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Home , Amitriptyline, Clomipramine, Imipramine, Maprotiline, Mianserin, Tetracyclic

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 , a A. WAKELING Ph.D., B.Sc., F.R.C.Psych., D.P.M.

Academic Department of Psychiatry, Royal Free Hospital School of , London NW3 2PF

Introduction their actions on central 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 . These claims the monoamine oxidase inhibitors (MAOI) and should be received with caution as there has been an compounds based on the 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 . 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 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 . important of these are cardiotoxicity, potential fatality in overdose, marked peripheral anticholin- on October 1, 2021 by guest. Protected ergic activity and reduction in 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 drugs. Included among these are; viloxa- there are well-tried effective treatments raises serious zine and , 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, 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 indicates that mianserin (Pinder and Fink, 1982). These include comparison accounts for about 11% of reported antidepressant with (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 of mian- Dreyfus and Pull, 1978) and with 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 . 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 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 have been re- http://pmj.bmj.com/ Mianserin has properties and drowsiness ported (Page, 1982; Achar, 1982). is the most frequently reported side effect. However, White cell 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 treatment. It typically presents with oral ulceration effects are rare and occur to a less extent than with and a sore throat. The 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 rate and dyscrasia. Nevertheless, it dictates that all patients . 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 , stomatitis or sore throat the tricyclic antidepressants. Experimental studies in drug should be stopped immediately and full haema- intact animal , whole animals and in healthy tological investigation started. It might be prudent, subjects further demonstrate a lack of cardiotoxicity where possible, for patients to have regular blood for mianserin (Harper and Hughes, 1977; Kopera et counts with a particular focus at between 4 and 6 al., 1980). weeks. It should be emphasized however that the key Postgrad Med J: first published as 10.1136/pgmj.59.690.229 on 1 April 1983. Downloaded from

Mianserin-efficacy and side effects 231 to the early detection of side effects is regular careful BURNS, B. & DE RIDDER, J.J. (1976) Mianserin hydrochloride: a and direct clinical observation of patients. novel antidepressant. British Journal of Psychiatry, 129, 342. CURSON, D.A. & HALE, A.S. (1979) Mianserin and agranulocytosis. British Medical Journal, 1, 378. Conclusions DALY, R.J., BROWNE, P.J. & MORGAN, E. (1979) Mianserin in the treatment of depressive illness. A comparison of amitriptyline. There is evidence to indicate that mianserin has Irish Journal of Medical Science, 148, 145. antidepressant activity. It is generally well tolerated DE BUCK, R. (1980) A comparison of the efficacy and side effects of and appears to have a low propensity for interaction mianserin and clomipramine in primary depression: a double with many of the commonly used drugs. Due to its blind randomized trial. Current Medical Research and Opinion, 6 (suppl. 7), 88. apparent lack of serious side effects, particularly the EDWARDS, J.G. (1979) Antidepressants and convulsions. Lancet, ii, absence of cardiotoxicity and anticholinergic effects 1368. and its safety in overdosage, it is now in widespread GHOSE, K., COPPEN, A. & TURNER, L. (1976) Autonomic actions and use. It is widely used in general practice and primary interactions of mianserin hydrochloride (Org. GB 94) and amitriptyline in patients with depressive illness. Psychopharmaco- care settings particularly among the elderly and those logy, 49, 201. with medical and cardiovascular problems. The HARPER, B. & HUGHES, I.E. (1977) A comparison in rabbit isolated recent reports of severe blood dyscrasias in a few hearts of the dysrhythmogenic potential of amitriptyline, mapro- patients receiving mianserin should, however, induce tiline and mianserin in relation to their ability to block noradre- naline uptake. British Journal of , 59, 651. caution. Blackwell (1981b) has cogently pointed out ITIL, T.M., POLVAN, N. & HSU, W. (1972) Clinical and EEG effects 'that a consistent feature of the literature on all of GB 94, a tetracyclic antidepressant. Current Research, psychotropic drugs is the extended time periods that 14, 395. occur between the introduction of a new compound KOPERA, H. (1980) Anticholinergic effects of mianserin. Current and the of its Medical Research and Opinion, 6 (suppl. 7), 132. discovery full range of adverse effects'. KOPERA, H., FLUCH, N., HARPF, H., KLEIN, W.W. & STULEMEIJER, He calls attention to the fact that new side effects S.M. (1980) Cardiovascular effects of mianserin. A comparative such as speech blockage are being recognized after 20 study with amnitriptyline and a placebo in healthy subjects. years of extensive use of the tricyclic antidepressants. International Journal of Clinical Pharmacology, 18, 104. KRETSCHMAR, J.H. (1980) Mianserin and amitriptyline in elderly It is important, therefore, to maintain a high level of hospitalised patients with depressive illness: a double blind trial. copyright. vigilance in the use of all psychotropic drugs and to Current Medical Research and Opinion, 6 (suppl. 7), 144. be alert to the possibility of new adverse effects MCHARG, A.M. & MCHARG, J.F. (1979) Leucopenia in association arising in apparently safe compounds. with mianserin treatment. British Medical Journal, 1, 623. Antidepressants are powerful drugs and as yet MONTGOMERY, S.A., CRONHOLM, B., ASBERG, M. & MONTGOM- ERY, D.B. (1978) Differential effects on suicidal ideation of their mode of action is incompletely understood. mianserin, maprotiline and amitriptyline. British Journal of There is a consensus of opinion that these com- Clinical Pharmacology, 5 (suppl. 1), 778. pounds are overprescribed particularly in the pri- MURPHY, J.E. (1975) A comparative trial of Org GB 94 and care Yet imipramine in the treatment of depression in general practice. mary setting. it is precisely here that high Journal of International Research, 3, 251. standards of clinical monitoring are often lacking. MURPHY, J.E. & K.M. A BRIDGEMAN, (1978) comparative trial of http://pmj.bmj.com/ mianserin and amitriptyline in the treatment of depression in References general practice. Journal ofInternational Medical Research, 6, 199. MURPHY, J.E., DONALD, J.F. & MOLLA, A.L. (1976) Mianserin in the ACHAR, K.N. (1982) Mainserin induced agranulocytosis. British treatment of depression in general practice. Practitioner, 217, 135. Medical Journal, 285, 208. PAGE, C.E. (1982) Mianserin induced agranulocytosis. British Medi- ADAMS, P.C., ROBINSON, A., REID, M.M., VISHU, M.C. & LIVING- cal Journal, 284, 1912. STONE, M. (1983) Blood dyscrasias and mianserin. Postgraduate PARE, C.M.B., KLINE, N., HALLSTROM, C. & COOPER, T.B. (1982) Medical Journal, 59, 31. Will amitriptyline prevent the 'cheese' reaction of monoamine ADVERSE DRUG REACTIONS ADVISORY COMMITTEE (1980) Medical oxidase inhibitors. Lancet, ii, 183.

