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Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation.

Nakayama K, Sakurai T, Katsu H.

Department of Psychiatry, Jikei University School of Medicine, 3-25-8 Nishi Shinbashi, Minato-ku, Tokyo 105-8461, Japan. Kazu-n yb3.so-net.ne.jp

Mirtazapine has a low affinity for 5-HT(1A) receptors but shows 5-HT(1A)-agonistic-like effects in behavioral pharmacology test. However, there is to date no clear evidence that mirtazapine enhances 5-HT(1A) neurotransmission. The object of the present study was to assess the effects of mirtazapine on dialysate levels of dopamine and 5-HT in the medial frontal cortex of freely moving rats and to determine whether this drug could modulate 5-HT(1A) neurotransmission. In vivo microdialysis was used to study the effects of mirtazapine on extracellular dopamine and 5-HT levels, and the effect of the 5-HT(1A) antagonist WAY100,356 on extracellular dopamine level increased by mirtazapine in the rat prefrontal cortex. Mirtazapine (4-16 mg/kg, i.p.) produced a dose-dependent increase in extracellular dopamine levels in the medial prefrontal cortex (mPFC) of freely moving rats without modifying those of 5-HT. In the presence of the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazineyl]ethyl]-N-(pyridinyl)-cyclohexane-carboxamide (WAY100,635; 0.3 mg/kg; i.p.), the influence of mirtazapine on cortical levels of dopamine was markedly attenuated. These results indicate that mirtazapine induces the enhancement of the output of cortical dopamine mediated via blockade of alpha(2)-adrenergic receptors and facilitation of post-synaptic 5-HT(1A) function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15145142&dopt=Abstract mirtazapine Remeron



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Therapeutic drug monitoring of mirtazapine and its metabolite desmethylmirtazapine by HPLC with fluorescence detection.

Meineke I, Kress I, Poser W, Ruther E, Brockmoller J.

Department of Clinical Pharmacology, University of Goettingen, Goettingen, Germany. imeineke med.uni-goettingen.de

A selective and sensitive HPLC method is described for therapeutic drug monitoring of the antidepressant drug mirtazapine and its active metabolite desmethylmirtazapine. Liquid/solid extraction with C18 cartridges was used for cleanup of plasma samples. The chromatographic separation was carried out on a phenylhexyl column. No interference from other coadministered antidepressants has been observed in 234 samples from 184 patients. The calibration range used was from 1 ng/mL to 100 ng/mL. The analytic method has proven robust and well suited for therapeutic drug monitoring. In addition to qualitative and quantitative validation data for the assay method, concentration measurements in samples from patients on mirtazapine therapy and the relevant dosing information are presented. Median drug levels after a 15-mg dose were 37 ng/mL mirtazapine and 20 ng/mL desmethylmirtazapine. When a 60-mg dose was administered, median concentrations of 83 ng/mL mirtazapine and 65 ng/mL desmethylmirtazapine were found.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15167628&dopt=Abstract mirtazapine Remeron



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Population pharmacokinetic analysis of mirtazapine.

Grasmader K, Verwohlt PL, Kuhn KU, Dragicevic A, von Widdern O, Zobel A, Hiemke C, Rietschel M, Maier W, Jaehde U, Rao ML.

Department of Psychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53121 Bonn, Germany.

OBJECTIVE: Mirtazapine belongs to the new generation of antidepressants that is commonly used in clinical routine. Therefore, we feel it mandatory to control compliance in the context of non-response, adverse events or other clinical situations by means of plasma concentration measurements. While controlled clinical studies have evaluated the effect of individual covariates on the pharmacokinetics of mirtazapine, our analysis aims to identify covariates within a naturalistic clinical setting. METHODS: We performed non-linear mixed-effects modelling with data from 65 depressed inpatients whose plasma concentrations were measured weekly during their stay in hospital. Each patient's age, height, weight, co-medication, alcohol, coffee and cigarette consumption, weekly serum creatinine concentrations, liver enzyme activity, blood pressure and pulse was noted. From 49 patients, the genotype of cytochrome P450 (CYP) isoenzymes 2D6, 2C9 and 2C19 was analysed. RESULTS: The clearance of CYP2D6 intermediate metabolisers was reduced by 26% compared with extensive metabolisers. No other factor significantly influenced the clearance of these patients. CONCLUSION: The variability of mirtazapine plasma concentrations in clinical routine is caused to a relevant degree by CYP2D6. This should be taken into account when therapeutic drug monitoring is carried out to check treatment adherence or when a special clinical situation, such as co-morbidity and add-on medication, demands careful dosing of this drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15289959&dopt=Abstract mirtazapine Remeron



