Mianserin

Mianserin

Systematic (IUPAC) name
(±)-2-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine
Clinical data
Trade names	Bolvidon (discontinued), Tolvon, Lerivon
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: B2
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only)
Routes of administration	Oral (tablets)
Pharmacokinetic data
Bioavailability	20–30%
Protein binding	95%
Metabolism	Hepatic (mediated by CYP2D6; most metabolism occurs via aromatic hydroxylation, N-oxidation and N-demethylation)
Biological half-life	21–61 hours
Excretion	Renal (4–7%) Faecal (14–28%)
Identifiers
CAS Number	24219-97-4 Y
ATC code	N06AX03 (WHO)
PubChem	CID: 4184
IUPHAR/BPS	135
DrugBank	DB06148 N
ChemSpider	4040 Y
UNII	250PJI13LM Y
KEGG	D08216 Y
ChEBI	CHEBI:51137 N
ChEMBL	CHEMBL6437 Y
Chemical data
Formula	C18H20N2
Molecular mass	264.365
SMILES c42c(N3C(c1ccccc1C2)CN(C)CC3)cccc4
InChI InChI=1S/C18H20N2/c1-19-10-11-20-17-9-5-3-7-15(17)12-14-6-2-4-8-16(14)18(20)13-19/h2-9,18H,10-13H2,1H3 Y Key:UEQUQVLFIPOEMF-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Mianserin

Mianserin (brand names: Depnon (IN), Lantanon (ZA), Lerivon (AR, BE, CZ, PL, RU, SK), Lumin (AU), Norval (UK), Tolvon (AU, HK^†, IE^†, NZ, SG^†), Tolmin (DK); where † indicates discontinued products) is a psychoactive drug of the tetracyclic antidepressant (TeCA) therapeutic family. It is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA) and has antidepressant, anxiolytic (anti-anxiety), hypnotic (sedating), antiemetic (nausea and vomiting-attenuating), orexigenic (appetite-stimulating), and antihistamine effects.

It is not approved for use in the US, but its analogue, mirtazapine, is. Mianserin was the first antidepressant to reach the UK market that was less dangerous than the tricyclic antidepressants in overdose.

Medical uses

When used for the treatment of depression, its efficacy appears comparable to that of amitriptyline, citalopram, clomipramine, dothiepin, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, moclobemide, nortriptyline, paroxetine, and trazodone. Mianserin received TGA approval in May 1996.

Similarly to its analogue, mirtazapine, mianserin has been tried as an augmentation strategy in treatment-resistant depression with some success. Mianserin has been tried, similarly to mirtazapine, as an adjunct in schizophrenia and has been found to reduce negative and cognitive symptoms.

Mianserin has demonstrated efficacy as a monotherapy for the treatment of Parkinson's disease psychosis in an open-label clinical trial.

Adverse effects

Side effects

Information sources:

Very common (incidence>10%) adverse effects include

• Constipation
• Dry mouth
• Somnolence/drowsiness (transiently at the beginning of therapy)

Common (1%<incidence≤10%) adverse effects include

• Somnolence/drowsiness (during maintenance therapy, that is, in some patients this side effect persists)
• Tremor
• Headache
• Dizziness
• Vertigo
• Dry mouth
• Weakness

Uncommon (0.1%<incidence≤1%) adverse effects include

• Weight gain — likely related to its potent antihistamine and 5-HT_2C receptor-antagonist effects.

Rare (0.01%<incidence≤0.1%) adverse effects include

• Oedema — the swelling of the body's tissues due to fluid draining into said tissues.
• Arthralgia (joint pain)
• Arthritis
• Rash
• Akathisia — a sense of inner restlessness that is often distressing for patients.
• Orthostatic hypotension — the dropping of blood pressure upon standing up leading to light-headedness, dizziness and even fainting
• Hypomania — an excessively elated/irritable mood that can be dangerous.
• Bradycardia — low heart rate.
• Disturbances of liver function (including jaundice) — the Australian Medicines Handbook recommends that patients with a history of liver disease undergo regular liver function tests and that treatment is ceased at the first sign of jaundice.
• Exanthema

