Mirtazapine (Remeron, Avanza, Zispin) is a tetracyclic antidepressant (TeCA) use

d primarily in the treatment of depression. It is also sometimes used as a hypno

tic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among
other indications. Along with its close analogues mianserin and setiptiline, mi
rtazapine is one of the few noradrenergic and specific serotonergic antidepressa
nts (NaSSAs).
Esmirtazapine, the (S)-(+)-enantiomer of mirtazapine, is currently under develop
ment for the treatment of insomnia and menopausal symptoms by the same company t
hat produced mirtazapine.[2]
Contents [hide]
1 Medical uses
1.1 Efficacy and tolerability
2 Adverse effects
2.1 Discontinuation
2.2 Interactions
2.3 Overdose
3 Pharmacology
3.1 Pharmacodynamics
3.2 Pharmacokinetics
4 Chemistry
5 History
6 Research
7 References
8 Further reading
9 External links
[edit]Medical uses
Mirtazapine's primary use is the treatment of major depressive disorder.[3] Mirt
azapine has been found to be useful in the treatment of generalized anxiety diso
rder,[4] social anxiety disorder,[5] obsessive-compulsive disorder,[6] panic dis
order,[7][8][9] post-traumatic stress disorder,[10][11] seasonal affective disor
der,[12] insomnia,[13][14][15] nausea and vomiting,[14][16][17][18][19][20][21]
diminished appetite and associated weight loss,[20][22][23] and itching[24][25][
26][27] as well, and it may be prescribed off-label for these conditions. There
are some reports which indicate that mirtazapine can be useful in the treatment
of acute manic episodes. This is due to its antagonism at the 5-HT2A receptors.[
citation needed]
[edit]Efficacy and tolerability
Mirtazapine has been found to be one of the most effective antidepressants avail
able and has a generally tolerable side effect profile. In a major systematic re
view published in 2009 which compared the efficacy and tolerability of 12 popula
r antidepressants, mirtazapine was found to be superior to all of the included S
SRIs and SNRIs, reboxetine, bupropion, and mianserin in terms of antidepressant
efficacy, while it was average in regards to tolerability.[28][29][30] Mirtazapi
ne has been demonstrated to be superior to trazodone as well.[31] Mirtazapine ha
s also been shown to be equal in efficacy to many of the TCAs, including amitrip
tyline, doxepin, and clomipramine, but with a much improved tolerability profile
.[28][32] However, two other studies found mirtazapine inferior to the TCA imipr
amine.[33][34] One study compared the combination of venlafaxine and mirtazapine
versus the MAOI tranylcypromine and found them to be equally effective, though
the MAOI was much less tolerable in terms of side effects and drug interactions.
[35]
[edit]Adverse effects
Common side effects of mirtazapine: dizziness, impaired cognition, disinhibition
, blurred vision, eye fatigue, worsening of existing eye floaters, photosensitiv
ity, photodermatitis, sedation, somnolence, depersonalization, malaise/lassitude
, increased appetite and subsequent weight gain,[36] dry mouth, constipation, an
d vivid, bizarre, lucid dreams or nightmares.[citation needed], joint pain (arth
ralgia), muscle pain (myalgia) and back pain[citation needed].
Rarer side effects: agitation/restlessness, irritability, aggression, hypomania,
apathy and/or anhedonia (i.e., inability to experience pleasurable emotions), l
oss of interest in previously enjoyed activities, excessive mellowness or calmne
ss, difficulty swallowing, shallow breathing, decreased body temperature, miosis
, nocturnal emissions, spontaneous orgasm, loss of balance, and restless legs sy
ndrome. Though used as an appetite stimulant, long-term use of mirtazapine has b
een found to suppress appetite.[citation needed] This is probably due to the los
s of efficacy of the drug over time, as tolerance develops with long-term use. [
28][37][38][39] Mirtazapine has also occasionally been reported to cause mild ha
llucinogenic effects in some patients, including mental imagery, auditory and vi
sual hallucinations.For the majority of patients, most of these side effects are
generally mild and become less prominent over time.[28].
Very rare, potentially serious adverse reactions may include allergic reaction,
edema, fainting, seizures, delirium, hepatotoxicity, bone marrow suppression, my
elodysplasia,[39] and agranulocytosis (occurs in 1/1,000 patients)[citation need
ed].
