Absence of an effect of mianserin on the actions of clonidine or methyldopa in hypertensive patients

Summary The concurrent administration of tricyclic antidepressants has been shown in man to result in a clinically significant impairment of the antihypertensive effect of clonidine. This interaction is thought to be related to competition for central ₂ receptors where clonidine acts as an agonist and the tricyclics act as antagonists. Although it seems to cause less cardiovascular effects than tricyclic antidepressants, the tetracyclic antidepressant, mianserin also has been reported to be an receptor antagonist and may, therefore, also interfere with the antihypertensive activity of centrally-acting drugs. This study investigates the effects of acute and chronic mianserin administration in patients with essential hypertension established on long term treatment with either clonidine or methyldopa. The first dose of mianserin was not associated with an increase in blood pressure and during a further two weeks of mianserin therapy there were no significant alterations in blood pressure, supine or erect. Similarly, mianserin did not alter heart rate either after acute or after chronic administration. Mianserin itself had a sedative effect but there was no interference with the sedation attributable to clonidine or methyldopa. Mianserin caused no reduction in salivary flow and did not influence the reduced saliva production caused by clonidine. Both clonidine and methyldopa are associated with a reduction in sympathetic outflow but there was no evidence in this study of any further change in plasma noradrenaline or 24 h urinary catecholamine excretion. This study demonstrates that if mianserin is given acutely or chronically, it does not interfere with the effects of the centrally acting antihypertensive drugs, clonidine and methyldopa. Mianserin may therefore be a suitable antidepressant for patients receiving these antihypertensive agents if drug treatment for depression is indicated.     

Interaction between mianserin and clonidine at α 2-Adrenoceptors

Summary The purpose of the present study was to characterize the effects of mianserin at ₂-adrenoceptors. Firstly, the action of mianserin on postganglionic sympathetic fibres has been studied using the tachycardia induced by stimulation of the cardiac nerve in dogs. Mianserin increased this tachycardia, but could not prevent the inhibitory effect of clonidine in this model. However, an antagonistic effect of mianserin against clonidine was observed when animals were pretreated with desipramine. Secondly, mianserin antagonized the inhibitory effect of clonidine on the electrically stimulated guinea-pig ileum. In high concentrations, mianserin reduced both electrically and acetylcholine induced contractions. Thirdly, mianserin antagonised the sleep induced by clonidine in chickens.These results are consistent with ₂-adrenoceptor blocking properties of mianserin in peripheral noradrenergic fibres in dogs, in cholinergic fibres in guinea-pig ileum and in the central nervous system in chickens.     

Mianserin: result of a decade of antidepressant research

Mianserin is a new tetracyclic compound being the active principle of the antidepressant drug Tolvon®. Originally synthesized as an antiallergic, the discovery of the antidepressant activity of mianserin was serendipitous.This review describes the historical development of mianserin as the first representative of a second generation of antidepressants. A summary is given of the clinical trials performed leading to a therapeutic profile of an antidepressant of similar efficacy as tricyclic products, however, with fewer and less severe side effects. Unlike tricyclic products mianserin lacks cardiotoxicity resulting in a superior safety also in overdosage.     

Effects of mianserin, a new antidepressant, on the in vitro and in vivo uptake of monoamines.

1 The effects of mianserin and of selected tricyclic antidepressants were compared in a number of monoamine uptake models. 2 The ability of mianserin to block the noradrenergic neurone membrane amine pump of rabbit brain stem slices was comparable to that of imipramine and amitriptyline and less than that of desipramine and nortriptyline. Both mianserin and desipramine were competitive inhibitors of noradrenaline uptake in vitro. The effect of mianserin on noradrenaline uptake in vivo was studied both peripherally and centrally. The ability of 6-hydroxydopamine to lower rat heart noradrenaline levels was found to be very sensitive to inhibition by tricyclic antidepressants. Mianserin was active in this model. However, its ability to block the 6-hydroxydopamine-induced fall in rat heart noradrenaline concentration was appreciably less than that of the tricyclics studied. 3 Mianserin, like tricyclic antidepressants, was essentially devoid of effect on dopamine uptake both in vitro and in vivo. 4 The ability of mianserin to inhibit [3H]-5-hydroxytryptamine uptake by rat hypothalamic synaptosomes was appreciably less than that of the tricyclic antidepressants studied. Mianserin was essentially devoid of effect on rat brain 5-hydroxytryptamine uptake in vivo. 5 It is concluded that in certain situations large doses of mianserin may block noradrenaline uptake in vivo. However, in no way does mianserin rival tricyclic antidepressants in blocking monoamine uptake in vivo. The clinical efficacy of mianserin cannot be attributed to inhibition of monoamine uptake.     

