Steady-State Plasma Concentrations of Mianserin and Its Major Active Metabolite, Desmethylmianserin

Otani, Koichi; Sasa, Hiroshi; Kaneko, Sunao; Kondo, Tsuyoshi; Fukushima, Yutaka

doi:10.1097/00007691-199304000-00008

Cited by 14 publications

(4 citation statements)

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“…A critical issue concerning the κ‐opioid agonist activity of mianserin is whether the observed receptor affinity is comparable with the tissue concentrations reached by the drug following therapeutic doses. In patients with depression, therapeutic mianserin plasma concentrations have been reported to range from 0.1 to 0.3 µM (Otani et al ., 1993). In mice, either acute or chronic administration of mianserin yielded brain concentrations that were at least 10‐fold higher than the plasma concentrations (Altamura et al ., 1987).…”

Section: Discussionmentioning

confidence: 99%

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

Olianas

Dedoni

Onali

2012

British J Pharmacology

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BACKGROUND AND PURPOSEAntidepressants 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 APPROACHEffects 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 [ KEY RESULTSMianserin displayed 12-and 18-fold higher affinity for k-than m-and d-opioid receptors respectively. In [ 35 S]GTPgS assays, mianserin selectively activated k-opioid receptors. The agonist activity was antagonized by the selective k-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed k-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing k-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full k-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full k-opioid receptor agonists in [ CONCLUSIONS AND IMPLICATIONSIn different cell systems, mianserin directly activates k-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants.

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Section: Discussionmentioning

confidence: 99%

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

Olianas

Dedoni

Onali

2012

British J Pharmacology

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“…Desmethylmianserin and 8-hydroxymianserin maintain antidepressant activities, but are less sedative than mianserin, whereas mianserin- N- oxide tends to be a comparatively inactive metabolite [ 100 ]. Thus, the 2 enantiomers display substantially different enantioselective variations in metabolism [ 101 , 102 ]. Studies conducted with mianserin or the active metabolite, desmethylmianserin, have found coadministration of benzodiazepines is not an important factor in deciding the dosage of mianserin [ 101 ].…”

Section: Tetracyclic Antidepressantsmentioning

confidence: 99%

Chirality of antidepressive drugs: an overview of stereoselectivity

et al. 2022

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Stereochemistry plays an important role in drug design because the enantiomers of a drug frequently vary in their biological action and pharmacokinetic profiles. Racemates of a drug with either an inactive or an unsafe enantiomer can lead to detrimental effects. The manufacturing industry may still produce racemates, but such decisions must pass through rigorous analyses of the pharmacological and pharmacokinetic characteristics of the particular enantiomer related to the racemates. The pharmacokinetics of antidepressants or antidepressive agents is stereoselective and predominantly favors one enantiomer. The use of pure enantiomers offers (i) better specificity than the racemates in terms of certain pharmacological actions, (ii) enhanced clinical indications, and (iii) optimized pharmacokinetics. Therefore, controlling the stereoselectivity in the pharmacokinetics of antidepressive drugs is of critical importance in dealing with depression and psychiatric conditions. The objective of this review is to highlight the importance of the stereochemistry of antidepressants in the context of the design and development of new chirally pure pharmaceuticals, the potential complications caused by using racemates, and the benefits of using pure enantiomers.

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“…The t1 =2 of mianserin is on average 30 h (range 14-60 h). Higher (on average by 42%) steady-state plasma concentrations per dose in women compared to men (Reis et al 2009) and a low but significant correlation between age and doseadjusted plasma concentrations of mianserin (Otani et al 1993;Reis et al 2009) have been reported.…”

Section: Mianserinmentioning

confidence: 99%

“…There is no convincing evidence for a clear relationship between plasma concentrations of mianserin and response. A therapeutic reference range of 15-70 ng/ mL for mianserin (non-enantiomeric assay) has been suggested (Hiemke et al 2018), based on early concentration-effect studies (Montgomery S et al 1978) and data on the range of concentrations achieved at therapeutic doses (Montgomery SA et al 1983;Otani et al 1993;Mihara, Otani, Tybring, et al 1997).…”

Section: Mianserinmentioning

confidence: 99%

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants

Eap

Gründer

Baumann

et al. 2021

The World Journal of Biological Psychiatry

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Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient. Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug. Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

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Steady-State Plasma Concentrations of Mianserin and Its Major Active Metabolite, Desmethylmianserin

Cited by 14 publications

References 0 publications

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

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

Chirality of antidepressive drugs: an overview of stereoselectivity

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants

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