Mirtazapine has a lower risk to cause many of the side effects encountered with
other antidepressants, such as decreased appetite, insomnia, nausea and vomiting
, diarrhea, urinary retention, increased body temperature, increased perspiratio
n/sweating, mydriasis, and sexual dysfunction (consisting of loss of libido and
anorgasmia).[28][32]
In general, some antidepressants may have the capacity to exacerbate some patien
ts' depression or anxiety or cause suicidal ideation, particularly early in the
treatment. It has been proven that mirtazapine has a faster onset of antidepress
ant action compared to SSRIs.[40]
[edit]Discontinuation
Mirtazapine and other antidepressants may cause a withdrawal syndrome upon disco
ntinuation.[28][41][42][43] It should be noted that withdrawal effects from most
psychoactive drugs (such as antidepressants) are common; but may be less severe
than seen with some benzodiazepines.[44] A gradual and slow reduction in dose i
s recommended in order to minimize withdrawal symptoms.[45] Effects of sudden ce
ssation of treatment with mirtazapine may include depression, anxiety, panic att
acks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhe
a, nausea and vomiting, flu-like symptoms such as allergies and pruritus, headac
he, and sometimes hypomania/mania.[41][42][46][47][48]
[edit]Interactions
The potential for dangerous drug interactions with mirtazapine is considered to
be very low, if not completely negligible. As a serotonin receptor antagonist, m
irtazapine will not cause serotonin syndrome at any dose, nor is it capable of c
ausing tyramine-induced hypertensive crisis, unlike the SSRIs and MAOIs, respect
ively. In fact, mirtazapine can actually be used to treat serotonin syndrome.[49
] However, mirtazapine is said to be an indirect agonist of the 5-HT1A receptor,
which can contribute to serotonin syndrome when combined with other serotonergi
c drugs.[50]
Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strateg
y is safe and is often used therapeutically.[32][35][51][52][53] Mirtazapine and
MAOIs are said to be contraindicated by some sources; however, there is no true
indication that this is actually the case, and there is no proper literature on
the subject warning against the combination whatsoever. Only a single study has
mentioned anything significantly important regarding the combination, and they
reported that it does not result in any incidence of serotonin-related toxicity.
[54] However, mirtazapine has been associated with inducing hypertension in clon
idine-treated patients.[55]
[edit]Overdose
Mirtazapine is relatively safe if an overdose is taken.[56] Unlike the TCAs, mir
tazapine shows no significant cardiovascular adverse effects at 7 to 22 times th
e maximum recommended dose.[32] Overdose with as much as 30 to 50 times the stan
dard dose has shown to be relatively non-toxic.[57][58]
12 fatalities have been attributed to mirtazapine overdose in literature.[59][60
] However, the fatal toxicity index (FTI: deaths per million prescriptions) for
mirtazapine is only 3.1 (95% CI: 0.1 to 17.2). This is similar to that observed
with SSRIs.[61]
[edit]Pharmacology
[edit]Pharmacodynamics
Mirtazapine is an antagonist/inverse agonist at the following receptors:[62][63]
5-HT2A receptor (Ki = 69 nM)
5-HT2B receptor (Ki = ? (~20-fold lower than for 5-HT2A/2C))[64]
5-HT2C receptor (Ki = 39 nM)
5-HT3 receptor (Ki = ? (similar to 5-HT2A/2C))[65]
5-HT7 receptor (Ki = 265 nM)
?1-adrenergic receptor (Ki = 608 nM)
?2A-adrenergic receptor (Ki = 20 nM)
?2C-adrenergic receptor (Ki = 18 nM)
H1 receptor (Ki = 1.6 nM)
mACh receptors (Ki = 794 nM)
As well as an inhibitor of the following transporters:
Norepinephrine transporter (Ki = 4,600 nM)
All affinities listed were assayed using human materials except those for ?1-adr
energic and mACh which are for rat tissues, due to human values being unavailabl
e.[62][63] Though not known to have ever been screened, mirtazapine may act on t
he 5-HT6 and ?2B-adrenergic receptors as well. Notably, mianserin (which is 6-de
sazamirtazapine) has been shown to have high affinity for 5-HT6 and does not pro
duce cAMP accumulation (indicating it is an antagonist).[66]
Antagonization of the ?2-adrenergic receptors which function largely as autorece
ptors and heteroreceptors enhances adrenergic and serotonergic neurotransmission
, notably central 5-HT1A receptor-mediated transmission in the dorsal raphe nucl
eus and hippocampus. Indirect ?1-adrenoceptor-mediated enhancement of 5-HT cell
firing and direct blockade of inhibitory ?2-heteroreceptors located on 5-HT term
inals are held responsible for the increase in extracellular 5-HT.[3][28][67][68
][69] Because of this, mirtazapine has been said to be a functional "indirect ag
onist" of the 5-HT1A receptor.[68] Increased activation of the central 5-HT1A re
ceptor is thought to be a major mediator of efficacy of most antidepressant drug
s.[70] Unlike most conventional antidepressants, however, mirtazapine is not a r
euptake inhibitor and has no appreciable affinity for the serotonin, norepinephr
ine, or dopamine transporters, nor is it an MAOI or have any efficacy at inhibit
ing/inducing any other enzyme for that matter.
