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In a double-blind trial in depressed outpatients, 80 subjects received either mianserin 30--80 mg daily or diazepam 15--40 mg daily, for 4 weeks. Most patients received 50--60 mg mianserin, or 25--30 mg diazepam, daily after the first week. Mianserin was significantly superior to diazepam in antidepressant efficacy from day 14 to the end of the trial, as measured by the Hamilton Rating Scale for Depression and the Beck Self-Rating Scale, and at day 28 as measured by the Clinical Global Impression. All three measures showed that the mianserin group started the trial with a significantly more severe degree of illness than the diazepam group, but this difference was already reversed by day 14. Side-effects were more frequent with mianserin treatment.

A group of 20 inpatients with moderate to severe primary affective disorder received 14 days of placebo treatment and were then randomly allocated to receive mianserin 10 mg 3 times daily or identical amitriptyline 25 mg 3 times daily for 1 week followed by 60 mg mianserin or 150 mg amitriptyline daily for a second week. Patients were rated for side-effects and depression (Hamilton Depression Scale) on days 0, 7, 14, 21 and 28. Probenecid 100 mg/kg was administered in 3 divided doses on days 13/14 and on days 27/28 of the trial, followed by collection of CSF. Blood samples for determination of antidepressant levels were collected on day 27. Both mianserin and amitriptyline produced a significant decrease in CSF levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), but only amitriptyline significantly lowered CSF levels of 5-hydroxyindole-3-acetic acid (5-HIAA). Neither drug affected CSF levels of homovanillic acid (HVA). Both mianserin and amitriptyline produced significant but indistinguishable improvement in mean Hamilton scores over 2 weeks of treatment. There was no relationship between therapeutic response and either plasma antidepressant levels or pre-treatment CSF monoamine metabolite levels in his small group of patients. The reductions of CSF levels of metabolites of NA (MHPG) and 5-HT (5-HIAA) are consistent with the known effects of amitriptyline on amine uptake. Mianserin may reduce CSF MHPG levels as a result of its effects upon NA release and/or uptake, but it appears to be devoid of influence upon central 5-HT metabolism.

Forty psychiatric out-patients with primary anxiety entered a double-blind trial comparing 2 weeks of treatment with mianserin 30--60 mg daily or diazepam 15--30 mg daily, followed by 2 weeks of single-blind placebo administration. Both drugs were effective anti-anxiety agents, but mianserin was significantly superior in efficacy as measured by the Physician's Global Rating of Severity of Illness. No differences between treatments were apparent using the Hamilton Rating Scale for Anxiety. There was no significant differences in terms of side-effects and both drugs increased anticholinergic effects such as dry mouth, blurred vision and constipation over baseline values. With one exception in the mianserin group, all patients who entered placebo treatment became worse.

Fifty elderly depressed patients were randomly assigned to double-blind treatment, using a flexible dose schedule, with either mianserin 20-60 mg or imipramine 75-150 mg. Medication was continued for four weeks. Eleven patients withdrew from the study. At the end of treatment there were no significant differences between mianserin and imipramine in antidepressant efficacy. A significantly greater number of side-effects occurred in the imipramine group (dry mouth, days 7 and 14; faintness, dizziness, weakness, day 21). When treating elderly depressed patients mianserin may be preferred to imipramine because of a lower incidence of induced side-effects.

S(+)-mianserin is the more potent enantiomer of mianserin in pharmacological tests indicative for antidepressant activity. Pharmacological tests indicative for sedation suggest that sedative effects are similar for mianserin and its enantiomers. Racemic mianserin had the optimal therapeutic ratio of antidepressant-like activity versus sedative properties when assessed by computerised EEG in healthy volunteers participating in a double-blind placebo-controlled single dose trial. Of the known metabolites, desmethylmianserin and 8-hydroxymianserin substantially retain pharmacological properties indicative for antidepressant activity but are less active than mianserin in tests indicative for sedation. Mianserin-N-oxide is inactive or only weakly active in most pharmacological tests. Desmethylmianserin occurs in human plasma after both single and multiple dosage to an extent of about one-third that of mianserin. Mianserin has optimal clinical efficacy as the racemate. Desmethyl-mianserin and 8-hydroxymianserin are pharmacologically active metabolites and may contribute to the overall antidepressant effects of mianserin.

1 Following a seven day drug-free period, 80 depressed outpatients were randomly allocated to receive mianserin 60 mg nocte or nomifensine 150 mg daily. Blindness was maintained by the use of a double-dummy technique. 2 All measures of efficacy showed a trend in favour of mianserin throughout the four week trial, including the Hamilton Depression Scale (HDS), the Beck Self-rating Depression Inventory (BDI), the Clinical Global Impression (CGI) and the Efficacy Index. 3 Significant advantages in efficacy for mianserin were observed at day 14 on the HDS and at days 7, 14 and 21 on the CGI. 4 Substantially more patients experienced marked or moderate improvement during treatment with mianserin than with nomifensine. Side-effects were low with both drugs. 5 On the basis of the present trial and a previous comparison, mianserin appears to be a more effective antidepressant than nomifensine.

