Mianserin Hydrochloride
White or almost white crystals or crystalline powder. Sparing-
ly soluble in water: slightly soluble in alcohol: soluble in
dichloromethane. A I % solution in water has a pH of 4.0 to
5.5. Protect from light.
Adverse Effects
The most common adverse effect associated with mianserin is
drowsiness. Mianserin also causes bone-marrow depression
usually presenting as leucopenia. granulocytopenia. or agran-
ulocylosis; aplastic anaemia has been reported. These adverse
haematological reactions generally occur during the first few
weeks of therapy and especially in the elderly.
Other side-effects reported include convulsions, disturbances
of liver function and jaundice, breast disorders (gynaecomas-
tia, nipple tenderness, and non-puerperal lactation ).
Dizziness,orthostatic hypotension, oedema, polyarthropathy, skin
rash, sweating, and tremor, Hyponatremia possibly due to
inappropriate secretion of
antidiuretic hormone, has been associated with the use of
antidepressanis. particularly in the elderly.
Antimuscarinic and cardiac side-effects are fewer and milder
than with tricyclic antidepressants: mianserin may be associ-
ated with a lower risk of cardiotoxicity in overdosage.
Effects on the blood. Between 1976 and the end of 1988
the Committee on Safely of Medicines in the UK had received
239 reports of adverse haematological reactions associated
with mianserin. They included 68 reports of agranulocytosis
and 84 reports of granulocytopenia or leucopenia where mi-
anserin was considered to be the probable or possible cause:
there had been 17 fatalities. Allowing for the pattern of pre-
scribing there was a greater number of reports of white blood
cell disorders in patients over 65 years of age but there was nc
sex difference. The data also indicated that the adverse reac-
tions were most likely to develop during the first three months
of therapy. By the end of 1992 the number of reports of mian-
serin-induced agranulocytosis received by the CSM had riser
to 79 and the number of reports of mianserin-induced neutro.
Penia was 105.
A case of fatal aplastic anaemia associated with mianserin has
also been reported.
Proposed mechanisms of mianserin haematotoxicity have in-
cluded a direct toxicity and an immunologically-mediatec
mechanisrn. Mianserin is administered as a racemic prepara-
tion and there is -also evidence from in vitro studies that the
metabolites of mianserin exhibit cytotoxicity. A significant
correlation between the desmethyl metabolite and cytotoxici-
ty was found and the formation of metabolites was greater
with the /?(-)-enantiomer than with the 5(+)-enantiomer.
Effects on the cardiovascular system. Although mian-
serin is considered to be less cardiotoxic than the
tricyclic antidepressants adverse effects have been noted
in individual patients. Two elderly patients developed
signs of disturbed cardiac function (cardiac failure,
atrial and ventricular fibrillation, bradycardia, and
frequent ventricular ectopic beats)which resolved after the
drug was discontinued. One of the
patients also developed hypokalaemia which was possibly
caused by mianserin. It was suggested that persons most
likely to experience problems were the elderly with a past
history of cardiovascular disorders. Further reports of
mianserin-induced cardiac effects include recurrent
ventricular fibrillation in a 61-year-old man after an
overdose of mianserin and bradycardia in a 50-year-old
woman following a therapeutic dose.
Effects on the liver. By March 1985 the Committee on
Safety of Medicines in the UK had received 57 reports of
hepatic reactions associated with mianserin from a
cumulative total of 5 million prescriptions. Reactions had
included jaundice and other abnormalities of liver
function, but no fatalities had been reported.
Case reports have also been published concerning jaundice:
the liver function returned to normal after discontinuation
of mianserin or dose reduction.
Effects on the musculoskeletal system. Hughes and
Coote in describing one patient who developed an acute pol-
yarthritis affecting the hands and feet 6 days after commenc
ing therapy with mianserin also mentioned that the UK
Committee on Safety of Medicines had received 19 reports of
arthritis and arthralgia associated with mianserin.
Effects on the skin. Reports of adverse dermatological re-
actions in individual patients related to mianserin therapy
have included toxic epidermal necrolysis' and erythema mul-
tiforme.
Effects on the tongue. Glossitis associated with mianserin
therapy has been reported in 2 patients.' Additionally, glossi
tis accompanied by severe facial oedema has been noted in
another patient. In all cases symptoms resolved after with-
drawal of mianserin.
Epileptogenic effect. By March 1985 the UK Committee
on Safety of Medicines had received 64 reports of convul-
sions associated with mianserin from a total of 5 million pre
scriptions.
In a previous review; concerning 40 of these cases it was con-
sidered that a causal connection could be established only
in a minority. It was suggested that mianserin is no more
epileptogenic than tricyclic antidepressants, an opinion
that was also shared by other reviewers.