More recent findings suggest that mirtazapine also possesses a second antidepres
sant property, which is likely to be just as important as its actions at the ?2-
adrenergic receptor in mitigating depression, mirtazapine's secondary antidepres
sant properties are likely to be mediated by its blockade of serotonin receptors
, notably 5-HT2C.[71][72][73][73] The 5-HT2C receptor normally works to inhibit
the release of the neurotransmitters dopamine and norepinephrine in various part
s of the brain, notably in the pleasure centers such as the ventral tegmental ar
ea (VTA).[74][75] By blocking it, mirtazapine disinhibits dopamine and norepinep
hrine activity in these areas, causing a pronounced antidepressant and anxiolyti
c response.[76] Indeed, the novel antidepressant agomelatine acts primarily as a
5-HT2C receptor antagonist and has antidepressant efficacy at least comparable
to that of the SSRIs and SNRIs.[77][78]
Antagonism of the 5-HT2A and 5-HT2C receptors has beneficial effects on anxiety,
sleep and appetite, as well as sexual function regarding the latter receptor.[2
8][32] Additionally, antagonism of the 5-HT3 receptor, the mechanism of action o
f antiemetic ondansetron, significantly improves pre-existing symptoms of nausea
, vomiting, diarrhea, and general irritable bowel syndrome in afflicted individu
als.[79] Mirtazapine may be used as an inexpensive antiemetic alternative to ond
ansetron.[17] 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.[80] M
irtazapine appears to enhance memory function as well and reverses scopolamine-i
nduced memory deficits in rodents,[81] effects which may be attributed to 5-HT3
antagonism.[82] In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TC
As increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors, lea
ding to a host of negative changes and side effects, the most prominent of which
include anorexia, insomnia, sexual dysfunction (impaired libido and anorgasmia)
, nausea, and diarrhea, among others. As a result, mirtazapine is often used in
conjunction with these drugs to reduce their side effect profile and to produce
a stronger antidepressant effect.[32][35][51][52][53][83]
Mirtazapine is a very strong H1 receptor antagonist and as a result, it can caus
e powerful sedative and hypnotic effects.[73] After a short period of chronic tr
eatment, however, the H1 receptor tends to sensitize and the antihistamine effec
ts become more tolerable. Many patients may also dose at night to avoid the effe
cts and this appears to be an effective strategy for combating them. Blockade of
the H1 receptor may improve pre-existing allergies, pruritus, nausea, and insom
nia in afflicted individuals; hence, this may actually be a positive thing for s
ome. It may also contribute to weight gain, however.[citation needed] Mirtazapin
e has very low affinity for the muscarinic acetylcholine receptors and therefore
lacks significant anticholinergic properties at clinically used doses.
Similarly to many other antidepressants, mirtazapine has been found to have anti
nociceptive properties and reduces the intensity of painful stimuli, and it has
been suggested that this may contribute to its antidepressant efficacy.[84] Unli
ke with SSRIs and similar antidepressants, however, these effects are produced t
hrough different pathways and appear to result from downstream modulation of ?-
and ?3-opioid receptors, an indirect action possibly related to its antagonism o
f the ?2-adrenergic receptor.[84][citation needed]
Mirtazapine 30 mg tablets.
[edit]Pharmacokinetics
Mirtazapine is typically prescribed in doses ranging from 15 mg to 45 mg. Howeve
r, in severely depressed individuals, doses as high as 120 mg have been used wit
h success.[citation needed] Mirtazapine has a half-life of approximately 2040 hou
rs. Like most other antidepressants, because of the therapeutic-latency mirtazap
ine may require as long as 24 weeks until the therapeutic benefits of the drug be
come evident.
[edit]Chemistry
The racemic mixture of enantiomers
Mirtazapine is a racemic mixture of enantiomers and the (S)-(+)-enantiomer is kn
own as esmirtazapine.
A four step chemical synthesis of mirtazapine has been published.[85][86]
[edit]History
Mirtazapine was introduced by Organon International in the United States in 1990
for the treatment of depression.
[edit]Research
Mirtazapine has had literature published on its efficacy (or lack thereof) in th
e following areas: for the treatment of sleep apnea/hypopnea syndrome,[87][88][8
9][90][91] headaches such as migraines,[92][93] tension headaches,[94][95][96] p
ost-dural puncture headaches[97] and cluster headaches,[98] hyperemesis gravidar
um,[99][100][101] irritable bowel syndrome,[102][103] gastroparesis,[104] dysgeu
sia,[citation needed] undifferentiated somatoform disorder,[105] autism and othe
r pervasive developmental disorders,[106][107][108][109][110] and neuroleptic-in
duced akathisia.[111][112][112][113][114][115][116]