Comparative study of the effects of mianserin, a tetracyclic antidepressant, and of imipramine on uptake and release of neurotransmitters in synaptosomes.

The effects of mianserin, a tetracyclic antidepressant, on uptake and release of [3H]noradrenaline (3H-NA), [3H]dopamine (3H-DA), [3H]-5-hydroxytryptamine(3H-5-HT) and [3H]gamma-amino-butyric acid (3H-GABA) in synaptosomes from different areas of the rat brain were investigated in a comparative study with the tricyclic antidepressant imipramine. Mianserin and imipramine were inhibitors of 3H-NA uptake in the hypothalamus, but could not increase 3H-NA release from noradrenergic nerve endings. This behaviour was similar to that of (+)-amphetamine. Both mianserin and imipramine had essentially no effect on 3H-DA transport mechanisms in striatal synaptosomes. (+)-Amphetamine, in contrast, strongly affected both 3H-DA uptake and release. Imipramine was stronger than mianserin in inhibiting 3H-5-HT accumulation by striatal synaptosomes. In contrast, mianserin stimulated 3H-5-HT release whereas imipramine was ineffective. Mianserin had virtually no inhibitory activity on 3H-5-HT uptake by rat blood platelets. Imipramine was a modest inhibitor of 3H-GABA accumulation by whole brain synaptosomes; mianserin had no effect. Both drugs did not alter 3H-GABA release. These results indicate that mianserin interferes in a way different from that to tricyclic antidepressants with the neurotransmitter transport mechanisms at the presynaptic level.     

Mianserin: Cardiovascular effects in elderly patients

Cardiovascular effects of the tetracyclic antidepressant drug mianserin were examined in a prospective study including ten elderly depressed patients (age 60-77 years). During 1 week on placebo and 5 weeks on mianserin, 60 mg per day, orthostatic blood pressure testing, recording of standard electrocardiogram, 24-h electrocardiographic recording and systolic time intervals were carried out along with frequent monitoring of plasma levels of mianserin (13-57 micrograms/l) and the primary metabolite desmethylmianserin (7-27 micrograms/l). Mianserin caused a significant increase in orthostatic systolic blood pressure drop, and this correlated well with the plasma mianserin levels (rs = 0.70). There were no significant changes in supine blood pressure or in orthostatic changes in heart rate. No cardiac conduction disturbances or arrhythmias were provoked, but mianserin caused changes in systolic time intervals indicating impairment of left ventricular contractility and performance. Like tricyclic antidepressants mianserin should thus be used with caution in patients with latent or overt cardiovascular disease.     

Interaction of mianserin and some hypotensive drugs in Wistar rats

Mianserin is thought to exert little effect on the cardiovascular system. In fact its safety in comparison with tricyclic drugs is high. Various experiments gave varying results as for the influence of the drug on arterial blood pressure in people and animals. Therefore, a study was undertaken in Wistar rats to evaluate interactions of mianserin administered intraperitoneally as a single dose, and for 21 days with 3 hypotensive drugs showing different mechanism of action (propranolol, enalapril, prazosine). The systolic, diastolic and mean blood pressure was measured with a LETICA apparatus. The results of the study revealed that administration of mianserin in normotensive rats leads to a short-term decrease in blood pressure and significantly enhanced the hypotensive effect of prazosine. Repeated doses of mianserin lead to a temporary increase in blood pressure after 2 weeks of administration. Single and repeated administration of mianserin did not change the hypotensive effect of propranolol and enalapril. Three-week therapy with mianserin significantly enhanced the hypotensive effect of prazosine.     

