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Br. J. clin. Pharmac. (1983) 15, 263S-268S THE PHARMACOLOGY OF MIANSERIN AN UPDATE R. J. MARSHALL Department of Pharmacology, Organon Laboratories Ltd., Newhouse, Lanarkshire MLI 5SH, Scotland, UK

Introduction involved in the actions of both the classical and newer atypical clinically effective Since its introduction into clinical medicine, agents. My intention in this paper is to briefly mianserin hydrochloride has been shown to be a discuss some of these newer areas with special potent and useful treatment for depressive illness reference to mianserin. and seems to offer real advantages over the established tricyclic in terms of fewer side-effects, lack of cardiotoxicity and greater Antagonism of presynaptic alpha-(@2) adrenoceptors safety in overdosage. In the proceedings of the last mianserin symposium published in this journal Although mianserin has been shown to be only (Peet & Turner, 1978), the pharmacology of weakly active (or inactive) in inhibiting in vivo mianserin pertaining to its mode of action was noradrenaline re-uptake (Leonard, 1974; Goodlet et succinctly reviewed in eight pages and pointed to al., 1977), there is good evidence that noradrenaline the atypical pharmacological profile of the drug in turnover and release are increased by the drug the standard battery of pharmacological tests for (Baumann & Maitre, 1977; Fludder & Leonard, predicting antidepressant activity (Table 1). Since 1979; Sugrue, 1980). The most likely mechanism then several comprehensive reviews on possible underlying these effects of mianserin is an mechanisms underlying antidepressant activity have antagonist action on the oc2-adrenoceptors which appeared (Sulser, 1979; Kostowski, 1981; Maj, are situated on the presynaptic nerve terminal and 1981; Waldmeier, 1981) and an excellent review of which regulate noradrenaline release [see Langer the pharmacology of mianserin published (van (1977) for a review]. Certainly the ability of Riezen et al., 1981). mianserin to potentiate noradrenaline-release The medicinal chemical design of potential evoked by K+ (Nickolson & Weiringa, 1981) or antidepressant agents has for many years been electrical stimulation (Baumann & Maitre, 1977) in dictated (some might even say hampered) by the brain slices suggests an o2-antagonist action. In 'biogenic amine hypotheses' [see Waldmeier (1981) addition, -binding studies have shown that for a recent review] which broadly state that certain mianserin can effectively displace [3H] types of are associated with (or are due from rat cortex (Maggi et al., 1980; Tang & to) deficient noradrenergic and/or serotoninergic Seeman, 1980; Peroutka & Snyder, 1981) with Ki neurotransmission in certain areas of the brain. values between 12 and 35nM. It should be noted These views have been rigorously challenged or that in this respect mianserin is at least 20-100 modified over the last few years, partly on the times more potent than the tricyclic antidepressants grounds that chronic treatment of animals with (Maggi et al., 1980). The relevance of a2- clinically-active antidepressants produces quite adrenoceptor block to the actions of mianserin has different biochemical and pharmacological effects however been recently confused by the observation from those seen after acute dosing (e.g., U'Prichard in rats that chronic mianserin therapy (10mg/kg i.p. et al., 1978; Maj, 1981; Sugrue, 1981). In addition a for 15 days) potentiates the auto-inhibitory actions wealth of evidence suggests that mechanisms other of noradrenaline on superfused hypothalamic than neuronal amine re-uptake inhibition may be synaptosomes (Cerrito & Raiteri, 1981). These interesting results, which are shown in Figure 1, Table 1 Atypical pharmacological profile of mianserin suggest that the noradrenergic release system may in the rat become more sensitive to the negative feedback regulatory action of released noradrenaline following long-term blockade of the presynaptic o;2- Mianserin mianserin. hypothermia Antagonism No effect adrenoceptors by catatonia Potentiation Inhibition The oc2-receptor blocking actions of mianserin are locomotion Potentiation No effect also readily demonstrated in sympathetically- Noradrenaline turnover Reduced Increased innervated peripheral tissues (Doxey et al., 1978; stereotypy Potentiation Inhibition Brown et al., 1980; Doggrell, 1980). The latter group of workers has compared the antagonist Adapted from Peet & Behagel (1978) actions of a series of antidepressant drugs on both 0306-5251/83/150263-06 $01.00 ©) The Macmillan Press Ltd., 1983 264S R.J. MARSHALL

