Mirtazapine
Mirtazapine, sold under the brand name Remeron among others, is an atypical antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is often used in cases of depression complicated by anxiety or insomnia. The effectiveness of Mirtazapine is comparable to other commonly prescribed antidepressants. It is taken by mouth. Common side effects include sleepiness, dizziness, increased appetite and weight gain. Serious side effects may include mania, low white blood cell count, and increased suicide among children. Withdrawal symptoms  may occur with stopping. It is not recommended together with an MAO inhibitor, although evidence supporting the danger of this combination has been refuted. It is unclear if use during pregnancy is safe. How it works is not clear, but it may involve blocking certain adrenergic and serotonin receptors. Chemically, it is a tetracyclic antidepressant (TeCA), and is closely related to mianserin. It also has strong antihistaminergic effects. Mirtazapine came into medical use in the United States in 1996. The patent expired in 2004, and generic versions are available. In 2019, it was the 106th most commonly prescribed medication in  the United States, with more than 6million prescriptions. Medical uses. Depression. Mirtazapine is primarily used for major depressive disorder and other mood disorders. Onset of action appears faster than some selective serotonin reuptake inhibitors (SSRI) and similar to tricyclic antidepressants. In 2010, NICE recommended generic SSRIs as first line choices, as they are "equally effective as other antidepressants and have a favourable risk–benefit ratio." With respect to mirtazapine, it found: "There is no difference between mirtazapine and other antidepressants on any efficacy measure, although in terms of achieving remission mirtazapine appears to have a statistical though not clinical advantage . In addition, mirtazapine has a statistical advantage over selective serotonin reuptake inhibitors in terms of reducing symptoms of depression, but the difference is not clinically important. However, there is strong evidence that patients taking mirtazapine are less likely to leave treatment early because of side effects, although this is not the case for patients reporting side effects or leaving treatment early for any reason." A 2011 Cochrane review that compared mirtazapine to other antidepressants found that, while it appears to have a faster onset in people for whom it works (measured at two weeks), its efficacy is about the same  as other antidepressants after six weeks' use. A 2012 review focused on antidepressants and sleep found that in many people with sleep disorders caused by depression, mirtazapine reduces the time it takes to fall asleep and increases the quality of sleep, but that in some people it can disturb sleep, especially at higher doses, causing restless leg syndrome in 8 to 28% of people and in rare cases causes REM sleep behavior disorder. This seemingly paradoxical dose–response curve of mirtazapine with respect to somnolence is owed to the exceptionally high affinity of the drug for the histamine H, 5 -HT, and 5-HT receptors; exhibiting near exclusive occupation of these receptors at doses ≤15 mg. However, at higher doses, inverse antagonism and constitutive activation of the α-, α-, and α-adrenergic receptors begins to offset activity at H1 receptors leading to decreased sonomolence and even a subjective sensation of "activation" in treated patients. A 2018 analysis of 21 antidepressants found them to be fairly similar overall. It found tentative evidence for mirtazapine being in the more effective group and middle in tolerability. After one week of usage, mirtazapine was found to have an earlier onset of action compared to  SSRIs. Other. There is also some evidence supporting its use in treating the following conditions, for which it is sometimes prescribed off-label: Doses of mirtazapine used for sleep range from 7.5 to 45 mg. Doses of 7.5 to 15 mg are recommended as mirtazapine may become more stimulating at higher doses. Side effects. A 2011 Cochrane review found that compared with other antidepressants, it is more likely to cause weight gain and sleepiness, but it is less likely to cause tremor than tricyclic antidepressants, and less likely to cause nausea and sexual dysfunction than SSRIs. Very common (≥10% incidence ) adverse effects include constipation, dry mouth, sleepiness, increased appetite (17%) and weight gain (>7% increase in <50% of children). Common (1–10% incidence) adverse effects include weakness, confusion, dizziness, fasciculations, peripheral edema, and negative lab results like elevated transaminases, elevated serum triglycerides, and elevated total cholesterol. 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 selective serotonin reuptake inhibitors (SSRI), 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, especially for people under the age of 25. Mirtazapine may induce arthralgia. A case report published in 2000 noted an instance in which mirtazapine counteracted the action of clonidine, causing a dangerous rise in blood pressure. Withdrawal. Mirtazapine and  other antidepressants may cause withdrawal symptoms upon cessation. A gradual and slow reduction in dose is recommended to minimize withdrawal symptoms. Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety, tinnitus, panic attacks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhea, nausea, vomiting, flu-like symptoms, allergy-like symptoms such as pruritus, headaches, and sometimes mania or hypomania. Overdose. 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 tricyclic antidepressants, 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 tricyclic antidepressants. 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. 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. As examples, fluoxetine and paroxetine, inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while carbamazepine, an inducer, considerably decreases them. Liver impairment and moderate chronic kidney disease have been reported to decrease the oral clearance of mirtazapine by about 30%; severe kidney disease decreases it by 50%. Mirtazapine in combination with an SSRI, , 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". Several case reports document serotonin syndrome induced by the combination  of mirtazapine with other agents (olanzapine, quetiapine, tramadol and venlafaxine). 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. The addition of mirtazapine to a monoamine oxidase inhibitor (MAOI), while potentially having typical or idiosyncratic (unique to the individual) reactions not herein described, does not appear to cause serotonin syndrome. This is in accordance with the fact that the 5-HT receptor is the predominant serotonin receptor thought to be involved in the pathophysiology of serotonin  syndrome (with the 5-HT receptor seeming to be protective). Mirtazapine is a potent 5-HT receptor antagonist, and cyproheptadine, a medication that shares this property, mediates recovery from serotonin syndrome and is an antidote against it. There is a possible interaction that results in a hypertensive crisis when mirtazapine is given to a patient that has already been on steady doses of clonidine. This involves a subtle consideration, when patients have been on chronic therapy with clonidine and suddenly stop the dosing, a rapid hypertensive rebound sometimes (20%) occurs from increased sympathetic outflow. Clonidine's blood pressure lowering effects  are due to stimulation of presynaptic α autoreceptors in the CNS which suppress sympathetic outflow. Mirtazapine itself blocks these same α autoreceptors, so the effect of adding mirtazapine to a patient stabilized on clonidine may precipitate withdrawal symptoms. Pharmacology. Pharmacodynamics. Mirtazapine is sometimes described as a noradrenergic and specific serotonergic antidepressant (NaSSA), although the actual evidence in support of this label has been regarded as poor. It is a tetracyclic piperazine-azepine. Mirtazapine has antihistamine, α-blocker, and antiserotonergic activity. It is specifically a potent antagonist or inverse agonist of the α-, α-, and α-adrenergic receptors, the serotonin 5 -HT, 5-HT, and the histamine H receptor. Unlike many other antidepressants, it does not inhibit the reuptake of serotonin, norepinephrine, or dopamine, nor does it inhibit monoamine oxidase. Similarly, mirtazapine has weak or no activity as an anticholinergic or blocker of sodium or calcium channels, in contrast to most TCAs. In accordance, it has better tolerability and low toxicity in overdose. As an H receptor antagonist, mirtazapine is extremely potent, and is in fact the most potent of all the TCAs and TeCAs. Antagonism of the H receptor is by far the strongest activity of mirtazapine, with the drug  acting as a selective H receptor antagonist at low concentrations. The ("S")-(+) enantiomer of mirtazapine is responsible for antagonism of the serotonin 5-HT and 5-HT receptors, while the ("R")-(–) enantiomer is responsible for antagonism of the 5-HT receptor. Both enantiomers are involved in antagonism of the H and α-adrenergic receptors, although the ("S")-(+) enantiomer is the stronger antihistamine. Although not clinically relevant, mirtazapine has been found to act as a partial agonist of the κ-opioid receptor at high concentrations (EC = 7.2 μM). α-Adrenergic receptor. Antagonism of the α-adrenergic receptors, which function largely  as inhibitory autoreceptors and heteroreceptors, enhances adrenergic and serotonergic neurotransmission, notably central 5-HT receptor mediated transmission in the dorsal raphe nucleus and hippocampus; hence, mirtazapine's classification as a NaSSA. Indirect α adrenoceptor-mediated enhancement of serotonin cell firing and direct blockade of inhibitory α heteroreceptors located on serotonin terminals are held responsible for the increase in extracellular serotonin. Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT receptor. Increased activation of the central 5-HT receptor is thought to be a major mediator of efficacy of most antidepressant drugs. 