known to inhibit the release of the neurotransmitters dopamine and norepinephrine in various parts of the brains of rodents, notably in reward pathways such as the ventral tegmental area. Accordingly, it was shown that by blocking the α2 adrenergic receptors and 5-HT2C receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats. In addition, mirtazapine's antagonism of 5-HT2A receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor. The newest research however has shown that mirtazapine is actually an inverse agonist of the 5-HT2C receptor. 5-HT2C inverse agonists have been shown to inhibit mesoaccumbens dopamine outflow attenuating the rewarding properties of various substances like morphine. This inhibition of dopamine may be stronger than thought as substances with 5-HT2C inverse agonist properties may have more activity to regulate dopamine neurotransmission than ones with competitive antagonism. With its newly understood properties of 5-HT2C inverse agonism, it is being investigated and shown to lower drug seeking behaviour, conditioned place preference and the rewarding effects of substances such as methamphetamine in various human and animal studies. It is also being investigated to help in substance abuse disorders with withdrawal effects and remission rates. but some studies have shown mixed benefit.
Antagonism of the 5-HT3 receptor, an action mirtazapine shares with the approved antiemetic ondansetron, significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and irritable bowel syndrome in afflicted individuals. Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron. Blockade of the 5-HT3 receptors has also shown to improve anxiety and to be effective in the treatment of drug addiction in several studies. In conjunction with substance abuse counseling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success. In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors leading to a host of negative changes and side effects, the most prominent of which including anorexia, insomnia, sexual dysfunction (loss of libido and anorgasmia), nausea, and 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.
Mirtazapine is a very strong H1 receptor inverse agonist and, as a result, it can cause powerful sedative and hypnotic effects. After a short period of chronic treatment, however, the H1 receptor tends to desensitize and the antihistamine effects become more tolerable. Many patients may also dose at night to avoid the effects, and this appears to be an effective strategy for combating them. Blockade of the H1 receptor may improve pre-existing allergies, pruritus, nausea, and insomnia in afflicted individuals. It may also contribute to weight gain, however. In contrast to the H1 receptor, mirtazapine has very low affinity for the mACh receptors, although anticholinergic side effects like dry mouth, constipation, and mydriasis are still commonly seen in clinical practise.
Like many other antidepressants, mirtazapine has been found to have antinociceptive properties in mice. However, unlike most other antidepressants, though similarly to venlafaxine, these effects are mostly mediated through downstream modulation of the endogenous opioid system, of which in the case of mirtazapine the μ opioid and κ3 opioid receptors are mainly involved. Interestingly, while virtually all antidepressants differ little in their maximal effectiveness in the treatment of major depression, mirtazapine and venlafaxine have demonstrated superior efficacy in treating severe types of depression such as psychotic depression and treatment-resistant depression. 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.
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.
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 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, Mirtel, 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.
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