Mirtazapine

Mirtazapine, sold under the brand name Remeron among others, is an atypical tetracyclic antidepressant, and as such is used primarily to treat depression.<ref name=Ant2001/><ref name=AHSF2018>Template:Cite web</ref> Its effects may take up to four weeks but can also manifest as early as one to two weeks.<ref name=AHSF2018/><ref name=Cochrane2011/> It is often used in cases of depression complicated by anxiety or insomnia.<ref name=Ant2001/><ref name=Nut2002>Template:Cite journal</ref> The effectiveness of mirtazapine is comparable to other commonly prescribed antidepressants.<ref name=TI2021>Template:Cite web</ref> It is taken by mouth.<ref name=AHSF2018/>

Common side effects include sleepiness, dizziness, increased appetite, and weight gain.<ref name="AHSF2018" /> Serious side effects may include mania, low white blood cell count, and increased suicide among children.<ref name="AHSF2018" /> Withdrawal symptoms may occur with stopping.<ref name="BNF74">Template:Cite book</ref> It is not recommended together with a monoamine oxidase inhibitor,<ref name="AHSF2018" /> although evidence supporting the danger of this combination has been challenged.<ref name="pmid16342227" /> It is unclear if use during pregnancy is safe.<ref name="AHSF2018" /> How it works is not clear, but it may involve blocking certain adrenergic and serotonin receptors.<ref name=Ant2001/><ref name=AHSF2018/> Chemically, it is a tetracyclic antidepressant,<ref name=AHSF2018/> and is closely related to mianserin. It also has strong antihistaminergic effects.<ref name=Ant2001>Template:Cite journal</ref><ref name=AHSF2018/>

Mirtazapine came into medical use in the United States in 1996.<ref name=AHSF2018/> The patent expired in 2004, and generic versions are available.<ref name=AHSF2018/><ref>Template:Cite book</ref> In 2023, it was the 99th most commonly prescribed medication in the United States, with more than 6Template:Nbspmillion prescriptions.<ref name="Top300Drugs">Template:Cite web</ref><ref>Template:Cite web</ref> Template:TOC limit

Medical uses

Mirtazapine is approved by the United States Food and Drug Administration for the treatment of major depressive disorder in adults.<ref name=":0">Template:Cite book</ref>

Depression

Mirtazapine is primarily used for major depressive disorder and other mood disorders.<ref name="pmid10446735">Template:Cite journal</ref><ref name="pmid21644844">Template:Cite journal</ref> Onset of action appears faster than some selective serotonin reuptake inhibitors and similar to tricyclic antidepressants.<ref name=Cochrane2011/><ref name="pmid12404667" />

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."<ref>Template:Cite book</ref> For mirtazapine, it found "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."<ref>Template:Cite book</ref>

A 2011 Cochrane review comparing mirtazapine to other antidepressants found that while it appeared to have a faster onset in people for whom it worked (measured at two weeks), its efficacy was about the same as other antidepressants after six weeks' use.<ref name=Cochrane2011>Template:Cite journal</ref>

A 2012 review focused on antidepressants and sleep found that mirtazapine reduced the time it took to fall asleep and improved the quality of sleep in many people with sleep disorders caused by depression, but that it could also disturb sleep in many people, especially at higher doses, causing restless leg syndrome in 8 to 28% of people and in rare cases causes REM sleep behavior disorder.<ref>Template:Cite journal</ref> 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-HT_2A, and 5-HT_2C receptors; exhibiting near exclusive occupation of these receptors at doses ≤15 mg. However, at higher doses, inverse agonism and constitutive activation of the α_2A-, α_2B-, and α_2C-adrenergic receptors begins to offset activity at H₁ receptors leading to decreased somnolence and even a subjective sensation of "activation" in treated patients.<ref>Template:Cite journal</ref>

A 2018 analysis of 21 antidepressants found them to be fairly similar overall.<ref name=Cip2018/> It found tentative evidence for mirtazapine being in the more effective group and middle in tolerability.<ref name=Cip2018>Template:Cite journal</ref>

After one week of usage, mirtazapine was found to have an earlier onset of action compared to selective serotonin reuptake inhibitors.<ref name="pmid12404667">Template:Cite journal</ref><ref name="Maudsley">Template:Cite book </ref>