Presynaptic α-adrenoceptors and the action of tricyclic antidepressant drugs in behavioural despair in rats

The influence of the -adrenolytics, yohimbine and phentolamine, given in low doses thought to block presynaptic -adrenoceptors, on the action of the tricyclic antidepressants imipramine, nortriptyline and amitriptyline in the behavioural despair test was investigated in Wistar rats. Antidepressant drugs given in a single dose or for 2 weeks reduced immobility in rats. Yohimbine potentiated the effect of nortriptyline or amitriptyline administered in a single dose and the effect of imipramine and amitriptyline given for 2 weeks. The potentiating effect of phentolamine was observed only in rats receiving a single dose of nortriptyline. Yohimbine given chronically for 3 weeks together with antidepressants counteracted the effect of imipramine and nortriptyline on behavioural despair. Similarly clonidine abolished the reduction of immobility induced by antidepressants given in a single dose. It is concluded that the despair test is a behavioural model which is sensitive to the noradrenergic component of the drugs and that the blockade of presynaptic -adrenoceptors facilitates the action of tricyclic antidepressants in this test.     

Comparative pharmacology of mianserin,its main metabolites and 6-azamianserin

Summary Mianserin, its main metabolites (8-hydroxymianserin, desmethylmianserin and mianserin-N-oxide) and a mianserin analogue, 6-azamianserin (ORG 3770), were compared with regard to effects on monoamine uptake systems, -adrenoceptors, rat exploratory activity and rat muricidal behaviour. Mianserin and desmethylmianserin inhibited noradrenaline uptake into synaptosomes (IC50's 30 and 60 nM, respectively) whereas the other compounds were much less active. Synaptosomal serotonin uptake was only inhibited to a small extent by desmethylmianserin (IC50 6 M) and 8-hydroxymianserin (IC50 9 M). Dopamine uptake was not affected by any of the compounds tested. All compounds except mianserin-N-oxide blocked presynaptic -receptors as shown by the potentiation of high-K-induced release of noradrenaline from rat cerebral cortex slices. For mianserin and 6-azamianserin this blockade was shown to be stereoselective. Desmethylmianserin was less potent than mianserin. Binding of ³H-dihydroergocryptine to rat cerebral cortex membranes was inhibited by all compounds except mianserin-N-oxide. Again, desmethylmianserin was less active than mianserin. None of the compounds appeared to block presynaptic -receptors in preference to postsynaptic -adrenoceptors. This was confirmed by the fact that the compounds studied failed to antagonize clonidine-induced sedation in the open field. Clonidine-induced diuresis, however, was stereoselectively inhibited by 6-azamianserin, but the involvement of 2-receptors in this phenomenon is not firmly established.Antihistamine properties as determined by ³H-mepyramine binding to rat brain membranes were most pronounced for 6-azamianserin. Mianserin was slightly less potent and desmethylmianserin and 8-hydroxymianserin were 10 and 30 times less potent than mianserin, respectively.Muricidal behaviour was inhibited by all compounds except mianserin-N-oxide. The least active was 8-hydroxymianserin. In contrast to mianserin and desmethylmianserin, the blockade of muricidal behaviour by 6-azamianserin was non-specific since it occurred at doses which caused a strong depression of rat open field behaviour. Mianserin was less sedative than 6-azamianserin whereas the metabolites showed no sedative effects at doses up to 32 mg/kg in the open field.It is concluded that the main metabolites of mianserin possess pharmacological properties which may add to the therapeutic potential of mianserin. Clinical testing of 8-hydroxymianserin and 6-azamianserin may give an answer to the question whether the antidepressant effect of mianserin is solely based upon its interaction with presynaptic -adrenoceptors or is due to a concomitant blockade of noradrenaline reuptake.     