0verdosage. Experience with 100 consecutive cases of in-
toxication with mianserin revealed that when it was the only
drug ingested symptoms were mild and neither deep coma
nor convulsions occurred. More serious symptoms were seen
in patients who had taken multiple drug overdoses and there
were 2 fatalities. The results suggested that following an
acute overdose mianserin is less toxic than the tricyclic
antidepressants. This conclusion was also supported by a
large follow up study comparing the outcome of suicide
attempts among patients who had taken mianserin in overdose
with those who had taken amitriptyline.
Precautions
Mianserin is contra-indicated in patients with severe liver
disease and in patients with mania. Patients with bipolar
disorder may switch from a depressive to a manic phase during
treatment with mianserin.
Although mianserin does not have the cardiotoxicity of the
tricyclic antidepressants, it should be used with caution
in patients with cardiovascular disorders, such as heart
block, or after recent myocardial infarction. It should be
used with caution in patients with diabetes mellitus,
epilepsy, and hepatic
or renal insufficiency. Patients with suicidal tendencies
should be carefully supervised during early treatment. Pa-
tients with angle-closure glaucoma or prostatic hyperplasia
should be monitored even though antimuscarinic effects are
rare.
A full blood count is recommended every 4 weeks during the
first 3 months of treatment, because of the risk of bonemar
row depression. Similarly, if a patient receiving mianserin
develops fever, sore throat, stomatitis, or other signs of
infection, treatment should be stopped and a full blood
count obtained. The elderly arc considered to be at special
risk of blood disorders from mianserin. For further details see
Effects on the Blood under Adverse Effects, above.
Drowsiness is often experienced at the start of mianserin
therapy and patients if affected should not drive or
operate machinery. For further details of the effects of
antidepressant therapy on driving see under Amitriptyline.
The manufacturers warn that if surgery is required the anaes
therist should be informed that the patient has received
mianserin (see also Anaesthesia under Amitriptyline).
The manufacturers recommend that mianserin should not be
given during breast feeding, but some authorities consider
the amount distributed into breast milk too small to be
harmful.
Mianserin should be withdrawn gradually to reduce the risk
of withdrawal symptoms.
Interactions
It Is recommended that mianserin should not be given to pa-
tients receiving MAOls or for at least 14 days after their
discontinuation. At least one week should elapse between
withdrawing mianserin and starting any drug liable to pro-
voke a serious reaction (e.g. phenelzine). Unlike
the tricyclics, mianserin does not diminish the effects of the
antihypertensives guanethidine, hydralazine, propranolol,
clonidine or bethanidine. However, it is still recommended
that blood pressure be monitored when mianserin is pre-
scribed with antihypertensive therapy. Plasma-phenytoin con-
centrations should be monitored carefully in patients
treated
concurrently with mianserin: phenytoin has been reported to
reduce concentrations of mianserin. There may be potentia-
tion of effects when mianserin is given concomitantly with
CNS depressants such as alcohol, anxiolytics, or antipsychot-
ics.
Antiepileptics. Reduced plasma concentrations and
half lives of mianserin and desmethyl mianserin were
observed in 6 patients also receiving antiepileptic therapy
consisting of phenytoin with either carbamazepine or
phenobarbitone.
Mianserin may antagonise the action of antiepileptics by low-
ering the convulsive threshold.
Pharmacokinetics
Mianserin is readily absorbed from the gastro-intestinal tract.
but its bioavailability is reduced to about 70% by extensive
first-pass metabolism in the liver.
Paths of metabolism of mianserin include aromatic hydroxy-
lation, N-oxidation. and /V-demethylation. Desmethylmian-
serin and 8-hydroxymianserin are pharmacologically active.
Mianserin is excreted in the urine, almost entirely as its me-
tabolites. either free or in conjugated form: some is also
found in the faeces.
Mianserin is widely distributed throughout the body and is
extensively bound to plasma proteins. It has been found to
have a biphasic plasma half-life with the duration of the
terminal phase ranging from about 6 to 40 hours. Mianserin
crosses the blood-brain barrier and the placenta. It is
distributed into breast milk.
Uses and Administration
Mianserin is a tetracyclic antidepressant. It does not appear to
have significant antimuscarinic properties, but has a marked
sedative action. Unlike the tricyclic antidepressants, mianser-
in does not prevent the peripheral reuptake of noradrenaline;
it blocks presynaptic adrenergic (a;) receptors and increases
the turnover of brain noradrenaline. Mianserin is also an an-
tagonist of serotonin receptors in some parts of the brain.
In the treatment of depression mianserin is given by
mouth as the hydrochloride in initial doses of 30 to 40 mg
daily increased gradually thereafter as necessary. The effec-
tive daily dosage is usually between 30 and 90 mg. The daily
dosage may be divided throughout the day or given as a single
dose at night. Divided daily dosages of up to 200 mg have
been given. The recommended initial daily dose in the elderly
is not more than 30 mg. which may be slowly increased if
necessary.
Mianserin should be withdrawn gradually to reduce the risk
of withdrawal symptoms.