Mianserin

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.

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