Very rare (Incidence≤0.01%) adverse effects include

• Seizures
• Blood dyscrasias (particularly neutropaenia — a drop in the neutrophils which are part of the body's immune system that is particularly tailored to destroying bacteria — and agranulocytosis — a potentially life-threatening drop in the white blood cells of the immune system leaving the patient open to potentially fatal infections.) — for this reason in the Australian Medicines Handbook 2013 and the British National Formulary 65 it is recommended that the prescribing physician checks the patient's complete blood counts (CBCs) at the initiation of treatment and then every four weeks until 3 months have passed. Some cases of mianserin-induced blood dyscrasias have been fatal.
• Neuroleptic malignant syndrome — an often life-threatening drug reaction that is characterised by:

- Tremor

- Hyperthermia (high body temperature)

- Muscle rigidity

- Autonomic dysregulation (e.g. tachycardia (high heart rate), diaphoresis (profuse sweating), urinary and faecal incontinence, difficulty swallowing, etc.)

- Mental status change (e.g. delirium, hallucinations, coma, stupor, etc.)

• Restless legs
• Cardiac arrest
• Cardiac failure

Rare/very rare adverse effects include

• Nasal congestion
• Paraesthesia
• Vision abnormality
• Diplopia — seeing double.
• Gynaecomastia — abnormal breast enlargement in males.
• Impotence
• Myalgia — muscle aches.
• Pruritus — itchiness
• Hypertension
• Tachycardia
• Tinnitus — hearing ringing in the ears in the absence of an actual sound.
• Confusion
• Agitation

Interactions

CYP2D6 inhibitors such as the selective serotonin reuptake inhibitors (SSRIs), quinidine, ritonavir, etc. would likely raise plasma levels of mianserin and hence could lead to mianserin toxicity. Conversely, CYP2D6 inducers would likely lead to reduced mianserin plasma concentrations and hence potentially diminish the therapeutic effects of mianserin.

Withdrawal

Abrupt or rapid discontinuation of mianserin may provoke a withdrawal, the effects of which may include depression, anxiety, panic attacks, 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 the following symptoms:

• Sedation
• Coma
• Hypotension
• Hypertension
• Tachycardia
• QT interval prolongation

and is relatively safe in overdose similarly to its successor mirtazapine.

Pharmacology

Mianserin is an antagonist/inverse agonist of the H₁, 5-HT_1D, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₃, 5-HT₆, 5-HT₇, α₁-adrenergic, and α₂-adrenergic receptors, and also inhibits the reuptake of norepinephrine. As a high affinity H₁ receptor inverse agonist, mianserin has strong antihistamine effects (sedation, weight gain, etc.). Contrarily, it has negligible affinity for the mACh receptors, and thus lacks anticholinergic properties. It was recently found to be a weak (K_i = 1.7 μM, EC₅₀ = 0.53 μM) κ-opioid receptor partial agonist.

In addition, mianserin also appears to be a potent antagonist of the neuronal octopamine receptor. What implications this may have on mood are currently unknown, however octopamine has been implicated in the regulation of sleep, appetite and insulin production and therefore may theoretically contribute to the overall side effect profile of mianserin.

Blockade of the H₁ and α1-adrenergic receptors has sedative effects, and also antagonism of the 5-HT_2A and α₁-adrenergic receptors inhibits activation of intracellular phospholipase C (PLC), which seems to be a common target for several different classes of antidepressants. 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.

Enantioselectivity

(S)-mianserin

(S)-(+)-Mianserin is approximately 200–300 times more active than its enantiomer (R)-(−)-mianserin.

Binding profile

Molecular target	Binding affinity (Ki [nM])
SERT	4000
NET	71
DAT	9400
5-HT1A	1500
5-HT1F	12.6
5-HT2A	3.21
5-HT2B	10.9
5-HT2C	2.59
5-HT6	68.1
5-HT7	56
α1 adrenoceptor	74 (Cloned rat receptor)
α2A adrenoceptor	4.8
α2B adrenoceptor	27
α2C adrenoceptor	3.8
D1 receptor	923
D2 receptor	2052
D3 receptor	2841
H1 receptor	1.0
H4 receptor	750

External links

• Treatments for Depression – Mianserin