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<ref name=Ant2001 /><ref name="pmid10453798">Template:Cite journal</ref><ref>Template:Cite journal</ref>
• Social anxiety disorder<ref name="pmid19453203">Template:Cite journal</ref>
• Obsessive–compulsive disorder<ref name="pmid19453203" />
• Panic disorder<ref name="pmid19453203" />
• Post-traumatic stress disorder<ref name="pmid19453203" />
• Low appetite/underweight<ref name="pmid12647431">Template:Cite journal</ref><ref name="pmid18001374">Template:Cite journal</ref><ref name="pmid12647979">Template:Cite journal</ref>
• Insomnia<ref name="Clark_2011">Template:Cite journal</ref><ref>Template:Cite journal</ref>
• Nausea and vomiting<ref name=Nut2002 /><ref name="pmid21602639">Template:Cite journal</ref><ref name="pmid17587360">Template:Cite journal</ref>
• Itching<ref name="pmid12509645">Template:Cite journal</ref><ref name="pmid16297004">Template:Cite journal</ref>
• Headaches and migraine<ref name="pmid21602639" /><ref name="pmid15549531">Template:Cite journal</ref><ref name="pmid17073214">Template:Cite journal</ref>

Adverse 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 tremors than tricyclic antidepressants, and less likely to cause nausea and sexual dysfunction than selective serotonin reuptake inhibitors.<ref name=Cochrane2011/>

Very common (≥10% incidence) adverse effects include constipation, dry mouth, sleepiness, increased appetite (17%) and weight gain (>7% increase in <50% of children).<ref name = "Remeron FDA label" /><ref name = AXIT>Template:Cite web</ref><ref name = EMC>Template:Cite web</ref><ref name = MS>Template:Cite web</ref><ref name = "AMH">Template:Cite web</ref><ref name = "BNF">Template:Cite book</ref><ref>Template:Cite web</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name = EMC/>

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 improve certain ones when taken in conjunction with them.<ref name=Ant2001/><ref name="pmid10333982"/> (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.<ref name=Ant2001/><ref name="pmid10333982"/>)

In general, some antidepressants, especially selective serotonin reuptake inhibitors, can paradoxically exacerbate some peoples' depression or anxiety or cause suicidal ideation.<ref name="pmid17143567">Template:Cite journal</ref> 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.<ref name="AHSF2018" />

Mirtazapine may induce arthralgia (non-inflammatory joint pain).<ref name=mirtaartha>Template:Cite journal</ref>

A case report published in 2000 noted an instance in which mirtazapine counteracted the action of clonidine, causing a dangerous rise in blood pressure.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

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.<ref name="pmid35105363">Template:Cite journal</ref>

Withdrawal

Stopping Mirtazapine and other antidepressants may cause withdrawal symptoms.<ref name="Ant2001" /><ref name="pmid11444761">Template:Cite journal</ref> A gradual and slow reduction in dose is recommended to minimize such symptoms.<ref name="pmid15819135">Template:Cite journal</ref> 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.<ref name="pmid10986577">Template:Cite journal</ref><ref name="pmid10789310">Template:Cite journal</ref><ref name="pmid12776393">Template:Cite journal</ref>

Overdose

Mirtazapine is considered to be relatively safe in the event of an overdose,<ref name="Maudsley"/> although it is considered slightly more toxic in overdose than most of the selective serotonin reuptake inhibitors (except citalopram).<ref>Template:Cite journal</ref> Unlike the tricyclic antidepressants, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose.<ref name="pmid10333982"/>

Twelve reported fatalities have been attributed to mirtazapine overdose.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref> The fatal toxicity index (deaths per million prescriptions) for mirtazapine is 3.1 (95% CI: 0.1 to 17.2).<ref name=":0" /> This is similar to that observed with selective serotonin reuptake inhibitors.<ref name="bmj325">Template:Cite journal</ref>Template:Unreliable medical source

Interactions

Concurrent use with inhibitors or inducers of the cytochrome P450 isoenzymes CYP1A2, CYP2D6, or CYP3A4 can result in altered concentrations of mirtazapine, as these are the main enzymes responsible for its metabolism.<ref name="pmid10885584"/><ref name=Ant2001 /> As examples, fluoxetine and paroxetine, inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while carbamazepine, an inducer, considerably decreases them.<ref name="pmid10885584" /> 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%.<ref name="pmid10885584" />

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".<ref name="isbn0-521-74609-4">Template:Cite book</ref><ref>Template:Cite journal</ref> Several case reports document serotonin syndrome induced by the combination of mirtazapine with other agents (olanzapine,<ref>Template:Cite journal</ref> quetiapine,<ref>Template:Cite journal</ref> tramadol and venlafaxine<ref>Template:Cite journal</ref>). Adding fluvoxamine to treatment with mirtazapine may cause a significant increase in mirtazapine concentration. This interaction may necessitate an adjustment of the mirtazapine dosage.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref>

