Mianserin

Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant which is used primarily in the treatment of depression in Europe and elsewhere in the world.[5] It is a tetracyclic antidepressant (TeCA). Mianserin is closely related to mirtazapine, both chemically and in terms of its actions and effects, although there are significant differences between the two drugs.

Mianserin
Clinical data
Trade namesTolvon, others
Other namesMianserin hydrochloride; Org GB 94[1][2]
Pregnancy
category
    Routes of
    administration    		By mouth
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: Not FDA approved
    Pharmacokinetic data
    Bioavailability20–30%[3]
    Protein binding95%[3]
    MetabolismLiver (CYP2D6; via aromatic hydroxylation, N-oxidation, N-demethylation)[3]
    Elimination half-life21–61 hours[4]
    ExcretionUrine: 4–7%[3]
    Feces: 14–28%[3]
    Identifiers
    CAS Number
    • 24219-97-4 Y
      21535-47-7 (hydrochloride)
      51152-88-6 ((S)-isomer)
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.041.884
    Chemical and physical data
    FormulaC18H20N2
    Molar mass264.365 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Medical uses

    Mianserin at higher doses (30-90mg/day) is used for the treatment of major depressive disorder.[5]

    It can also be used at lower doses (around 10mg/day) to treat insomnia.[6][7]

    Contraindications

    It should not be given to be people younger than 18 years old, as it can increase the risk of suicide attempts and suicidal thinking, and it can increase aggressiveness.[5]

    While there is no evidence that it can harm a fetus from animal models, there is no data showing it safe for pregnant women to take.[5]

    People with severe liver disease should not take mianserin, and it should be used with caution for people with epilepsy or who are at risk for seizures, as it can lower the threshold for seizures.[5]

    Side effects

    Very common (incidence>10%) adverse effects include constipation, dry mouth, and drowsiness at the beginning of treatment.[4][5]

    Common (1%<incidence≤10%) adverse effects include drowsiness during maintenance therapy, tremor, headache, dizziness, vertigo, and weakness.[4]

    Uncommon (0.1%<incidence≤1%) adverse effects include weight gain.[4]

    Withdrawal

    Abrupt or rapid discontinuation of mianserin may provoke a withdrawal, the effects of which may include depression, anxiety, panic attacks,[8] decreased appetite or anorexia, insomnia, diarrhea, nausea and vomiting, and flu-like symptoms, such as allergies or pruritus, among others.

    Overdose

    Overdose of mianserin is known to produce sedation, coma, hypotension or hypertension, tachycardia, and QT interval prolongation.[9]

    Interactions

    Mianserin may make drugs that have effects on the brain, like alcohol, anxiolytics, hypnotics and antipsychotics, have stronger effects. It can make antiepileptic medicines work less well. People should not take monoamine oxidase inhibitors and mianserin at the same time.[5]

    Carbamazepine and phenobarbital will cause the body to metabolize mianserin faster and may reduce its effects. There is a risk of dangerously low blood pressure if people take mianserin along with diazoxide, hydralazine, or nitroprusside. Mianserin can make antihistamines and antimuscarinics have stronger effects. Mianserin should not be taken with apraclonidine, brimonidine, sibutramine, or the combination drug of artemether with lumefantrine.[5]

    Pharmacology

    Pharmacodynamics
    See also: Pharmacology of antidepressants and Tetracyclic antidepressant § Pharmacology
    Mianserin[10]
    SiteKi (nM)SpeciesRef
    SERT4,000Human[11]
    NET71Human[11]
    DAT9,400Human[11]
    5-HT1A400–2,600Human[12][13]
    5-HT1B≥2,800Rat[14]
    5-HT1D220–400Human[15][16]
    5-HT1ENDNDND
    5-HT1F13Human[12]
    5-HT2A1.6–55Human[17][18]
    5-HT2B1.6–20Human[19][20]
    5-HT2C0.63–6.5Human[17][21]
    5-HT35.8–300Rodent[22][13]
    5-HT4NDNDND
    5-HT5ANDNDND
    5-HT655–81Human[23][24]
    5-HT748–56Human[25][26][27]
    α134Human[28]
    α273Human[28]
      α2A4.8Human[25]
      α2B27Human[29]
      α2C3.8Human[25]
    D1426–1,420Human[13][25]
    D22,100–2,700Human[28][30]
    D32,840Human[28]
    D4NDNDND
    D5NDNDND
    H10.30–1.7Human[31][28][25]
    H2437Human[32]
    H395,500Human[32]
    H4>100,000Human[32][33]
    mACh820Human[28]
    MOR21,000Human[34]
    DOR30,200Human[34]
    KOR530 (EC50)Human[34]
    Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

