Efficacy and Side Effects of Mianserin, a Tetracyclic Antidepressant A
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Postgrad Med J: first published as 10.1136/pgmj.59.690.229 on 1 April 1983. Downloaded from Postgraduate Medical Journal (April 1983) 59, 229-231 Efficacy and side effects of mianserin, a tetracyclic antidepressant A. WAKELING Ph.D., B.Sc., F.R.C.Psych., D.P.M. Academic Department of Psychiatry, Royal Free Hospital School of Medicine, London NW3 2PF Introduction their actions on central neurotransmitter systems and differing claims are made that their antidepressant Antidepressant drugs have been in extensive use actions are relatively free from the adverse or for over 20 years. Initially 2 groups of compounds, unwanted effects of the tricyclics. These claims the monoamine oxidase inhibitors (MAOI) and should be received with caution as there has been an tricyclic compounds based on the imipramine confi- insufficient experience in the use of many of them. guration were widely used. In the early 1960's after a Mianserin, however, is probably the most widely few years ofwide use, interest in the MAOI group fell used of these compounds and considerable clinical following the recognition of a serious adverse effect. experience of its use has been accumulated over the Blackwell (1963) described the occurrence of hyper- copyright. tensive crisis with occasional fatalities when these last few years. compounds were taken with certain foodstuffs. It is of interest, however, that in recent years there has Mianserin been some resurgence of interest in these compounds Mianserin is a tetracyclic compound structurally and the suggestion that their dangers may have been distinct from both the classical tricyclic antidepres- exaggerated (Tyrer, 1979) or might be ameliorated by sants and from bridged tricyclics of the maprotiline combination with tricyclics (Pare et al., 1982). Inter- type. It was originally designed as an anti-allergic est in the tricyclic group however has continued drug, but early trials suggested mood elevating unabated and over the years at least 20 antidepres- qualities and in 1972 antidepressant-like central http://pmj.bmj.com/ sants based on the original imipramine configuration nervous system activity was detected by computer- have been produced. There is now a widespread and ized electroencephalographic studies in volunteers extensive accumulated experience of these com- (Itil, Polvan and Hsu, 1972). Subsequently, a variety pounds and although they remain the most widely of clinical trials have indicated that mianserin prescribed antidepressant, it is now clear that they possesses antidepressant activity equal to that of the have a number of serious disadvantages. The most widely-used tricyclic antidepressants. important of these are cardiotoxicity, potential fatality in overdose, marked peripheral anticholin- on October 1, 2021 by guest. Protected ergic activity and reduction in seizure threshold Efficacy (Blackwell, 1981a). As these disadvantages exist to There are particular difficulties in assessing the some extent with all the tricyclics produced so far, efficacy of new putative antidepressant compounds. there have, not surprisingly, been active attempts to The most rigorous tests of efficacy involve the use of produce different and safer antidepressant com- randomized placebo-controlled double-blind clinical pounds. trials utilizing large numbers of patients, with stan- Over the last few years a number of different dardized and validated procedures used for clinical compounds have come into use as antidepressants diagnosis and assessment. However the use of pla- and these constitute the 'second generation' anti- cebo in patients with severe depressive illness when depressant drugs. Included among these are; viloxa- there are well-tried effective treatments raises serious zine and zimelidine, both bicyclic compounds; nomi- ethical issues. Due to this, new antidepressant com- fensine, a tetrahydro-isoquinoline derivative; mapro- pounds are usually compared in trials with standard tiline, a bridged tricyclic compound and the tetra- tricyclic antidepressants. Such trials not surprisingly cyclic compound mianserin. All differ somewhat in can give rise to complex problems of interpretation. 