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.<ref name="AHSF2018" />

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.<ref name="pmid16460699" /> This is per the fact that the 5-HT_2A receptor is the predominant serotonin receptor thought to be involved in the pathophysiology of serotonin syndrome (with the 5-HT_1A receptor seeming to be protective).<ref name="pmid16460699" /><ref name="pmid16342227" /> Mirtazapine is a potent 5-HT_2A receptor antagonist, and cyproheptadine, a medication that shares this property, mediates recovery from serotonin syndrome and is an antidote against it.<ref name="pmid16342227" /><ref name="pmid23145389">Template:Cite journal</ref>

There is a possible interaction that results in a hypertensive crisis when mirtazapine is given to a patient who 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.<ref>Template:Cite web</ref>

Mirtazapine has been used as a hallucinogen antidote to block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).<ref name="YatesMelon2024">Template:Cite journal</ref><ref name="Suran2024">Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

Mirtazapine<ref name="PDSP">Template:Cite web</ref>

	Ki (nM)	Species	Ref
Template:Abbrlink	10000+	Human	<ref name="pmid9537821">Template:Cite journal</ref><ref name="pmid16517171" />
Template:Abbrlink	4600+	Human	<ref name="pmid17471183" /><ref name="pmid9537821" />
Template:Abbrlink	10000+	Human	<ref name="pmid9537821" /><ref name="pmid16517171" />
5-HT1A	3330–5010	Human	<ref name=Ant2001 /><ref name="pmid16517171" />
5-HT1B	3534–12600	Human	<ref name=Ant2001 /><ref name="pmid16517171" />
5-HT1D	794–5010	Human	<ref name=Ant2001 /><ref name="pmid16517171" />
5-HT1E	728	Human	<ref name="pmid16517171" />
5-HT1F	583	Human	<ref name="pmid16517171" />
5-HT2A	6.3–69	Human	<ref name=Ant2001 /><ref name="pmid16517171" />
5-HT2B	200	Human	<ref name=Ant2001 />
5-HT2C	8.9–39	Human	<ref name=Ant2001 /><ref name="pmid16517171" />
5-HT3	8.1 70 (Template:Abbr)	Human	<ref name="A review of the pharmacological and">Template:Cite journal</ref> <ref name=" Eisensamer" />
5-HT4L	10000+	Human	<ref name="pmid16517171" />
5-HT5A	670	Human	<ref name="pmid16517171" />
5-HT6	Template:Abbr	Template:Abbr	Template:Abbr<ref name="pmid16517171" />
5-HT7	265	Human	<ref name="pmid16517171" />
α1A	1815	Human	<ref name="pmid16517171" />
α2A	20–158	Human	<ref name="pmid16517171" /><ref name="Proudman" />
α2B	88	Human	<ref name="pmid16517171" />
α2C	18–110	Human	<ref name="pmid16517171" /><ref name="Proudman" />
β	10000+	Human	<ref name="pmid16517171" />
D1	4167	Rat
D2	5454+	Human	<ref name="pmid16517171" />
D3	5723	Human	<ref name="pmid16517171" />
D4	2518	Human	<ref name="pmid16517171" />
H1	0.14–1.6	Human	<ref name="pmid22033803">Template:Cite journal</ref><ref name=Ant2001/><ref name="pmid16517171">Template:Cite journal</ref>
H2	10000+	Rat	<ref name="pmid3419539">Template:Cite journal</ref><ref name="pmid22033803" />
H3	83200	Human	<ref name="pmid22033803" />
H4	100000+	Human	<ref name="pmid22033803" />
Template:Abbrlink	670	Human	<ref name=Ant2001 /><ref name="pmid17471183">Template:Cite journal</ref>
Template:Abbrlink	6905	Rat	<ref name="pmid16517171" />
Template:Abbrlink	10000+	Rat	<ref name="pmid16517171" />
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Mirtazapine is sometimes described as a noradrenergic and specific serotonergic antidepressant (NaSSA),<ref name=Ant2001 /> although the actual evidence in support of this label has been regarded as poor.<ref name="pmid16342227" /> It is a tetracyclic piperazine-azepine.<ref>Template:Cite web</ref>

