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R M Pinder

Publications and source records attributed to R M Pinder.

At least 19 recordsLinked to original sources
PubMed1997

Designing a new generation of antidepressant drugs.

Although longer-term adaptive changes in receptor sensitivity may better explain the delayed onset of action of antidepressants, the mechanism based on acutely elevated noradrenaline (NA) and serotonin (5-HT) synaptic levels remains the basis for new drug design. The dual action concept, which postulates that effects on both NA and 5-HT are more advantageous than a selective action on serotonin reuptake (SSRI), has been used to design new antidepressants such as venlafaxine and mirtazapine. Both drugs enhance NA and 5-HT neurotransmission with little affinity for receptors mediating tricyclic-like side effects. Mirtazapine, the prototype noradrenergic and specific serotonergic antidepressant (NaSSA), specifically enhances 5-HT1 neurotransmission and blocks 5-HT2 and 5-HT3 receptors, and in contrast to venlafaxine lacks SSRI-like and adverse cardiovascular side effects. The unique pharmacological action of mirtazapine is a result of implementation of two concepts: dual action as a basis of efficacy combined with receptor-specific action as a basis of tolerability.

Adrenergic Uptake Inhibitors↗
PubMed1989

Why do fatal overdose rates vary between antidepressants?

Age specific death rates for poisoning with different antidepressant drugs, based on mortality statistics and the numbers of prescriptions dispensed, were calculated for England and Wales 1979-1985. There are marked variations in mortality associated with different drugs; the highest rates are found with amitriptyline and dothiepin whereas the lowest were associated with mianserin and clomipramine. For all drugs considered, the calculated mortality rates for the over 65 year olds, though still substantial, were lower than those in patients under 65 years of age, probably because of a diminished detection rate of poisoning in this older age group. A high proportion of the fatal overdoses implicating amitriptyline and dothiepin involved more than one substance. The rank order of mortality rates from antidepressants was identical in the different age groups. The implications of these findings are discussed. It is concluded that the variations in mortality rates are mostly due to variations in the inherent toxicity of the drugs (particularly their cardiovascular effects) and only in part due to possible differences in compliance. It is suggested that when antidepressant drugs are prescribed, the risk of death from overdose should be taken into account. Tricyclic drugs, particularly amitriptyline, dothiepin, doxepin, trimipramine and maprotiline, should be avoided in patients at risk of suicide, whatever the age of the patient.

Adult↗
PubMed1988

Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers.

The neurochemical and autonomic pharmacological profile of 1,2,3,4,10, 14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c]pyrido[2, 3-c] [2] benzazepine [+/-)Org 3770) and the related antidepressant drug, mianserin, have been compared. The uptake of [3H]noradrenaline ([3H]NA) in vitro was weakly affected by (+/-)Org 3770 (pKi = 5.6) in contrast to mianserin (pKi = 7.4). Both (+/-)Org 3770 and mianserin facilitated the release of [3H]NA in slices of cortex. The effects of NA mediated by alpha 2-adrenoceptors on the release of both [3H]NA or [3H]serotonin ([3H]5-HT) were antagonized by (+)Org 3770 with pKi values of 8.4 and 8.1, respectively. However, (-)Org 3770 only antagonized the effect of NA on the release of [3H]5-HT (pA2 = 7.7). The binding of [3H]rauwolscine to alpha 2-adrenoceptors was inhibited by (+/-)Org 3770 and mianserin with identical affinity (pKi = 7.0), whereas the binding of [3H]prazosin to alpha 1-adrenoceptors was less potently affected by (+/-)Org 3770 (pKi = 6.4) than by mianserin (pKi = 7.1). A similar difference was found for alpha 1- and alpha 2-adrenoceptors in vas deferens of the rat. The binding of [3H]mianserin to 5-HT2 receptors was less potently blocked by (+/-)Org 3770 (pKi = 8.1) than by mianserin (pKi = 9.4) while the binding of [3H]mepyramine to histamine-1 receptors was more potently affected by (+/-)Org 3770 (pKi = 9.3) than by mianserin (pKi = 8.75). The binding of [3H]quinuclidinylbenzilate to muscarinic cholinergic receptors was blocked equally by (+/-)Org 3770 (pKi = 6.1) and mianserin (pKi = 6.3). Similar data on tryptamine-D, histamine-1 and muscarinic cholinergic receptors in isolated organs were obtained. A prominent role for the blockade of alpha 2-adrenoceptors in the therapeutic effects of mianserin and (+/-)Org 3770 in depression is suggested, probably excluding a role of inhibition of the uptake of NA.

Animals↗
PubMed1985

Adrenoreceptor interactions of the enantiomers and metabolites of mianserin: are they responsible for the antidepressant effect?

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.

Animals↗
PubMed1985

Mianserin and imipramine in the treatment of elderly depressed patients.

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.

Aged↗
PubMed1983

A double-blind trial of mianserin and nomifensine in depressed outpatients.

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.

Adult↗
PubMed1983

The potential therapeutic role of the enantiomers and metabolites of mianserin.

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.

Animals↗
PubMed1983

Pharmacological aspects of mianserin.

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.

Adult↗
PubMed1982

Monoamine metabolites in cerebrospinal fluid of depressed patients during treatment with mianserin or amitriptyline.

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.

Adult↗
PubMed1982

A multicentre placebo-controlled trial comparing the efficacy of mianserin and chlordiazepoxide in general practice patients with primary anxiety.

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.

Adolescent↗
PubMed1982

Mianserin.

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Animals↗