Journal ofAustralia, ii, 673. PICHOT, P., DREYFUS, J.F. & PULL, C. (1978) A double blind on October 1, 2021 by guest. Protected BLACKWELL, B. (1963) Hypertensive crisis due to MAOI. Lancet, ii, multicentre trial comparing mianserin and imipramine. British 849. Journal of Clinical Pharmacology, S (suppl. I), 87S. BLACKWELL, B. (198 la) Adverse effects ofantidepressant drugs. Part PINDER, R.M. & FINK, M. (1982) Mianserin. In: Modern Problems of I: Monoamine oxidase inhibitors and tricyclics. Drugs, 21, 201. Pharmacopsychiatry (ed. T. A. Blau). Karger, Basel. BLACKWELL, B. (1981 b) Adverse effects ofantidepressant drugs. Part SHAW, W.L. (1980) The comparative safety ofmianserin in overdose. 2: Second generation antidepressant and rational decision making Current Medical Research and Opinion, 6 (suppl. 7), 44. in antidepressant therapy. Drugs, 21, 273. SMITH, A.H.W., NAYLOR, G.S. & MOODY, J.P. (1978) Placebo- BLAHA, L., PINDER, R.M. & STULEMEIJER, S.M. (1980) Double- controlled double-blind trial of mianserin hydrochloride. British blind trial of mianserin versus clomipramine. Current Medical Journal of Clinical Pharmacology, 5 (suppl. 1), 678. Research and Opinion, 6 (suppl. 7), 99. TYRER, P. (1979) Clinical use of monoamine oxidase inhibitors. In: BRANCONNIER, R.J., COLE, J.O. & GHAZVINIAN, S. (1981) The Psychopharmacology of Affective Disorders (eds E. S. Paykel and therapeutic profile of mianserin in mild elderly depressives. A. Coppen), p. 159. Oxford, Univetsity Press, Oxford. Psychopharmacology Bulletin, 17, 129. WHEATLEY, D. (1975) Controlled of a new antidepres- BURGESS, C.D., MONTGOMERY, S., WADSWORTH, J. & TURNER, L. sant (Org GB 94) of novel chemical formulation. Current Therapy (1979) Cardiovascular effects of amitriptyline, mianserin, zimeli- Research, 18, 849. dine and nomifensin in depressed patients. Postgraduate Medical WILSON, W.H., PETRIE, W.M. & BAN, T.A. (1980) Possible lack of Journal, 55, 704. anticholinergic effects with mianserin: a pilot study. Journal of COPPEN, A., GUPTA, R., MONTGOMERY, S., GHOSE, K., BAILEY, J., Clinical Psychiatry, 41, 63. (Received 26 October 1982)