Mirtazapine has antihistamine, α₂-blocker, and antiserotonergic activity.<ref name=Ant2001 /><ref name="pmid9090573">Template:Cite journal</ref> It is specifically a potent antagonist or inverse agonist of the α_2A-, α_2B-, and α_2C-adrenergic receptors,<ref name="Proudman">Template:Cite journal</ref> the serotonin 5-HT_2A, 5-HT_2C, and the histamine H₁ receptor.<ref name=Ant2001 /><ref name="pmid9090573" /> Unlike many other antidepressants, it does not inhibit the reuptake of serotonin, norepinephrine, or dopamine,<ref name=Ant2001 /><ref name="pmid9090573" /> nor does it inhibit monoamine oxidase.<ref name="pmid21200377">Template:Cite journal</ref> Similarly, mirtazapine has weak or no activity as an anticholinergic or blocker of sodium or calcium channels, in contrast to most tricyclic antidepressants.<ref name=Ant2001 /><ref name="pmid16517171" /><ref name="pmid9090573" /> In accordance, it has better tolerability and low toxicity in overdose.<ref name=Ant2001 /><ref name="pmid11357798">Template:Cite journal</ref> As an H₁ receptor antagonist, mirtazapine is extremely potent, and is in fact one of the most potent H₁ receptor inverse agonists among tricyclic and tetracyclic antidepressants and most antihistamines in general.<ref name="pmid17471183" /><ref name="BruntonChabner2011">Template:Cite book</ref><ref name="SchatzbergNemeroff2017">Template:Cite book</ref> Antagonism of the H₁ receptor is by far the strongest activity of mirtazapine, with the drug acting as a selective H₁ receptor antagonist at low concentrations.<ref name=Ant2001 /><ref name="pmid16517171" />

The (S)-(+) enantiomer of mirtazapine is responsible for antagonism of the serotonin 5-HT_2A and 5-HT_2C receptors,<ref name = MD/> while the (R)-(–) enantiomer is responsible for antagonism of the 5-HT₃ receptor.<ref name = MD>Template:Cite book</ref> Both enantiomers are involved in antagonism of the H₁ and α₂-adrenergic receptors,<ref name = AXIT/><ref name = MD/> although the (S)-(+) enantiomer is the stronger antihistamine.<ref name="pmid23728612" />

Although not clinically relevant, mirtazapine has been found to act as a partial agonist of the κ-opioid receptor at high concentrations (EC₅₀ = 7200nM).<ref name="pmid22708686">Template:Cite journal</ref>

α₂-Adrenergic receptor

Antagonism of the α₂-adrenergic receptors, which function largely as inhibitory autoreceptors and heteroreceptors, enhances adrenergic and serotonergic neurotransmission, notably central 5-HT_1A receptor mediated transmission in the dorsal raphe nucleus and hippocampus; hence, mirtazapine's classification as a NaSSA. Indirect α₁ adrenoceptor-mediated enhancement of serotonin cell firing and direct blockade of inhibitory α₂ heteroreceptors located on serotonin terminals are held responsible for the increase in extracellular serotonin.<ref name=Ant2001/><ref name="pmid10446735"/><ref name="pmid7912194">Template:Cite journal</ref>Template:Unreliable medical source<ref name="pmid9361334">Template:Cite journal</ref><ref name="pmid15145142">Template:Cite journal</ref>Template:Unreliable medical source Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT_1A receptor.<ref name="pmid9361334"/> Increased activation of the central 5-HT_1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs.<ref name="pmid11212592">Template:Cite journal</ref>

5-HT₂ receptor

Antagonism of the 5-HT₂ 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.<ref name="pmid16433010">Template:Cite journal</ref><ref name="pmid18709360">Template:Cite journal</ref> Mirtazapine increases dopamine release in the prefrontal cortex.<ref>Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation.</ref><ref name="pmid10762339"/> Accordingly, it was shown that by blocking the α₂-adrenergic receptors and 5-HT_2C receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats.<ref name="pmid10762339">Template:Cite journal</ref> 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.<ref name=Ant2001/><ref name="pmid10333982">Template:Cite journal</ref> Mirtazapine has been shown to lower drug seeking behaviour (more specifically to methamphetamine) in various human and animal studies.<ref name="Graves_2012">Template:Cite journal</ref><ref name="pmid22065532">Template:Cite journal</ref><ref name="pmid18945553">Template:Cite journal</ref> It is also being investigated in substance abuse disorders to reduce withdrawal effects and improve remission rates.<ref name="Graves_2012"/><ref name="pmid18633741">Template:Cite journal</ref><ref name="pmid22095579">Template:Cite journal</ref><ref name="pmid23617468">Template:Cite journal</ref>

