Differential Effects on Suicidal Ideation of Mianserin, Maprotiline and Amitriptyline S

Br. J. clin. Pharmac. (1978), 5, 77S-80S

DIFFERENTIAL EFFECTS ON SUICIDAL IDEATION OF MIANSERIN, MAPROTILINE AND AMITRIPTYLINE S. MONTGOMERY Academic Department of Psychiatry, Guy's Hospital Medical School, London Bridge, London SE1 9RT, UK B. CRONHOLM, MARIE ASBERG Karolinska Institute, Stockholm D.B. MONTGOMERY Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, U K

1 Eighty patients suffering from primary depressive illness were treated for 4 weeks, following a 7-d (at least) no-treatment period, with either mianserin 60 mg daily (n = 50), maprotiline 150 mg at night- time (n = 15) or amitriptyline 150 mg at night-time (n = 15) in double-blind controlled trials run concurrently in the same hospital on protocols having the same design and entry criteria. 2 The effects of the three drugs were examined for their proffle of action using a new depression rating scale (Montgomery and Asberg Depression Scale, MADS) claimed to be more sensitive to change. There was no significant difference in mean entry scores or mean amelioration of depression on the MADS or the Hamilton Rating Scale (HRS) between the three drugs, but individual items on the MADS did show significant differences in amelioration. A highly significant (P < 0.01) difference was observed in favour of mianserin against maprotiline on both items of'suicidal thoughts' and 'pessimistic thoughts' on the MADS. The suicidal item on the HRS showed a similar tendency which did not reach significance. 3 This finding is considered in relation to a possible mode of action of mianserin and the relevance to reported subgroups ofdepressive illness with increased suicidal ideation. 4 The increasing problems of self-poisoning with tricyclic and tetracyclic antidepressants are dis- cussed in relation to the reported relative lack oftoxicity of mianserin.

