Summary
Synopsis: Mianserin1 is a tetracyclic compound advocated for the treatment of depressive illness and depression associated with anxiety. It combines antidepressant activity with a sedative effect and has an EEG and clinical activity profile similar to that of amitriptyline. It has an overall efficacy comparable with amitriptyline and imipramine in depressive illness, but at dosages which have achieved a similar overall clinical improvement, mianserin causes significantly fewer anticholinergic side effects than amitriptyline or imipramine and also appears less likely than these drugs to cause serious cardiotoxicity on overdosage. Mianserin also has antianxiety activity, but its role in treating patients with anxiety associated with primary depression has still to be clarified. Mianserin appears to be well tolerated by the elderly and by patients with cardiovascular disease, including those recovering from a recent myocardial infarction, and does not appear to antagonise the action of adrenergic neurone blocking antihypertensive drugs or affect the anticoagulant action of phenprocoumon.
Pharmacodynamic Studies: The profile of action of mianserin differs from that of the tricyclic antidepressants. It combines presynaptic α-adrenoceptor blocking activity with antihistamine properties but has no central anticholinergic activity, and little effect on central serotoninergic mechanisms. It has been found to have an electroencephalographic (EEG) profile in humans similar to that of amitriptyline.
In man, mianserin in therapeutic dosage has no effect on peripheral noradrenaline uptake in the tyramine pressor test, and unlike the tricyclic antidepressants does not significantly decrease the antihypertensive action of bethanidine or guanethidine. Experimental studies in animals indicate that mianserin is less liable to cause cardiotoxicity than the tricyclic drugs, amitriptyline, imipramine or clomipramine, or the modified tricyclic drug maprotiline. Unlike amitriptyline, mianserin did not produce postural hypotension in volunteers or adverse cardiovascular (ECG) effects in volunteers or depressed patients, including those with heart disease.
The anticholinergic effects of mianserin in intact animals and in man are negligible compared with those of amitriptyline or cyproheptadine. Central anticholinergic effects in rats are absent, except at high dosages. Mianserin also possesses sedative activity. Thus, the decrease in critical flicker frequency (an indirect measure of sedation) produced by mianserin 5mg, was not significantly different from that after nitrazepam 10mg. Mianserin had no particular adverse effect on sleep.
Pharmacokinetic Studies: Mianserin appears to be readily absorbed after oral administration, peak plasma concentrations being attained 2 to 3 hours after ingestion. Plasma concentration increases progressively during continued treatment, reaching possible steady state in 2 weeks. An increase in interindividual variability in plasma concentration in patients over 55 years has been reported in 1 study, but other investigators have found no such correlation between age and plasma concentration. Bioavailability after oral administration is about 30%. Significant hepatic ‘first pass’ metabolism has been demonstrated in the rat.
Distribution data in humans is lacking, but studies in the rat indicate wide distribution and ready penetration into the central nervous system. The high protein binding and apparent volume of distribution is comparable with that of the tricyclic antidepressants.
Most of a dose of mianserin is metabolised, only 4 to 7% being present in the urine unchanged. The predominant route of biotransformation in the human is aromatic hydroxylation, N-oxidation and N-demethylation. There are no published data indicating whether or not the metabolites are pharmacologically active. Urinary excretion accounts for about 70% of administered radioactivity, 58% being excreted in 24 hours. Faecal excretion accounted for 8 to 28% of a dose. The rate of elimination is not influenced by haemodialysis. The mean elimination half-life is about 10 to 17 hours.
Reports on the relationship between plasma concentration and clinical effects have been at some variance and remain to be clarified; findings suggesting both curvilinear and linear effects, as well as no positive correlation.
Therapeutic Trials: Results of open and controlled trials in patients with depressive illness indicate that mianserin has antidepressant activity at dosages of 30 to 120mg daily in divided doses or as a single bedtime dose of 60mg. The therapeutic trials have generally involved relatively small numbers of patients, and have been of short duration. The majority of double-blind studies have compared mianserin with amitriptyline and have found no statistically significant difference in the efficacy of the drugs, as assessed by changes in psychiatric symptom rating scales, particularly the Hamilton Rating Scale for depression. The comparability of treatment groups has been less than ideal in some studies, despite random allocation, whilst in others in which the investigation has been conducted at several centres, it is not stated whether or not the groups were comparable within or between participating centres.
Differences in the profile of activity of mianserin and amitriptyline in depressive illness have been noted in limited investigations in some studies, but further studies in larger numbers of patients will be needed to clarify the apparent differences in the profile of action of mianserin and amitriptyline. No significant differences could be detected between the therapeutic efficacy of mianserin and imipramine. Both drugs were superior to placebo in 1 study in general practice patients, but not in a study in hospitalised patients receiving concomitant psychotherapy. Thus, whilst mianserin cannot be regarded as superior, nor as inferior, to the tricyclic antidepressants in alleviating the symptoms of depressive illness, it has the advantage of seldom causing anticholinergic side effects, and importantly, appears less likely than the tricyclic antidepressants to cause serious cardiotoxicity on overdosage.
Mianserin appears to have antianxiety activity, as evidenced by findings in studies comparing mianserin with diazepam, but further studies will be needed to determine its role in mixed depression-anxiety syndromes relative to that of tricyclic derivatives such as doxepin or combinations of amitriptyline and perphenazine.
Side Effects are generally mild and tend to disappear as treatment continues. Anticholinergic side effects seldom occur with mianserin and in some studies have occurred less frequently during the study than did similar symptoms before treatment in depressed patients. In the clinical experience to date, mianserin has not been associated with adverse cardiovascular effects at therapeutic doses, and importantly, unlike the tricyclic antidepressants has not been associated with serious cardiotoxicity on overdosage. Although experience is relatively limited, mianserin appears to be well tolerated by the elderly and by patients with cardiovascular disease. It does not appear to influence the antihypertensive effects of guanethidine or bethanidine, or the anticoagulant effects of phenprocoumon.
Dosage should be individualised, but initially should be 30mg daily in both hospitalised patients and in outpatients. The usually effective dose is 40 to 80mg daily, but dosages of up to 120mg daily have been used in hospitalised patients. The total daily dosage may be given as a single dose at bedtime or in divided doses during the day.
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Various sections of the manuscript reviewed by: F.J. Ayd, Baltimore, Md.; USA; N. Bark, Rockland Research Institute, New York, USA; G.D. Burrows, University of Melbourne, Victoria, Australia; M. Fink, State University of New York, Stony Brook, USA; J.F. Freyfus, Faculte de Medecine Cochin Port-Royal, Paris, France; L.E. Hollister, Veterans Administration Hospital, Palo Alto, Calif.; USA; M.O. Jaskari, Lastaajantie, Martinniemi, Finland; H. Kopera, University of Graz, Graz, Austria; B.L. Leonard, University College, Galway, Ireland; M. Mattila, University of Helsinki, Helsinki, Finland; S. Montgomery, Guy’s Hospital, London, England; P. Pichot Faculte de Medecine Cochin Port-Royal, Paris, France; G.F.M. Russell, University of London, England; D. Wheatley, General Practitioner Research Group, Twickenham, England.
‘Bolvidon’, ‘Lantanon’, ‘Lerivon’, ‘Tolvin’ (Organon); ‘Norval’ (Bencard).
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Brogden, R.N., Heel, R.C., Speight, T.M. et al. Mianserin: A Review of its Pharmacological Properties and Therapeutic Efficacy in Depressive Illness. Drugs 16, 273–301 (1978). https://doi.org/10.2165/00003495-197816040-00001
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DOI: https://doi.org/10.2165/00003495-197816040-00001