The effects of imipramine, mianserin and trazodone on the chronotropic, inotropic and coronary vascular responses in the isolated perfused rat heart

1. The cardiovascular effects of the tricyclic antidepressant imipramine and two second generation antidepressants mianserin, a tetracyclic, and trazodone, a triazolopyridine derivative, were investigated in the isolated perfused rat heart. 2. Imipramine caused cardiac slowing and a negative inotropic effect at 2.5 microM after 30 min of perfusion. Conversely mianserin and trazodone had no effect on heart rate at 5 microM with inotropic state remaining above control values after 30 min of perfusion. 3. Varying effects on coronary flow, which appear to correlate well with the documented receptor actions of each drug, were demonstrated. Imipramine caused a decrease in coronary flow at 1.25 and 2.5 microM, followed by an increase at 10 microM. Mianserin decreased coronary flow at all concentrations between 1 and 20 microM. Trazodone elicited a marked elevation in coronary flow over the dose range of 2.5 to 250 microM. 4. The results in this model suggest that although the second generation agents appear to cause less cardiodepression all three agents elicit quantitatively different coronary vascular responses.     

A comparison of various antidepressant drugs demonstrates rapid desensitisation of α2-adrenoceptors exclusively by sibutramine hydrochloride

The functional status of presynaptic and post-synaptic ₂-adrenoceptors in murine brain was respectively monitored using the hypoactivity (sedation) and mydriasis (pupil dilatation) responses to clonidine (0.1 mg/kg IP). Both responses were attenuated 24 h after 3 days of injection of sibutramine hydrochloride (3 mg/kg IP). To ascertain whether this property was exclusive to sibutramine, the following antidepressant drugs were also tested for their ability to down-regulate ₂-adrenoceptors rapidly: amitriptyline, doxepin, nomifensine, desipramine, amoxapine, fluoxetine, zimeldine, tranylcypromine and mianserin. When given for 3 or 5 days at the low dose of 3 mg/kg IP, none of the other antidepressants reduced clonidine-induced hypoactivity or mydriasis. Furthermore, increasing the dose of amitriptyline, doxepin, nomifensine, desipramine, amoxapine and tranylcypromine to 10 mg/kg IP did not enable these antidepressants to attenuate the ₂-adrenoceptor-mediated responses after 3 days of treatment. An electroconvulsive shock (ECS; 200 V, 2 s) given once daily attenuated clonidine-induced mydriasis, but not hypoactivity, when administered for 3 days and both responses when administered for 5 days. In conclusion, this comparative study using antidepressant treatments with differing pharmacological modes of action demonstrated that sibutramine was the only drug which rapidly down-regulated pre- and postsynaptic ₂-adrenoceptors. ECS down-regulated postsynaptic ₂-adrenoceptors when given for 3 days, but required 5 days to desensitise both ₂-adrenoceptor populations.     

The atypical antidepressant mianserin exhibits agonist activity at κ-opioid receptors

BACKGROUND AND PURPOSE

Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors.

EXPERIMENTAL APPROACH

Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [³⁵S]GTPγS binding and MAPK phosphorylation.

KEY RESULTS

Mianserin displayed 12- and 18-fold higher affinity for κ- than µ- and δ-opioid receptors respectively. In [³⁵S]GTPγS assays, mianserin selectively activated κ-opioid receptors. The agonist activity was antagonized by the selective κ-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed κ-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing κ-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPγS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full κ-opioid agonists (–)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full κ-opioid receptor agonists in [³⁵S]GTPγS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A.

CONCLUSIONS AND IMPLICATIONS

In different cell systems, mianserin directly activates κ-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants.     

Antagonism by mianserin and classical alpha-adrenoceptor blocking drugs of some cardiovascular and behavioral effects of clonidine.

Antagonism of pressor responses to sympathetic outflow stimulation and alpha-adrenoceptor agonists in pithed spontaneously hypertensive rats was used to estimate postsynaptic alpha-adrenoceptor blocking activity of mianserin, phentolamine, phenoxybenzamine, piperoxan and yohimbine. Estimation of presynaptic alpha-adrenoceptor blocking activity of these drugs was obtained by studying their ability to antagonize clonidine-induced suppression of positive chronotropic responses to sympathetic outflow stimulation. In this manner, evidence was obtained that mianserin causes selective presynaptic alpha-adrenoceptor blockade. Mianserin, piperoxan and yohimbine antagonized clonidine-induced avoidance blockade or hypotension in spontaneously hypertensive rats, but methysergide, phenoxybenzamine and phentolamine were ineffective. These results suggest that mianserin may antagonize the central effects of clonidine by blockade of noradrenergic presynaptic or autoreceptors and possibly explain the antidepressant effect of mianserin as due to indirect activation of central noradrenergic neurons.     