Introduction SUICIDAL ideation and acts are often considered to suicidal ideation. One trial compared a single nightly be part of depressive illness, and the assessments of dose against divided doses of mianserin, as reported in the efficacy of antidepressants have generally looked this issue (Montgomery et al., 1978). The other trial, at improvement of the depressive illness itself rather comparing amitriptyline and maprotiline, is part of a than this symptom separdtely. Suicidal behaviour, larger plasma level study to be published. The trials however, often occurs in the absence of depressive had protocols with the same design and entry and ex- illness, and the increasing abuse of tricyclic and clusion criteria. Allocation was not made randomly tetracyclic antidepressant drugs in self-poisoning is a but by factors like the availability oftablets, and so on, cause of concern (OPCS, 1976). and the analysis was made retrospectively. There were Ideally, an antidepressant should have some specific no significant differences on entry between the effects on suicidal ideation in those patients at risk, in patients. These trials were part of a larger cross- addition to its general antidepressant effect. It should cultural investigation examining psychopathology also preferably be less toxic in case of self-poisoning. (Montgomery et al., 1977) which demonstrated the Mianserin is reported to be relatively less toxic in over- close similarity of the group to a sample of Swedish dosage (Crome & Newman, 1977) but this needs depressed inpatients. further investigation. In relation to suicidal ideation, The introduction of a new scale for depression Fleischhauer & Van Riezen (1974) have reported a (MADS), which has been constructed to be more sen- marked reduction in this symptom in an open study. sitive to treatment changes (Montgomery & Asberg, We have taken advantage of two double-blind trials unpublished), facilitated this investigation. We were being carried out in the same hospital at the same time particularly interested in the suicidal thought item on to examine the effects of different antidepressants on the MADS which has clearly defined scale steps for 78S S. MONTGOMERY, B. CRONHOLM, MARIE ASBERG & D.B. MONTGOMERY suicidal ideation irrespective of acts. The HRS a (Hamilton, 1967), which we used simultaneously, has the disadvantage of including acts in the scale steps. These are unlikely to occur in a trial setting and decrease the sensitivity of this item on the HRS for measuring suicidal ideation. We examined the profile of the effect of mianserin on the ten items of the MADS against maprotiline, which is a pure noradrenaline (NA) uptake inhibitor, C and against a standard reference, amitriptyline, which 0 has mixed NA and 5-hydroxytryptamine (5-HT) uptake inhibition effects, to see what differences emerged. sE 5 ~ lfi C Methods Fifty patients were treated with mianserin 60 mg in a double-blind trial comparing 26 with a night-time dose and 24 with divided doses (Montgomery et al., 1978). Fifteen patients were treated with amitriptyline and 15 with maprotiline at a dose of 150 mg at night as part of a double-blind trial which was running concurrently in the same hospital on protocols having the same design and the same entry criteria. The treating psy- Figure 1 Difference in amelioration (mean +s.e.m.) chiatrist was aware of treatment with mianserin but of suicidal ideation (MADS) between mianserin (a), not with amitriptyline or maprotiline, and patients amitriptyline (b) and maprotiline (c). **P<0.01; were only told they would receive a standard anti- *P<0.1. depressant. Raters were blind to actual treatment and in half of the cases ratings were carried out by two raters based on a conjoint interview at the end of Figure 2 shows a proffle of action of all ten items which independent HRS and MADS ratings were of the MADS for mianserin compared with completed. The correlation between raters was maprotiline. satisfactory (HRS entry r=0.89, MADS entry r= 0.89). The assessments made at weeks 0 and 4 were Discussion compared. A prerequisite for treatment studies of different components of the depressive syndrome is a sensitive Results and reliable instrument for each of the symptoms. An We have found (Montgomery et al., 1978) that there accurate profile of symptom changes should provide was no apparent difference between the two dosage information on the differential biochemical action of regimens of mianserin. This allowed us to combine the different drugs. The significant differences obtained on mianserin patients into a single group for the purpose of two symptom items out of ten on the MADS in a this study. Mean age and entry scores on the HRS, the study comprising relatively few patients speaks in MADS and the Beck Self-Rating Inventory for all three support ofthe sensitivity ofthe instrument. This is par- groups are shown in Table 1. There are no significant ticularly apparent in view of how relatively rarely such differences in entry or amelioration. Figure 1 shows the difference in amelioration of suicidal ideation as rated on the MADS between Table 1 Mean age and HRS, MADS and Beck mianserin, amitriptyline and maprotiline. There is a entry scores of patients receiving mianserin, highly significant difference between mianserin and amitriptyline and maprotiline maprotiline (t= 2.79; P < 0.01). The 'suicidal thoughts' item on the HRS shows the same tendency which does HRS MADS Beck Age not reach significance. The difference between (yrs) mianserin and amitriptyline shows a trend in favour of Mianserin Mean 24.64 17.24 26.28 44.4 mianserin. (t= 1.83; P<0.1). The pesimistic thoughts S.e.m. 0.79 0.59 1.71 2.12 item also shows a highly sgificant change (t=2.56; Maprotiline Mean 22.1 16.45 26.91 43.2 P <0.02) in favour ofmiansenm against maprotiline but S.e.m. 0.85 0.54 3.08 3.35 the difference between mianserin and amitriptyline does Amitriptyline Mean 23.37 15.87 21.47 41.47 not reach a trend. S.e.m. 1.11 1.15 2.66 3.66 SUICIDAL IDEATION 79S

06 *** of a very high incidence of suicidal acts (4096) in a group of depressives with low CSF 5-HIAA, referred to as 'serotonin [5-HT] depression' (Asberg et al., 05 * 1976a,b). The association of 5-HT turnover distur- bance with suicidal behaviour receives additional support from the findings of Shaw et al. (1967) of low E *> > levels of the metabolite in the brains of suicides, and CD the finding of Buchsbaum et al. (1976) of an association between suicidal behaviour and low levels of the 03 -0) 5-HT-metabolizing enzyme, monoamine oxidase CD0CA (MAO), in blood platelets. It is therefore conceivable 02 -. that drugs could be developed which have an effect on E suicidal behaviour without necessarily having equivalent effects on the other components of depressive illness. The mechanism of action of 01 mianserin is not known but it would be interesting to study in detail its possible effect on 5-HT neurones. 0 Clinically, two major components of depressive illness have often been delineated-dysphoric mood and the subjective and objective phenomena of psychomotor retardation (Cronholm & Ottosson, 1960). It has been suggested by Carlsson et al. (1969) that C)j these components reflect disturbances of serotoninergic and catecholominergic neurones, 0~~~~ respectively; and the differential effects of antidepres- C-5~~~~~~~~~~. sant drugs on the neuronal systems might account for differences in the clinical spectrum of effects. The finding of Walinder et al. (1976) of a more Figure 2 Profile of action of mianserin compared pronounced effect on dysphoric mood but no with maprotiline on the MADS. ***PO<001Q (= 2.79); **P<0.02 (t=2.56); *trend Ptryptophan is added to the 5-HT uptake inhibitor, clomipramine, is in line with this theory. Interestingly, in our study the pure NA uptake blocker, maprotiline, shows a differences between antidepressant drugs are found in trend towards more pronounced effect on variables large patient groups (Angst, 1973). which might reflect special aspects of psychomotor When compared with maprotiline, and also to a retardation (lassitude, concentration difficulties). lesser extent with amitriptyline, mianserin had a more Mianserin seems to have a more pronounced effect pronounced effect on suicidal ideation. The large on suicidal ideation and dysphoric mood; amitrip- differences observed, however, could hardly be tyline, which has effects on both neuronal systems, accounted for by anything other than differential drug occupies a position in between. It is possible that the effects despite the nature ofthe trials. These differences same differential effect might occur in suicidal are suggestive in terms of current biochemical behaviour syndromes which are not associated with hypotheses ofdepressive illness. overt depressive illness. Our findings, which indicate Recently the existence of a new suicidal behaviour that mianserin has an advantage with suicidal syndrome characterized by a low cerebrospinal fluid behaviour in depressive illness coupled with its (CSF) 5-hydroxyindoleacetic acid (5-HIAA) has been reported lower toxicity, suggests that the use of the proposed and a suggested clinical picture described by drug should be investigated in suicidal ideation in the Cronholm et al. (1977). This arose from the discovery absence of overt depressive illness.