.., noradrenergic transmission arose from the observations that chronic administration of antidepressant drugs to animals leads to a decrease in the density and/or sensitivity of central j- adrenoceptors (Vetulani & Sulser, 1975; Vetulani et al., 1976; Banerjee et al., 1977; Wolfe et al., 1978). Chronic treatment of rats with mianserin results in an attenuation of noradrenaline-induced increases in cAMP without any apparent accompanying reduction in the number of 3-binding sites as assessed by ligand-binding (Mishra et al., 1980;

r: Sellinger-Barnette et al., 1980).- More recently it has been demonstrated that in rats treated for 10 days _> lU: ~~~~~~~~'IL.:-L;.i:j.:.ii L_ ;.S with mianserin (30mg/kg, s.c.) there is a marked decrease in the sensitivity of cingulate cortical Figure 1 Reduction by extracellular noradrenaline of neurones to microiontophoretically applied K + evoked [3H] noradrenaline release in noradrenaline (Olpe et al., 1981). This reduced hypothalamic synaptosomes from control rats (0) and sensitivity of cortical neurones to the from animals chronically treated with mianserin(n). action of noradrenaline was not observed 24h after Control responses to K+ in absence of noradrenaline a single injection of mianserin or after chronic are shown for untreated (0) and mianserin-treated (A) treatment with the weak noradrenaline re-uptake animals. From Cerrito & Raiteri (1981), with inhibitor, (Figure 2). It is tempting to permission. speculate that the reduced 0-adrenoceptor sensitivity (assessed either by biochemical or acl (rat anococcygeus muscle) and ;2 (rat vas electrical measurements) observed in animals after deferens) adrenoceptors and concluded that 1) not chronic antidepressant treatment may be at least all antidepressants block o2-receptors, 2) none of partly produced by a desensitisation of the post- the antidepressants showed marked selectivity for synaptic 3-receptor caused by excessive levels of aC2-receptors, and 3) all the antidepressants studied noradrenaline in the . However other were much weaker than in blocking mechanisms cannot be excluded [see Sulser (1979) either cxl or a-adrenoceptors in these tissues (Table for a discussion]. 2). Using such peripheral test systems, compounds possessing selective x2-adrenoceptor antagonist properties have been identified (Chapleo et al., Interaction with serotoninergic transmission 1981; Michel & Whiting, 1981). Whether any of these compounds possess useful clinical Unlike many of the tricyclic antidepressants, antidepressant potency remains to be elucidated. mianserin does not inhibit neuronal 5-HT re-uptake in the brain (Raiteri et al., 1976; Goodlet et al., Down-regulation of P-adrenoceptors 1977). Although mianserin is a potent antagonist at 5-HT receptors in peripheral tissue (Vargaftig et al., The idea that depression is associated with an 1971; van Riezen, 1972) there remains some Ioverfunction' (rather than an 'underfunction') of controversy regarding its interaction with 5-HT

Table 2 a-Adrenoceptor antagonist properties of antidepressants in peripheral tissues of the rat (Prejunctiona)c.2 (Post4junctionaboc. Ratio Rat vas deferens' Rat anococcygeusb pre/post 7.9 x 10-9 8.9x 10-7 113 2.9 x 10-6 1.4 x 10-9 0.0005 8.6 x 10-6 5.8x 10-8 0.007 Mianserin 6.5 x 10-7 1.8 x 10-7 0.28 1.1 x 10-6 1.8 x 10-7 0.16 1.3 x 10-5 >3.5 x 10-s Adalpted from Brown et al. (1980). 'Molar concentration causing 20% reversal. bMolar pA2 versus noradrenaline contractions PHARMACOLOGY OF MIANSERIN 265S