The effects of some putative antidepressant agents on the schedule-controlled behavior of the pigeon

Numerous second-generation antidepressants with pharmacological profiles and chemical structures different from those of the tricyclic antidepressants have recently been developed. We examined the actions of four of these compounds (mianserin, maprotiline, trazodone and fluvoxamine) on the responding of pigeons under two different multiple (mult) schedules of grain presentation (a mult fixed-interval (FI) 600-s fixed-ratio (FR) 30-response and a mult FI 200-s FI 200-s in which responding in one component was punished by intermittent presentation of a brief electric shock). The rate of FI 600-s responding was greatly increased by several doses of maprotiline and mianserin, which either did not affect or produced only small increases in the rate of FR 30 responding. Fluvoxamine and trazodone did not produce similar differential effects. Relatively low doses of maprotiline, mianserin and trazodone decreased the FI quarter-lifes. Fluvoxamine only decreased the FI quarter-life at a dose that largely eliminated responding. Mianserin produced proportionally greater increases in the rate of punished FI 200-s responding than in the rate of unpunished FI 200-s responding. Selective effects on punished responding were not seen with maprotiline, fluvoxamine and trazodone.     

Interactions between cardioactive drugs and antidepressants

Summary The most important cardiovascular interactions between cardioactive drugs and monoamino-oxidase inhibitors or tricyclic antidepressants are reviewed. Post-ganglion blocking agents (e.g., guanethidine), clonidine, reserpine, and -methyldopa should not be used in patients needing antidepressant therapy. For hypertension, diuretics, -blokkers, and vasodilators should be used. In patients with cardiac disease negative interactions between membrane-stabilizing antiarrhythmic agents and tricyclic antidepressants may be observed. Caution is recommended when using both drugs. On the other hand, the use of digitalis is relatively free of negative interactions. Some of the mechanisms possibly involved are discussed. The practical implications of such effects are presented and some clinically useful guidelines are suggested.     

Chronic effects of miaserin on noradrenaline metabolism in the rat brain: Evidence for a pre-synaptic α-adrenolytic action in vivo

Chronic administration of the pre-synaptic -adrenoreceptor agonist clonidine decreases the concentration of the extra-neuronal metabolite of noradrenaline normetanephrine in the amygdaloid cortex and increases it in the mid-brain. Conversely, blockade of these pre-synaptic receptors by yohimbine increases the normetanephrine concentration in the amygdaloid cortex and decreases it in the mid-brain. Mianserin had a qualitatively similar action to that of yohimbine. When given clinically to rats in combination with clonidine, mianserin antagonizes both the depression of behaviour of the rats in the open field apparatus and also the effects of the -agonist in reducing the concentration of normetanephrine in the amygdaloid cortex. It thus appears that the chronic effects of mianserin are due to an increase in noradrenaline release as a consequence of the inhibition of pre-synaptic -adrenoreceptors.     

The tetracyclic antidepressant mianserin: evaluation of its blockade of presynaptic alpha-adrenoceptors in a self-stimulation model using clonidine

It has been suggested that the tetracyclic antidepressant mianserin may be an antagonist at inhibitory presynaptic alpha-adrenoceptors. If mianserin exerted a selective antagonist effect it should produce effects that are essentially opposite to those of a selective agonist such as clonidine. This hypothesis was investigated in a shuttle-box self-stimulation model previously shown to be sensitive to alpha-adrenergic drugs. In this model a presynaptic alpha-adrenoceptor antagonist would be expected to enhance self-stimulation and to reverse the inhibitory effects of clonidine. Mianserin (2.5-4.0 mg/kg) did not enhance self-stimulation, but instead produced a selective inhibition of reward. Further, mianserin did not reverse the inhibitory effects of clonidine on self-stimulation. These data suggest that if mianserin is an antagonist of the presynaptic alpha-adrenoceptors it is not a selective antagonist. It is possible that the presynaptic alpha-adrenoceptor antagonism may be effects on postsynaptic alpha-adrenoceptors and/or on a presynaptic noradrenaline reuptake mechanism.     