Mirtazapine significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and irritable bowel syndrome in affected individuals.<ref name="pmid11585276">Template:Cite journal</ref> Mirtazapine may be used as an inexpensive antiemetic alternative to Ondansetron.<ref name="pmid17587360"/> In conjunction with substance abuse counseling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success.<ref name="pmid22065532" /><ref name="pmid18633741" /><ref name="pmid22095579" /><ref name="pmid23617468" /> In contrast to mirtazapine, the selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, and some tricyclic antidepressants acutely increase the general activity of the 5-HT_2A, 5-HT_2C, and 5-HT₃ receptors, leading to a number of negative changes and side effects, the most prominent of which include anorexia, insomnia, nausea, and diarrhea, among others. However, most of these adverse effects are temporary, since down regulation of 5-HT_2A receptors eventually occurs following chronic SSRI treatment, and desensitization of 5-HT₃ receptors often occurs within a week or less. This is precisely why SSRIs have a delayed antidepressant and anxiolytic effect, and occasionally, an acute anxiogenic effect before down regulation occurs. Mirtazapine, on the other hand, is an antagonist of the 5-HT_2A receptor, and antagonists at this receptor typically induce reverse tolerance.<ref>Template:Cite journal</ref> Thus, the antidepressant and anxiolytic effects of mirtazapine occur more rapidly than with SSRIs. Furthermore, its reduced incidence of sexual dysfunction (such as loss of libido and anorgasmia) could be a product of negligible binding to the serotonin transporter and antagonism of the 5-HT_2A receptors; however, Mirtazapine's high affinity towards and inverse agonism of the 5-HT_2C receptors may greatly attenuate those pro-sexual factors (as evidenced by the pro-sexual effects of drugs like m-CPP and lorcaserin which agonize 5-HT_2C receptors in a reasonably selective manner). As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.<ref name="pmid10333982"/><ref name="pmid15560319">Template:Cite journal</ref>

Mirtazapine does not have pro-serotonergic activity and thus does not cause serotonin syndrome.<ref name="pmid16342227">Template:Cite journal</ref><ref name="pmid16460699">Template:Cite journal</ref> This is in accordance with the fact that it is not a serotonin reuptake inhibitor or monoamine oxidase inhibitor, nor a serotonin receptor agonist.<ref name="pmid16342227" /><ref name="pmid16460699" /> There are no reports of serotonin syndrome in association with mirtazapine alone, and mirtazapine has not been found to cause serotonin syndrome in overdose.<ref name="pmid16342227" /><ref name="pmid16460699" /><ref name="pmid24228948">Template:Cite journal</ref> However, there are a handful of case reports of serotonin syndrome occurring with mirtazapine in combination with serotonergic drugs like selective serotonin reuptake inhibitors, although such reports are very rare, and do not necessarily implicate mirtazapine as causative.<ref name="pmid16342227" /><ref name="pmid19994622">Template:Cite journal</ref><ref name="pmid20430060">Template:Cite journal</ref><ref name="pmid22752315">Template:Cite journal</ref>

5-HT₃ receptor

(R)-(–)-mirtazapine is a potent 5-HT₃ blocker.<ref name="Eisensamer">Template:Cite journal</ref> It may relieve chemotherapy-related and advanced cancer-related nausea.<ref name="pmid17587360"/>

H₁ receptor

Mirtazapine is a very strong H₁ receptor antagonist and, as a result, it can cause powerful sedative and hypnotic effects.<ref name=Ant2001 /> A single 15 mg dose of mirtazapine to healthy volunteers has been found to result in over 80% occupancy of the H₁ receptor and to induce intense sleepiness.<ref name="pmid23728612">Template:Cite journal</ref> After a short period of chronic treatment, however, the H₁ receptor tends to sensitize 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 affected individuals. It may also contribute to weight gain, however. In contrast to the H₁ 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.<ref name="pmid9090576">Template:Cite journal</ref>

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 N-demethylation and hydroxylation via cytochrome P450 enzymes, CYP1A2, CYP2D6, CYP3A4.<ref>Template:Cite journal</ref><ref name="A review of the pharmacological and"/> The overall elimination half-life is 20–40 hours, and this is independent of dosage.<ref name="pmid10885584" /> It is conjugated in the kidney for excretion in the urine, where 75% of the drug is excreted,<ref>Template:Cite book</ref> and about 15% is eliminated in feces.<ref name=Schatzberg/>Template:Rp Desmethylmirtazapine is an active metabolite of mirtazapine which is believed to contribute about 3-10% to the drug's overall effects and has a half-life of about 25 hours.<ref name="pmid10885584" />