5 -HT receptor. Antagonism of the 5-HT subfamily of receptors and inverse agonism of the 5-HT receptor appears to be in part responsible for mirtazapine's efficacy in the treatment of depressive states. Mirtazapine increases dopamine release in the prefrontal cortex. Accordingly, it was shown that by blocking the α-adrenergic receptors and 5-HT receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats. In addition, mirtazapine's antagonism of 5-HT receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor. Mirtazapine has been shown to lower  drug seeking behaviour(more specifically to methamfetamine) in various human and animal studies. It is also being investigated in substance abuse disorders to reduce withdrawal effects and improve remission rates. Mirtazapine 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. 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 selective serotonin reuptake inhibitors (SSRI), serotonin–norepinephrine reuptake inhibitors (SNRI), Monoamine oxidase inhibitors (MAOI), and some  Tricyclic antidepressants (TCA) increase the general activity of the 5-HT, 5-HT, and 5-HT 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, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect. Mirtazapine does not have pro-serotonergic activity and thus does not cause serotonin syndrome. This is in accordance with the fact that it is not a serotonin reuptake inhibitor or  monoamine oxidase inhibitor (MAOI), nor a serotonin receptor agonist. There are no reports of serotonin syndrome in association with mirtazapine alone, and mirtazapine has not been found to cause serotonin syndrome in overdose. However, there are a handful of case reports of serotonin syndrome occurring with mirtazapine in combination with serotonergic drugs like SSRIs, although such reports are very rare, and do not necessarily implicate mirtazapine as causative. 5-HT receptor. It is a potent 5-HT blocker. It may relieve chemotherapy-related and advanced cancer-related nausea. H receptor. Mirtazapine is a very strong H receptor inverse agonist and , as a result, it can cause powerful sedative and hypnotic effects. A single 15 mg dose of mirtazapine to healthy volunteers has been found to result in over 80% occupancy of the H receptor and to induce intense sleepiness. After a short period of chronic treatment, however, the H 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 H 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 H receptor, mirtazapine has only low affinity for the muscarinic acetylcholine receptors, although anticholinergic side effects like dry mouth, constipation, and mydriasis are still sometimes seen in clinical practice. Pharmacokinetics. The oral bioavailability of mirtazapine is about 50%. It is found mostly bound to plasma proteins, about 85%. It is metabolized primarily in the liver by demethylation and hydroxylation via cytochrome P450 enzymes, CYP1A2, CYP2D6, CYP3A4. One of its major metabolites is desmethylmirtazapine. The overall elimination half-life is 20–40 hours. It is conjugated in the kidney for excretion  in the urine, where 75% of the drug is excreted, and about 15% is eliminated in feces. Chemistry. Mirtazapine is a tetracyclic piperazinoazepine; mianserin was developed by the same team of organic chemists and mirtazapine differs from it via addition of a nitrogen atom in one of the rings. It is a racemic mixture of enantiomers. The ("S")-(+)-enantiomer is known as esmirtazapine. Analogues of mirtazapine include mianserin, setiptiline, and aptazapine. Synthesis. A chemical synthesis of mirtazapine has been published. The first step of synthesis is a condensation reaction between the molecule 2-chloro 3-cyanopyridine and the molecule 1-methyl-3 -phenylpiperazine. History. 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. Society and culture. Generic names. "Mirtazapine" is the English and French generic name of the drug and its , , , , , and . Its generic name in Spanish and in Portuguese is "mirtazapina" and in German and Swedish is "Mirtazapin". Brand names. Mirtazapine is marketed under many brand names worldwide, including Adco-Mirteron, Afloyan, Amirel, Arintapin Smelt, Avanza, Axit, 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, Mirzest, Mitaprex, Mitaxind, Mitocent, Mitrazin, Mizapin, Motofen, Mytra, Norset, Noxibel, Pharmataz, Promyrtil, Rapizapine, Ramure, Razapina, 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. Research. The  use of mirtazapine has been explored in several additional conditions: Veterinary use. Mirtazapine also has some veterinary use in cats and dogs. Mirtazapine is sometimes prescribed as an appetite stimulant for cats or dogs experiencing loss of appetite due to medical conditions such as chronic kidney disease. It is especially useful for treating combined poor appetite and nausea in cats and dogs. Mirtazapine is indicated for bodyweight gain in cats experiencing poor appetite and weight loss resulting from chronic medical conditions. There are two options for administration: tablets given orally, and an ointment applied topically to the inner surface of  the ear. The most common side effects include signs of local irritation or inflammation at the site where the ointment is applied and behavioural changes (increased meowing, hyperactivity, disoriented state or inability to co-ordinate muscle movements, lack of energy/weakness, attention-seeking, and aggression).