Mianserin markedly and selectively increases extracellular dopamine in the prefrontal cortex as compared to the nucleus accumbens of the rat

The atypical antidepressant mianserin, administered at doses of 1, 5 and 10 mg/kg SC, dose-dependently increased up to about 6 times extracellular dopamine in the medial prefrontal cortex of the rat, as estimated by vertical concentric microdialysis probes. Mianserin failed to modify extracellular dopamine in the nucleus accumbens. Mianserin also dose-dependently increased extracellular noradrenaline in the prefrontal cortex. Yohimbine, an ₂ antagonist, increased extracellular dopamine in the prefrontal cortex but the maximal increase was lower than that elicited by mianserin. Yohimbine also increased extracellular noradrenaline in the prefrontal cortex, but to a lesser extent than dopamine. Clonidine, an ₂ agonist, decreased extracellular dopamine and noradrenaline in the prefrontal cortex but failed to affect extracellular dopamine in the nucleus accumbens. Ritanserin, a 5HT₂ antagonist, at doses of 1.0 mg/kg, failed to increase extracellular dopamine in the prefrontal cortex, but significantly potentiated the increase in extracellular noradrenaline due to yohimbine. Ritanserin failed to potentiate the increase in extracellular noradrenaline elicited by yohimbine in the prefrontal cortex. The results are interpreted to indicate that mianserin increases extracellular DA as a result of the concurrent blockade of ₂ and 5HT₂ receptors. Failure to affect extracellular dopamine in the nucleus accumbens is explained as due to the lack of a significant effect of ₂ and 5HT₂ tone on DA release in the nucleus accumbens as compared to the prefrontal cortex. The results are consistent with the postulated relationship between antidepressant drug action and the ability to increase extracellular dopamine in the prefrontal cortex.     

Stimulation of drug metabolism in man by tricyclic antidepressants

Summary Plasma antipyrine half-lives were measured in thirty adult subjects before and after 7 and 28 days treatment with one of five tricyclic antidepressants. Overall, considering the five antidepressants together, there was a small but significant reduction in half-life after both periods of treatment. In four subjects studied, increased urinary output of 6-hydroxycortisol following chronic nortriptyline treatment provides further evidence of a stimulatory effect of tricyclic antidepressant on drug metabolism. In a separate study, the induction effect of tricyclic antidepressants was found to be much less marked than that with amylobarbitone. It would seem therefore that tricyclic antidepressants are less likely than barbiturates, to bring about drug interactions by altering drug metabolism.     

Pharmacological studies of MO-8282, a new antidepressant

We investigated the pharmacological characteristics of MO-8282 as a novel antidepressant. MO-8282 inhibited the specific binding of 3H-clonidine to cerebro-cortical membrane fractions from rats about five times more potently than mianserin, and it competed with clonidine in the twitch response of the isolated guinea-pig ileum under field stimulation. The results indicated that MO-8282 possessed alpha 2-adrenergic receptor blocking activity. MO-8282 in a dose of 30 mg/kg (p.o.) showed no inhibition against the uptake of noradrenaline, dopamine and serotonin in the rat brain, whereas mianserin inhibited the uptake of serotonin specifically. MO-8282, similar to mianserin, had no effect on spontaneous release of 3H-noradrenaline and slightly stimulated the release of 3H-serotonin from the rat cerebrocortical synaptosome. The turnover rate of noradrenaline in rat brain was accelerated by administration of MO-8282 (30 mg/kg) for 15 days; however, that of dopamine and serotonin was not affected. The above findings indicate that MO-8282, unlike tricyclic antidepressants, mainly exerts alpha 2-adrenoceptor blocking action on the central noradrenergic system, similar to mianserin. In addition, the fact that MO-8282 unlike mianserin showed no inhibition against uptake of serotonin in brain suggests that the alpha 2-adrenoceptor blocking of MO-8282 is more specific and potent than that of mianserin.