|Systematic (IUPAC) name|
|Trade names||Bolvidon (discontinued), Tolvon|
|Metabolism||Hepatic (mediated by CYP2D6; most metabolism occurs via aromatic hydroxylation, N-oxidation and N-demethylation)|
|(what is this?)|
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.
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.
- Very common (incidence>10%) adverse effects include
- 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)
- Dry mouth
- Uncommon (0.1%<incidence≤1%) adverse effects include
- Weight gain — likely related to its potent antihistamine and 5-HT2C 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)
- 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.
- Very rare (Incidence≤0.01%) adverse effects include
- 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
- Vision abnormality
- Diplopia — seeing double.
- Gynaecomastia — abnormal breast enlargement in males.
- Myalgia — muscle aches.
- Pruritus — itchiness
- Tinnitus — hearing ringing in the ears in the absence of an actual sound.
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.
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 of mianserin is known to produce the following symptoms:
- QT interval prolongation
and is relatively safe in overdose similarly to its successor mirtazapine.
Mianserin is an antagonist/inverse agonist of the H1, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 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 (Ki = 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-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. 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.
(S)-(+)-Mianserin is approximately 200–300 times more active than its antipode (R)-(−)-mianserin.
|Molecular target||Binding affinity (Ki [nM])|
|α1 adrenoceptor||74 (Cloned rat receptor)|
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