Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant that is used primarily in the treatment of depression in Europe and elsewhere in the world. It is a tetracyclic antidepressant (TeCA). Mianserin is closely related to mirtazapine, both

chemically A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...

and in terms of its actions and effects, although there are significant differences between the two drugs.

Medical uses

Mianserin at higher doses (30-90mg/day) is used for the treatment of major depressive disorder. It can also be used at lower doses (around 10mg/day) to treat insomnia.

Contraindications

It should not be given, except if based on clinical need and under strict medical supervision, to people younger than 18 years old, as it can increase the risk of suicide attempts and suicidal thinking, and it can increase aggressiveness. While there is no evidence that it can harm a fetus from animal models, there are no data showing it safe for pregnant women to take. 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. If based on clinical decision, normal precautions should be exercised and the dosages of mianserin and any concurrent therapy kept under review and adjusted as needed.

Side effects

Very common (incidence>10%) adverse effects include constipation, dry mouth, and drowsiness at the beginning of treatment. Common (1% Uncommon (0.1%

Withdrawal

Abrupt or rapid discontinuation of mianserin may provoke a

withdrawal Withdrawal means "an act of taking out" and may refer to: * Anchoresis (withdrawal from the world for religious or ethical reasons) * ''Coitus interruptus'' (the withdrawal method) * Drug withdrawal * Social withdrawal * Taking of money from a ban ...

, the effects of which may include depression, anxiety, panic attacks, decreased

appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to regu ...

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.Taylor D, Paton C, Kapur S, Taylor D. The Maudsley prescribing guidelines in psychiatry. 11th ed. Chichester, West Sussex: John Wiley & Sons; 2012.

Interactions

Mianserin may enhance the sedative effects of drugs such as alcohol, anxiolytics, hypnotics, or antipsychotics when co-administered. It may decrease the efficacy of antiepileptic medications. 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 Brimonidine is a medication used to treat open-angle glaucoma, ocular hypertension, and rosacea. In rosacea it improves the redness. It is used as eye drops or applied to the skin. Common side effects when used in the eyes include itchiness, re ...

, sibutramine, or the combination drug of artemether with lumefantrine.

Pharmacology

Pharmacodynamics

Mianserin appears to exert its effects via antagonism of histamine and

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

receptors, and inhibition of norepinephrine reuptake. More specifically, it is an

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

at most or all sites of the histamine H₁ receptor,

5-HT_1D, 5-HT_1F, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₃, 5-HT₆, and 5-HT₇ receptors, and adrenergic α₁- and α₂-adrenergic receptors, and additionally a norepinephrine reuptake inhibitor. As an H₁ receptor inverse agonist with high affinity, mianserin has strong antihistamine effects (e.g.,

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

). Conversely, it has low affinity for the muscarinic acetylcholine receptors, and hence lacks anticholinergic properties. Mianserin has been found to be a low affinity but potentially significant partial agonist of the κ-opioid receptor (K_i = 1.7 μM; EC₅₀ = 0.53 μM), similarly to some

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and we ...

s (TCAs). Blockade of the H₁ and possibly α₁-adrenergic receptors has

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but t ...

effects, and also antagonism of the 5-HT_2A and α₁-adrenergic receptors inhibits activation of intracellular

phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...

(PLC), which seems to be a common target for several different classes of

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...

s. By antagonizing the

somatodendritic Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

and presynaptic α₂-adrenergic receptors, which function predominantly as inhibitory autoreceptors and heteroreceptors, mianserin disinhibits the release of norepinephrine,

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

, and

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...

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). However, the actual evidence in support of this label has been regarded as poor.

Pharmacokinetics

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

feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a relati ...

Chemistry

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. (''S'')-(+)-Mianserin is approximately 200–300 times more active than its

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

(''R'')-(−)-mianserin; hence, the activity of mianserin lies in the (''S'')-(+)

isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...

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. Mianserin was one of the first antidepressants to reach the UK market that was less dangerous than the

s in overdose; as of 2012 it was not prescribed much in the UK.

Society and culture

Generic names

''Mianserin'' is the English and German generic name of the drug and its and , while ''mianserin hydrochloride'' is its , , and . Its generic name in

French French (french: français(e), link=no) may refer to: * Something of, from, or related to France ** French language, which originated in France, and its various dialects and accents ** French people, a nation and ethnic group identified with Franc ...

and its are ''miansérine'', in Spanish and Italian and its are ''mianserina'', and in Latin is ''mianserinum''.

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, Bonserin, Bolvidon, Deprevon, Lantanon, Lerivon, Miansan, Serelan, Tetramide, and Tolvin among others.

Availability

Mianserin is not approved for use in the United States, but is available in the United Kingdom and other European countries. A mianserin generic drug received approval in May 1996 and is available in

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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.