    Mianserin appears to exert its effects via antagonism of histamine and serotonin receptors, and inhibition of norepinephrine reuptake. More specifically, it is an antagonist/inverse agonist at most or all sites of the histamine H1 receptor, serotonin 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, and adrenergic α1- and α2-adrenergic receptors, and additionally a norepinephrine reuptake inhibitor.[35][36] As an H1 receptor inverse agonist with high affinity, mianserin has strong antihistamine effects (e.g., sedation). Conversely, it has low affinity for the muscarinic acetylcholine receptors, and hence lacks anticholinergic properties.[28] Mianserin has been found to be a low affinity but potentially significant partial agonist of the κ-opioid receptor (Ki = 1.7 μM; EC50 = 0.53 μM),[34] similarly to some tricyclic antidepressants (TCAs).[37]

    Blockade of the H1 and possibly α1-adrenergic receptors has sedative effects,[4] and also antagonism of the 5-HT2A and α1-adrenergic receptors inhibits activation of intracellular phospholipase C (PLC), which seems to be a common target for several different classes of antidepressants.[38] By antagonizing the somatodendritic and presynaptic α2-adrenergic receptors which function predominantly as inhibitory autoreceptors and heteroreceptors, mianserin disinhibits the release of norepinephrine, dopamine, serotonin, and acetylcholine in various areas of the brain and body.

    Along with mirtazapine, although to a lesser extent in comparison, mianserin has sometimes been described as a noradrenergic and specific serotonergic antidepressant (NaSSA).[39] However, the actual evidence in support of this label has been regarded as poor.[40]

    Pharmacokinetics

    The bioavailability of mianserin is 20 to 30%.[3] Its plasma protein binding is 95%.[3] Mianserin is metabolized in the liver by the CYP2D6 enzyme via N-oxidation and N-demethylation.[3] Its elimination half-life is 21 to 61 hours.[3] The drug is excreted 4 to 7% in the urine and 14 to 28% in feces.[3]

    Chemistry
    (S)-Mianserin.

    Mianserin is a tetracyclic piperazinoazepine; mirtazapine was developed by the same team of organic chemists and differs via addition of a nitrogen atom in one of the rings.[41][42] (S)-(+)-Mianserin is approximately 200–300 times more active than its enantiomer (R)-(−)-mianserin; hence, the activity of mianserin lies in the (S)-(+) isomer.

    History

    It was developed but not discovered by Organon International; the first patents were issued in The Netherlands in 1967, and it was launched in France in 1979 under the brand name Athymil, and soon thereafter in the UK as Norval. Investigators conducting clinical trials in the US submitted fraudulent data, and it was never approved in the US.[43]:21[44]:318

    Mianserin was one of the first antidepressants to reach the UK market that was less dangerous than the tricyclic antidepressants in overdose; as of 2012 it was not prescribed much in the UK.[45]

    Society and culture
    Mianserin.

    Generic names

    Mianserin is the English and German generic name of the drug and its INN and BAN, while mianserin hydrochloride is its USAN, BANM, and JAN. Its generic name in French and its DCF are miansérine, in Spanish and Italian and its DCIT are mianserina, and in Latin is mianserinum.[46][1][47][2]

    Brand names

    Mianserin is marketed in many countries mainly under the brand name Tolvon. It is also available throughout the world under a variety of other brand names including Athymil, Bolvidon, Deprevon, Lantanon, Lerivon, Miansan, Serelan, Tetramide, and Tolvin among others.[1][2][46]

    Availability

    Mianserin is not approved for use in the United States, but is available in the United Kingdom and other European countries.[48][49] A mianserin generic drug received TGA approval in May 1996 and is available in Australia.[50]

    Research

    The use of mianserin to help people with schizophrenia who are being treated with antipsychotics has been studied in clinical trials; the outcome is unclear.[51][52]

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