0032-5473/83/0400-0229 $02.00 © 1983 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.59.690.229 on 1 April 1983. Downloaded from 230 A. Wakeling Placebo controlled trials. Smith, Naylor and The lack of cardiotoxicity with mianserin is Moody (1978) demonstrated the superiority of mian- probably associated with its apparent safety in serin over placebo in an important trial including 41 overdose. Overdosage with mianserin commonly severely depressed women. However, this trial lasted causes drowsiness, but there is an absence ofthe more only 2 weeks because of the ethical considerations serious complications found in tricyclic or maprotil- involved. Two further placebo controlled trials utiliz- ine overdose. Shaw (1980) in a survey of 84 cases of ing mildly depressed patients suggested active anti- mianserin overdose from the London Poisons Unit depressant effect for mianserin (Murphy, Donald reported no deaths and an absence of cardiac and Molla, 1976; Branconnier, Cole and Ghazvinian, arrhythmias and convulsions. Management of mian- 1981). serin overdosage is limited to gastric lavage within Comparison with tricyclic antidepressants. A large the first 2 hr after ingestion, with monitoring of vital number of double-blind trials of varying methodolo- functions. In contrast to Shaw's findings however, gical sophistication comparing mianserin with stan- Edwards (1979) reporting data from the Committee dard tricyclic antidepressants have been reported on Safety of Medicines indicates that mianserin (Pinder and Fink, 1982). These include comparison accounts for about 11% of reported antidepressant with amitriptyline (Wheatley, 1975; Coppen et al., related convulsions. This clearly requires continuing 1976; Montgomery et al., 1978; Murphy and Bridge- observation and draws attention to the need for full man, 1978; Daly, Brown and Morgan, 1979; Kretsch- reporting to the relevant safety bodies of all adverse mar, 1980) with imipramine (Murphy, 1975; Pichot, drug effects. The other serious side effect of mian- Dreyfus and Pull, 1978) and with clomipramine serin is the occasional occurrence of blood dyscrasias. (Blaha, Pinder and Stulemeijer, 1980; De Buck, Blood dyscrasias. Between January 1974 and Octo- 1980). The detection of differences in efficacy be- ber 1981, the Committee on Safety of Medicines tween 2 compounds both having active properties, in received 17 reports of blood dyscrasias associated small groups of patients is difficult. It is therefore with mianserin. These included 7 cases of agranulo- perhaps not surprising that almost all of these cytosis, 8 cases of granulocytopenia, one case of comparisons between mianserin and tricyclics have generalized leucopenia and one case of pancyto-copyright. concluded that they are indistinguishable in efficacy penia. Curson and Hale (1979) and McHarg and and onset of action. An important factor however McHarg (1979) published some details on 2 of these emanating from these trials is the apparent paucity of cases. Four of them were reported to the Australian side effects emerging on treatment with mianserin. Drug Evaluation Committee (1980) following the Daily dosage in these studies ranged from 20-30 mg introduction of mianserin in Australia in April 1978. for mianserin and 75-300 mg for the tricyclics. Adams et aL (1983), in this journal, provide clinical details on a further 4 of these cases, one of whom died. In the last few months, 2 additional cases of Side effects mianserin-induced agranulocytosis have been re- http://pmj.bmj.com/ Mianserin has sedative properties and drowsiness ported (Page, 1982; Achar, 1982). is the most frequently reported side effect. However, White cell depression usually occurs early, typi- this often diminishes within the first week. The cally at between 4 and 6 weeks after the start of clinical trials suggest that peripheral anticholinergic treatment. It typically presents with oral ulceration effects are rare and occur to a less extent than with and a sore throat. The neutrophil count in most of tricyclics. These observations from therapeutic trials these cases was severely reduced to 0 2 x 109/litre or are supported by experimental double-blind studies less, but, typically, complete recovery occurred once on October 1, 2021 by guest. Protected in depressed patients (Ghose, Coppen and Turner, the drug was withdrawn. 1976; Wilson, Petrie and Ban, 1980) and in normal This association of mianserin with a small number volunteers (Kopera, 1980). of cases of blood dyscrasia should be viewed against A further important feature emerging from clinical the background that all psychotropic drugs are trials with mianserin is an apparent lack of cardiovas- reported as being associated with some form of blood cular problems such as increased heart rate and dyscrasia. Nevertheless, it dictates that all patients hypotension. Burgess et al. (1979), in an analysis of receiving mianserin should be carefully observed the cardiovascular effects of mianserin and other particularly during the first few weeks of treatment. antidepressants, reported that mianserin lacked the In the event of the patient developing symptoms of cardiotoxic and negative inotropic effects of the infection such as fever, stomatitis or sore throat the tricyclic antidepressants. Experimental studies in drug should be stopped immediately and full haema- intact