Typical steady-state serum concentrations of mirtazapine range from 33 to 56 nmol/l after five daily doses of 7.5 mg mirtazapine or 41 and 74 nmol/l after 15 mg mirtazapine.<ref>Template:Cite journal</ref>

Chemistry

Mirtazapine is a tetracyclic piperazinoazepine; mianserin was developed by the same team of organic chemists and mirtazapine differs from it via the addition of a nitrogen atom in one of the rings.<ref name=Schatzberg/>Template:Rp<ref>Template:Cite web</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref name=Schatzberg>Template:Cite book</ref>Template:Rp<ref>Template:Cite journal</ref><ref>Template:Cite web</ref>

Society and culture

File:Mirtazapine generic.png

A 15 mg tablet of generic mirtazapine

Generic names

Mirtazapine is the English and French generic name of the drug and its Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, and Template:Abbrlink.<ref name="IndexNominum2000">Template:Cite book</ref><ref name="Drugs.com">Template:Cite web</ref><ref name="MortonHall2012">Template:Cite book</ref> Its generic name in Spanish, Italian, and Portuguese is mirtazapina and in German, Turkish and Swedish is mirtazapin.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

Brand names

Mirtazapine is marketed under many brand names worldwide, including Adco-Mirteron, Afloyan, Amirel, Arintapin Smelt, Avanza, Axit, Azapin, Beron, Bilanz, Blumirtax, 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, Mirtanza, Mirtapax, Mirtapil, Mirtapine, Mirtaron, Mirtastad, Mirtax, Mirtaz, Mirtazap, Mirtazapin, Mirtazapina, Mirtazapine, Mirtazapinum, Mirtazelon, Mirtazon, Mirtazonal, Mirtel, Mirtimash, Mirtin, Mirtine, Mirtor, 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, Zapsy,Zestat, Zismirt, Zispin, Zuleptan, and Zulin.<ref name="Drugs.com" />

Music

Musician Hayley Williams wrote and released a song titled Mirtazapine describing the positive effects of the medication.<ref>Template:Cite web</ref>

Research

The use of mirtazapine has been explored in several additional conditions:

• Found ineffective for Sleep apnea/hypopnea<ref name="pmid19388881">Template:Cite journal</ref><ref name="pmid18548827">Template:Cite journal</ref>
• Secondary symptoms of autistic spectrum conditions and other pervasive developmental disorders<ref name="pmid15584771">Template:Cite journal</ref><ref name="pmid12589395">Template:Cite journal</ref>
• Antipsychotic-induced akathisia.<ref name="pmid19378382">Template:Cite journal</ref><ref name="pmid18460588">Template:Cite journal</ref>
• Drug withdrawal, dependence and detoxification<ref>Template:Cite journal</ref>
• Negative, depressive and cognitive symptoms of schizophrenia (as an adjunct)<ref>Template:Cite book</ref>
• A case report has been published in which mirtazapine reduced visual hallucinations in a patient with Parkinson's disease psychosis (PDP).<ref>Template:Cite journal</ref> This is in alignment with recent findings that inverse agonists at the 5-HT_2A 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 at doses too low to antagonize the D₂ receptor, but sufficiently high doses to inversely agonize the 5-HT_2A receptors.<ref name="Maudsley" />
• Eight case reports have been reported in five papers on the use of mirtazapine in the treatment of hives as of 2017.<ref>Template:Cite journal</ref>
• Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B). Found ineffective and potentially harmful.<ref>Template:Cite journal</ref>

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 acute post-surgical pain and medical conditions like chronic kidney disease.<ref name="Dowling_2023">Template:Cite web</ref> It is especially useful for treating combined poor appetite and nausea in cats and dogs.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Mirataz EPAR">Template:Cite web</ref><ref name="Mirataz FDA label">Template:Cite web</ref>

There are two options for administration: tablets given orally, and an ointment applied topically to the inner surface of the ear.<ref name="Mirataz EPAR" /><ref name="Mirataz FDA label" /> The most common side effects of the latter include local irritation or inflammation at the site where the ointment is applied and behavioural changes, such as increased meowing, hyperactivity, disoriented state, inability to coordinate muscle movements, lack of energy/weakness, attention-seeking, and aggression.<ref name="Mirataz EPAR" /><ref name="Mirataz FDA label" />