100 Table 3 5-HT properties of some antidepressants 90 80 EC50(mglkg) Tryptamine 70. 5-HTP head twitch convulsions Drug Mouse Rat Rat 60 0.038 0.26 5.0 ,,- -/ Mianserin 0.094 0.84 1.5 50 .0 0 Amitriptyline 1.3 5.5 4.7 40 as 40 Trazodone 5.2 9.3 3.8 .=co ' 30 from Maj (1981) ._ Adapted ;r,C 20 0 0 c 10 co brain remain to be elucidated but it has been 40 0 I I a suggested (Maj, 1981) that 5-HT antagonists may 0. C, 100 release a 'serotoninergic brake' on noradrenergic c -b neurones, leading to an increased noradrenaline 90 turnover and availability (see Figure 3). .C0 80 0c 70 -receptor antagonism 60 - - - - 1It is well established that mianserin possesses potent 50 histamine-receptor antagonist properties in peripheral tissues (van Riezen et al., 1981). 40 Mianserin has a higher affinity (KB 10-9M) for histamine (H1) receptors in intestinal smooth 30 muscle than those (H2) in cardiac muscle 20 (KB-10-M). Several lines of evidence suggest that histamine may play some neurotransmitter role in 10 mammalian brain (Schwartz, 1977, 1979; Green et | |I I Ifi | t E | z al., 1979) and the presence of both types of 0 10 30 90 histamine receptors has been demonstrated [see 'Dose' of NE in nA Schwartz et al., (1981)]. The demonstration that Figure 2 Dose-response curves for the depressant histamine-induced (H2) increases in cAMP in action of microiontophoretically administered hippocampus homogenates could be inhibited in a noradrnenaline to cortical neurones of rats treated either competitive fashion by submicromolar chronic-ally ( ) or acutely (---) with either a) concentrations of antidepressants (Table 4) has led mianseirin (30mg/kg, s.c.) or b) iprindole (10mg/kg, to the suggestion that H2-receptor blockade may be i.p.). Firom Olpe et al. (1981), with permission. important for antidepressant action (Green & Maayani, 1977; Kanof & Greengard, 1978). In this respect the antidepressant drugs were more potent serotoniinergic transmission and 5-HT receptors in the than the standard H2-antagonist, . brain [ssee van Riezen et al., (1981), Maj (1981)]. However a number of major objections have been Certain]ly in some test systems, mianserin has been raised against this interesting hypothesis [see shown to be a potent antagonist of 5-HT or Schwartz et al. (1981)]. One of these objections tryptamline (Table 3) and in this respect is usually concerns the fact that none of the antidepressants more rpotent than other antidepressant agents. display much antagonism of Jtamine-induced Ligand--binding studies also support the view that a gastric acid secretion, an effect Mch is mediated central 5-HT antagonist action of mianserin cannot through stimulation of H2-receptors and which is be rule(d out as an important mechanism for its readily blocked by the H2-antagonist, cimetidine. It antidepiressant action (e.g., Whitaker & Cross, is therefore of interest to note the recent 1980; Fiall & Ogren, 1981; Peroutka & Snyder, observation, that mianserin inhibits pentagastrin- 1981). 1rhe ways in which serotoninergic inhibition induced gastric acid secretion in man [see Wilson et interact with noradrenergic transmission in the al. (1983, this issue)]. 266S R.J. MARSHALL

Figure 3 Possible sites of action of mianserin at central noradrenergic synapse. On presynaptic terminal mianserin blocks inhibitory H2, cx2 or 5-HT receptors, leading to increased noradrenaline release. actions probably linked to blockade of postsynaptic H1 and a,-receptors.

Table 4 Inhibition of histamine-sensitive adenylate for various pharmacologically-characterized binding cyclase in guinea pig hippocampus sites. However it still remains unclear how this binding modifies central neurotransmission, Ki(uM) especially in depressive states. A simplistic Antidepressants Homogenates representation of possible ways in which mianserin 0.20 modulate noradrenergic neurotransmission is Amitriptyline 0.04 could 0.30 shown in Figure 3. The most prominent effect of Amitriptyline 0.04 mianserin is the acceleration of cerebral Mianserin 0.06 noradrenaline turnover which is probably brought H2-antagonists about by blockade of presynaptic oc2-adrenoceptors. Cimetidine 0.7 Mianserin is also a potent antagonist of 5-HT 0.9 receptors at least in some parts of the brain and HI-antagonists this effect clearly deserves more attention. With 0.03 respect to modulation of 0-adrenoceptor sensitivity, Cyproheptadine 0.04 there seem to be differences between mianserin and other antidepressants. In conclusion the present From Schwartz et al. (1981) state of the art is accurately reflected in the concluding remarks made at a recent symposium In contrast to the controversy surrounding H2- on antidepressants: 'Whatever mechanism or antagonist actions of antidepressants, there is clear mechanisms are eventually prqved, no one evidence that many (but not all) antidepressants are questions that they (the antidepressants) have potent antagonists of Hl-receptors. Whether enhanced our understanding of neurochemical blockade of Hi-receptors is involved in either the processes.... Most of all, the drugs help the sick, therapeutic or undesirable effects of antidepressants even while they humble, confuse and frustrate those remains unclear. A recent analysis strongly suggests who study them' (Green, 1981). that H1-receptor block correlates well with sedative action but is not a prerequisite for antidepressant activity (Schwartz et al., 1981).