In a double-blind multicentre trial in general practice, 144 patients with primary anxiety received daily treatment with mianserin or chlordiazepoxide, 30-60 mg, or placebo. There were no statistically significant differences in efficacy between the three treatments in the 106 patients who completed the 6-week trial. However, there was a substantial trend in favour of mianserin (P = 0.1), but not chlordiazepoxide, over placebo as assessed by the difference in overall improvement on the Hamilton Anxiety Scale. This trend may be clinically significant since more patients dropped out from the placebo group because of lack of effect or deterioration than did from the active treatment groups, particularly during the latter part of the trial. Side effects occurred to a similarly low extent with all treatments, except that mianserin caused more weight gain and, initially, more drowsiness than placebo, while placebo produced more nausea and vomiting. Taken together with the evidence from previous trials in patients with anxiety, these results support the notion that mianserin has anxiolytic properties.

1 S(+)-mianserin is the more potent enantiomer of mianserin in pharmacological tests indicative for antidepressant activity. Pharmacological tests indicative for sedation suggest that sedative effects are similar for mianserin and its enantiomers. 2 Of the three compounds, mianserin had the optimal therapeutic ratio of antidepressant-like activity versus sedative properties when assessed by computerised EEG in healthy volunteers participating in a double-blind placebo-controlled single dose trial. 3 Of the known metabolites, desmethylmianserin and 8-hydroxymianserin substantially retain pharmacological properties indicative for antidepressant activity but are less active than mianserin in tests indicative for sedation. Mianserin-N-oxide is inactive or only weakly active in most pharmacological tests. 4 Desmethylmianserin occurs in human plasma after both single and multiple dosage to an extent of about one-third that of mianserin. 5 Mianserin has optimal efficacy as the racemate. Desmethylmianserin and 8-hydroxymianserin are pharmacologically active metabolites and may contribute to the overall antidepressant effects of mianserin.

Mianserin (60 mg daily) was compared with chlorimipramine (150 mg daily) in the treatment of 145 depressed in- and outpatients in four centres. The trial was double-blind and fully randomized. Both drugs were effective antidepressants. No significant differences in efficacy could be demonstrated by means of the Hamilton rating scale for depression, the Beck self-rating scale or the clinical global impression, for both in- and outpatients. Hypotension, dry mouth and tremor increased significantly more in inpatients with chlorimipramine than with mianserin. At the end of treatment weight gain was increased significantly more in outpatients after treatment with mianserin. No differences could be demonstrated between the drugs for other side-effects.

The effects of mianserin, a tetracyclic antidepressant, on sleep stages and on the nocturnal secretion of cortisol, ACTH, growth hormone, prolactin and tryptophan were studied on 11 normal male volunteers in a double-blind, placebo-controlled study. Mianserin increased Stage 3 time (p less than 0.001) and Stage 4 time (p less than 0.01). It reduced the number of REM periods (p less than 0.001), the REM latency after sleep onset (p less than 0.01) and both the total and percentage REM time (p less than 0.05). A reduction in both the total sleep time (p less than 0.05) and the percentage of total time in bed (p less than 0.05) were the only significantly carry-over effects from the drug treatment period. No significant difference in any biochemical measurement was found between placebo and drug treatment.

Mianserin is a tetracyclic antidepressant whose postulated mechanism of action involves release of noradrenaline mediated via cortical alpha 2-adrenergic autoreceptor blockade. This property resides stereoselectively in the S(+)-enantiomer of mianserin, which is also more potent in behavioural tests indicative of antidepressant activity, and in the reversal of clonidine-induced effects. Cortical receptor binding studies have indicated that although a similar stereoselectivity prevails for the inhibition of both alpha 2-binding (clonidine) and alpha 1-binding (prazosin), mianserin and its enantiomers are more potent antagonists at alpha 2- than at alpha 1-binding sites. However, no stereoselectivity is apparent for the antagonism of cortical alpha 2-heteroreceptors controlling serotonin release. Following chronic administration, (+/-)- and S(+)-mianserin, but not the R(-)-enantiomer, produce functional supersensitivity at alpha 2-autoreceptors which is unaccompanied by changes in clonidine binding. Neither mianserin nor its enantiomers alter the sensitivity of alpha 2-heteroreceptors following chronic administration. Like mianserin and its S(+)-enantiomer, but unlike R(-)-mianserin and the 8-hydroxy metabolite, the desmethyl metabolite inhibits noradrenaline uptake in vitro. 8-hydroxymianserin and, to a lesser extent, desmethylmianserin release noradrenaline from cortical slices via alpha 2-autoreceptor antagonism, but only the 8-hydroxy metabolite blocks alpha 2-autoreceptors and alpha 2-heteroreceptors in synaptosomal preparations. It is likely that S(+)-mianserin, desmethylmianserin, and 8-hydroxymianserin contribute substantially to the overall facilitating effect of mianserin on noradrenergic transmission in vivo. As yet it is unclear whether this effect is exclusively responsible for the antidepressant activity of mianserin or whether the stereoselectivity also shown by the mianserin enantiomers towards serotonin receptors plays a complementary role.