References ANGST, J. (1973). In Depressive Illness, ed. Kielholz, P., 5-HIAA in the cerebrospinal fluid-A biochemical 269. Berne, Stuttgart, Vienna: Hans Huber. suicide predictor? Arch. gen. Psych., 33, 1193-1197. ASBERG, M., THOREN, P., TRASKMAN, L., BER- BUCHSBAUM, M.S., COURSEY, R.D., & MURPHY, TILSSON, L., & RINGBERGER, W. (1976a). D.L. (1976). The boichemical high risk paradigm: "Serotonin depression", a biochemical sub-group within behavioural and familial correlates of low platelet the affective disorders. Science, 191,478-481. monamine oxidase activity. Science, 194, 339-341. ASBERG, M., TRASKMAN, L., & THOREN, P. (1976b). CARLSSON, A., CORRODI, H., FUXE, K., & 80S S. MONTGOMERY, B. CRONHOLM, MARIE ASBERG & D.B. MONTGOMERY

HOKFELT, T. (1969). Effects of some antidepressant MONTGOMERY, S., McAULEY, R., & drugs on the depletion of intraneuronal brain MONTGOMERY, D. (1978). Relationship between catecholamine stores caused by 4a-dimethyl-meta- mianserin plasma levels and antidepressant effect in a tyramine. Eur. J. Pharmac., 5, 367-373. double-blind trial comparing a single night-time and CROME, P., & NEWMAN, B. (1977). Poisoning with divided daily dosage regimens. Br. J. clin. Pharmnac., 3, maprotiline and mianserin. Br. med. J., 2, 260. 71S-76S. CRONHOLM, B., ASBERG, M., MONTGOMERY, S., & MONTGOMERY, S., ASBERG, M., TRASKMAN, L., & SCHALLING, D. (1977). Suicidal behaviour syndrome MONTGOMERY, D. (1977). Crosscultural studies on with low CSF 5-HIAA. Br. med. J., 1, 776. the use of the CPRS in English and Swedish depressed CRONHOLM, B. & OTTOSSON, J.U. (1960). Experimen- patients. Acta. Psychiat. Scand., suppl., (in press). tal studies of therapeutic action of electroconvulsive OFFICE OF POPULATION CENSUSES AND therapy in endogenous depression. Acta. Psychiat. SURVEYS. (1976). Deaths by Poisoningfrom Solid and Scand., 35, suppl. 145, 69-101. Liquid Substances, 1974. London: OPCS. FLEISCHHAUER, J., & RIEZEN, H. VAN (1974). SHAW, D.M., CAMPS, F.E., & ECCLESTON, E. (1967). Investigations of the clinical and pharmacological action 5-Hydroxytryptamine in the hind brain of depressive picture of the tetracyclic substance mianserin. suicides. Br. J. Psychiat., 113, 1407-1410. Arzneimittel Forschung, 24, 1129-1131. WALINDER, J., SKOTT, A., CARLSSON, A., NAGY, HAMILTON, M. (1967). Development of a rating scale for A., & ROOS, B.E. (1976). Potentiation ofthe antidepres- primary depressive illness. Br. J. soc. clin. Psychol., 6, sant action of clomipramine by tryptophan. Arch. gen. 278-296. Psych., 33, 1384-1389.