Conclusions The author should like to acknowledge the assistance of It is clear, that in common with other Mr I. McFarlane for literature searching and Mrs A. Jones antidepressants, mianserin possesses high affinity and Ms L. Hopton for secretarial assistance. PHARMACOLOGY OF MIANSERIN 267S

References MAJ, J. (1981). Serotoninergic mechanisms of antidepressant drugs. Pharmakopsychiat., 14, 35-39. BANERJEE, S., KUNG, L., RIGGI, S. & CHANDA, S. (1977). MICHEL, A.D. & WHITING, R.L. (1981). 2-(2-Imidazoyl Development of cx- receptor subsensitivity by methyl)- 1 ,4-benzodioxans, a series of selective a2- antidepressants. Nature, 268, 455-456. adrenoceptor antagonists. Br. J. Pharmac., 74, 255-256. BAUMANN, P. & MAITRE, L. (1977). Blockade of MISHRA, R., JANOWSKY, A. & SULSER, F. (1980). Action presynaptic oc-receptors and of amine uptake in the rat of mianserin and on the brain by the antidepressant, mianserin. Naunyn- receptor coupled adenylate cyclase system in brain: Schmeid. Arch. Pharmacol., 300, 31-37. subsensitivity without reduction in ,- BROWN, J., DOXEY, J.C. & HANDLEY, S. (1980). Effects of binding. Neuropharmacol., 19, 983-990. oa-adrenoceptor agonists and antagonists and of NICKOLSON, V.J. & WEIRINGA, J.H. (1981). Presynaptic antidepressant drugs on pre- and postsynaptic a- a-block and inhibition of noradrenaline and 5- adrenoceptors. Eur. J. Pharmacol., 67, 33-40. hydroxytryptamine reuptake by a series of compounds CERRITO, F. & RAITERI, M. (1981). Supersensitivity of related to mianserin. J. Pharm. Pharmac., 33, 760-766. central noradrenergic presynaptic OLPE, H.R., SCHELLENBERG, A. & STEINMANN, M. W. following chronic treatment with the antidepressant (1981). Differential actions of mianserin and iprindole mianserin. Eur. J. Pharmacol., 70, 425-426. on the sensitivity of cortical neurons to noradrenaline: CHAPLEO, C.B., DOXEY, J.C., MYERS, P.L. & ROACH, A.G. effect of clonidine treatment. Eur. J. Pharmacol., 72, (1981). RX781094, a new potent, selective antagonist of 381-385. c2-adrenoceptors. Br. J. Pharmac., 74, 842. PEET, M. & BEHAGEL, H. (1978). Mianserin-a decade of DOGGRELL, S.A. (1980). Effect of mianserin on scientific development. Br. J. clin. Pharmac., 5 (Suppl. noradrenergic transmission in the rat anococcygeus 1), 5S-lOS. muscle. Br. J. Pharmac., 68, 241-250. PEET, M. & TURNER, P. (1978). Proceedings of a DOXEY, J.C., EVERITT, J. & METCALF, G. (1978). symposium on mianserin-October 1977. Br. J. clin. Mianserin-an analysis of its peripheral autonomic Pharmac., 5 (Suppl. 1). actions. Eur. J. Pharmacol., 51, 1-10. PEROUTKA, S.J. & SNYDER, S.H. (1981). [3H] Mianserin: FLUDDER, J.M. & LEONARD, B.E. (1979). Chronic effects differential labelling of serotonin2 and histamine1 of mianserin on noradrenaline in the rat receptors in rat brain. J. Pharmac. exp. Ther., 216, 142- brain: evidence for a presynaptic a-adrenolytic action in 148. vivo. Psychopharmacol., 64, 329-332. RAITERI, M., ANGELINI, F. & BERTOLINI, A. (1976). GOODLET, I.E., MIREYLEES, S.E. & SUGRUE, M.F. (1977). Comparative study of the effects of mianserin, a Effects of mianserin, a new antidepressant, on the in antidepressant, and of imipramine, on uptake vitro and in vivo uptake of monoamines. Br. J. and release of neurotransmitters in synaptosomes. J. Pharmac. 61, 307-313. Pharm. Pharmac., 28, 483-488. GREEN, J.P. (1981). Typical and atypical antidepressants. SCHWARTZ, J.C. (1977). mechanisms in T.LP.S., October, vii-ix. brain. Ann. Rev. Pharmacol. Toxicol., 17, 325-339. GREEN, J.P., JOHN, C.L. & WEINSTEIN, H. (1979). In: SCHWARTZ, J.C. (1979). Minireview: histamine receptors Psychopharmacology-A Generation of Progress, ed. in the brain. Life Sci., 25, 895-912. Lipton, M. A., Dimascio, A & Killam, K. F., p. 319. SCHWARTZ, J.C., GARBARG, M. & QUACH, T.T. (1981). New York: Raven Press. Histamine receptors in brain as targets for tricyclic GREEN, J.P. & MAAYANI, S. (1977). Tricyclic antidepressants. T.IP.S., May, 122-125. antidepressant drugs block histamine H2-receptors in SELLINGER-BARNETTE, M.M., MENDELS, J. & FRAZER, brain. Nature, 269, 163-167. A. (1980). The effect of psychoactive drugs on beta- HALL, H. & OGREN, S.O. (1981). Effects of antidepressant adrenergic binding sites in rat brain. Neuropharmacol., drugs on different receptors in the brain. Eur. J. 19, 447-455. Pharmacol., 70, 393-407. SUGRUE, M.F. (1980). Changes in rat brain monoamine KANOF, P.D. & GREENGARD, P. (1978). Brain histamine turnover following chronic antidepressant receptors as targets for antidepressant drugs. Nature, administration. Life Sci., 26, 423-429. 272, 329-333. SUGRUE, M.F. (1981). Effects of acutely and chronically KOSTOWSKI, W. (1981). Brain noradrenaline, depression administered antidepressants on the clonidine-induced and antidepressant drugs:Jfacts and hypotheses. T.IP.S., decrease in rat brain 3-methoxy-4- December, 314-317. hydroxyphenylethylene glycol sulphate content. Life LANGER, S.Z. (1977). Presynaptic receptors and their role Sci., 28, 377-384. in the regulation of transmitter release. Br. J. Pharmac., SULSER, F. (1979). New perspectives on the mode of 60, 481-498. action of antidepressant drugs. T.IP.S., December, 92- LEONARD, B.E. (1974). Some effects of a new tetracyclic 94. antidepressant compound Org GB94 on the metabolism TANG, S.W. & SEEMAN, P. (1980). Effect of antidepressant of monamines in the rat brain. Psychopharmacol., 36, drugs on serotoninergic receptors. Naunyn-Schmeid. 221-236. Arch. Pharmacol., 311, 255-261. MAGGI, A., U'PRICHARD, D.C. & ENNA, S.J. (1980). U'PRICHARD, D., GREENBERG. D. SHEEHAN, P. & Differential effects of antidepressant treatment on brain SNYDER, S. (1978). Tricyclic antidepressants; receptors. Eur. J. Pharmacol., 61, 91- therapeutic properties and affinity for noradrenergic 98. receptor binding sites in the brain. Science, 199, 197-198. 268S R.J. MARSHALL

