mirtazapine mirtazapine mirtazapine, sold under the brand name remeron amongst others, is an atypical tetracyclic 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. mirtazapineclinical datatrade namesremeron, mirataz, avanza, othersother namesmepirzapine; 6-azamianserin; org-3770ahfs/drugs.commonographmedlineplusa697009license data us dailymed: mirtazapine us fda: mirtazapine pregnancycategory au: b3 routes ofadministrationby mouth (tablets), topicaldrug classnassaatc coden06ax11 (who) legal statuslegal status au: s4 (prescription only) ca: ℞-only uk: pom (prescription only) us: ℞-only eu: rx-only pharmacokinetic databioavailability50%protein binding85%metabolismliver (cyp1a2, cyp2d6, cyp3a4)metabolitesdesmethylmirtazapine (contributes 3–10% of activity)elimination half-life20–40 hoursexcretionurine: 75%feces: 15%identifiers iupac name (±)-5-methyl-2,5,19-triazatetracyclononadeca-1(15),8,10,12,16,18-hexaene cas number85650-52-8 ypubchem cid4205iuphar/bps7241drugbankdb00370 ychemspider4060 yuniia051q2099qkeggd00563 ychebichebi:6950 ychemblchembl654 ycomptox dashboard (epa)dtxsid0023325 echa infocard100.080.027 chemical and physical dataformulac17h19n3molar mass265.360 g·mol−13d model (jsmol)interactive imagechiralityracemic mixturedensity1.22 g/cm3melting point114 to 116 °c (237 to 241 °f)boiling point432 °c (810 °f)solubility in watersoluble in methanol and chloroform mg/ml (20 °c) smiles n1cccc3c1n4c(c2ccccc2c3)cn(c)cc4 inchi 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 ykey:ronzaemnmfqxra-uhfffaoysa-n y (verify) 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 a monoamine oxidase inhibitor, although evidence supporting the danger of this combination has been challenged. 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, 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 2020, it was the 104th most commonly prescribed medication in the united states with more than 6 million prescriptions. medical uses mirtazapine is approved by the united states food and drug administration for the treatment of major depressive disorder in adults. depression mirtazapine is primarily used for major depressive disorder and other mood disorders. onset of action appears faster than some selective serotonin reuptake inhibitors and similar to tricyclic antidepressants. in 2010, the national institute for health and care excellence recommended generic selective serotonin reuptake inhibitors 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 significant. 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 h1, 5-ht2a, and 5-ht2c receptors; exhibiting near exclusive occupation of these receptors at doses ≤15 mg. however, at higher doses, inverse antagonism and constitutive activation of the α2a-, α2b-, and α2c-adrenergic receptors begins to offset activity at h1 receptors leading to decreased somnolence 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 selective serotonin reuptake inhibitors. other there is also some evidence supporting its use in treating the following conditions, for which it is sometimes prescribed off-label: generalized anxiety disorder social anxiety disorder obsessive–compulsive disorder panic disorder post-traumatic stress disorder low appetite/underweight insomnia nausea and vomiting itching headaches and migraine 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 selective serotonin reuptake inhibitors. 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 (muscle twitches), peripheral edema (swelling, usually of the lower limbs), 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 selective serotonin reuptake inhibitors, and may actually improve certain ones when taken in conjunction with them. (those adverse effects include decreased appetite, weight loss, insomnia, nausea and vomiting, diarrhea, urinary retention, increased body temperature, excessive sweating, pupil dilation and sexual dysfunction.) in general, some antidepressants, especially selective serotonin reuptake inhibitors, 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 (non-inflammatory joint pain) a case report published in 2000 noted an instance in which mirtazapine counteracted the action of clonidine, causing a dangerous rise in blood pressure. in a study comparing 32 antidepressants of all pharmacological classes, mirtazapine was one of the antidepressants most likely to cause nightmare disorder, sleepwalking, restless legs syndrome, night terrors and sleep paralysis. mirtazapine has been associated with an increased risk of death compared to other antidepressants in several studies. however, it is more likely that the residual differences between people prescribed mirtazapine rather than a selective serotonin reuptake inhibitor account for the difference in risk of mortality. 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 selective serotonin reuptake inhibitors (except citalopram). unlike the tricyclic antidepressants, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose. 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 selective serotonin reuptake inhibitors. interactions concurrent use with inhibitors or inducers of the cytochrome 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 a selective serotonin reuptake inhibitor, serotonin–norepinephrine reuptake inhibitor, or tricyclic antidepressant as an augmentation strategy is considered to be relatively safe and is often employed therapeutically but caution should be given when combined with fluvoxamine. there is 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). adding fluvoxamine to treatment with mirtazapine may cause a significant increase in mirtazapine concentration. this interaction may necessitate adjustment of the mirtazapine dosage. according to information from the manufacturers, mirtazapine should not be started within two weeks of any monoamine oxidase inhibitor usage; likewise, monoamine oxidase inhibitors should not be administered within two weeks of discontinuing mirtazapine. the addition of mirtazapine to a monoamine oxidase inhibitor, 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-ht2a receptor is the predominant serotonin receptor thought to be involved in the pathophysiology of serotonin syndrome (with the 5-ht1a receptor seeming to be protective). mirtazapine is a potent 5-ht2a 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 α2 autoreceptors in the cns which suppress sympathetic outflow. mirtazapine itself blocks these same α2 autoreceptors, so the effect of adding mirtazapine to a patient stabilized on clonidine may precipitate withdrawal symptoms. pharmacology pharmacodynamics