VAN RIEZEN, H. (1972). Different central effects of the 5- antidepressant treatments reduces reactivity of the HT antagonists mianserin and cyproheptadine. Arch. noradrenergic cyclic AMP generating system in limbic int. Pharmacodyn. Ther. 198, 256-269. forebrain. Nature, 257, 495-496. VAN RIEZEN, H., PINDER, R.M., NICKOLSON, V.J., WALDMEIER, P.C. (1981). Noradrenergic transmission in HOBBELEN, P., ZAYED, I. & VAN DER VEEN, F. (1981). depression: under or over function? Pharmakopsychiat., Mianserin, a really different anti-depressant. In: 14, 3-9. Pharmacological and Biological Properties of Drug WHITAKER, P.M. & CROSS, A.J. (1980). 3H-Mianserin Substances, vol. 3. Washington: American binding of calf caudate: possible involvement of Pharmaceutical Association. receptors in antidepressant drug action. VARGAFTIG, B.B., COIGNET, J.L., DE VOS, C.J., GRIJSEN, Biochem. Pharmac., 29, 2709-2712. H. & BONTA, I.L. (1971). Mianserin hydrochloride: WILSON, J.A., READ, J.R.M., BOYD, E.J.S., & WORMSLEY, peripheral and central effects in relation to antagonism K.G. (1983). Inhibition of pentagastrin-stimulated and against 5-hydroxytryptamine and tryptamine. Eur. J. overnight gastric secretion by mianserin. Br. J. clin. Pharmacol., 16, 336-346. Pharmac., 15 (Suppl.), 329S-333S. VETULANI, J., STAWARZ, R.J., DINGELL, J.V., & SULSER, WOLFE, B.B., HARDEN, T.K., SPORN, J.R. & MOLINOFF, F. (1976). A possible common mechanism of action of P.B. (1978). Presynaptic modulation of beta-adrenergic antidepressant treatments. Naunyn-Schmeid. Arch. receptors in rat cerebral cortex after treatment with Pharmacol., 293, 109-114. antidepressants. J. Pharmacol. exp. Ther., 207, 446-454. VETULANI, J. & SULSER, F. (1975). Action of various