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Mirtazapine acutely inhibits basal and K(+)-stimulated release of corticotropin-releasing hormone from the rat hypothalamus via a non-genomic mechanism.

Fabricio AS, Tringali G, Pozzoli G, Navarra P.

Institute of Pharmacology, Catholic University Medical School, Largo Francesco Vito 1, 00168, Rome, Italy, pnavarra rm.unicatt.it.

RATIONALE: Originally described as a pivotal mediator of acute neuroendocrine responses to stress, corticotropin-releasing hormone (CRH) is currently envisioned as a peptide neurotransmitter involved in the pathogenesis of anxiety and depressive disorders; it has been postulated that antidepressant drugs are clinically effective insofar as they are able to reduce central CRH production and release.OBJECTIVES AND METHODS: In this study we used a well validated in vitro model, i.e. acute rat hypothalamic explants, to investigate the effects of the antidepressant mirtazapine on the production and release of CRH from the hypothalamus in short-term experiments. CRH release was assessed through the measurement of CRH immunoreactivity in the incubation medium.RESULTS: We found that mirtazapine reduces in a concentration-dependent manner both basal and K(+)-stimulated CRH release in 30-min and 60-min experiments. Mirtazapine had no effect on CRH mRNA expression in 1-h and 3-h experiments; the intra-hypothalamic levels of peptide were not reduced, and even tended to increase, with respect to controls.CONCLUSION: Mirtazapine reduces CRH release from CRH-containing neurons in the rat hypothalamus through a mechanism independent from the modulation of CRH gene expression and peptide production.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15300357&dopt=Abstract mirtazapine Remeron



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New method for the chiral evaluation of mirtazapine in human plasma by liquid chromatography.

de Santana FJ, Cesarino EJ, Bonato PS.

Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Av. Cafe SN, CEP 14040-903, Ribeirao Preto, SP, Brazil.

A simple, rapid and sensitive high-performance liquid chromatography (HPLC) method was developed for the enantioselective analysis of the new antidepressant drug mirtazapine in human plasma. The procedure involved liquid-liquid extraction using toluene, followed by liquid chromatography coupled to UV detection at 292 nm. The chromatographic separation of the (+)-(S)- and (-)-(R)-enantiomers of mirtazapine was achieved on a Chiralpak AD column (250 mm x 4.6 mm, 10 microm particle size) protected with a CN guard column, using hexane-ethanol (98:2, v/v) plus 0.1% diethylamine as the isocratic mobile phase, at a flow rate of 1.2 ml/min. The total analysis time was less than 12 min per sample. The recoveries of (+)-(S)- and (-)-(R)-mirtazapine were in the 88-111% range with a linear response over the 6.25-625 ng/ml concentration range for both enantiomers. The quantification limit (LOQ) was 5 ng/ml. Within-day and between-day assay precision and accuracy were studied at three concentration levels (10, 50 and 250 ng/ml). For both mirtazapine enantiomers, the coefficients of variation (CV) and deviation from the theoretical value were lower than 15% at all concentration levels. The method proved to be suitable for pharmacokinetic studies. Copyright 2004 Elsevier B.V.

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Altered response to mirtazapine on gene expression profile of lymphocytes from Alzheimer's patients.

Palotas A, Puskas LG, Kitajka K, Palotas M, Molnar J, Pakaski M, Janka Z, Penke B, Kalman J.

Department of Psychiatry, Albert Szent-Gyorgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, H-6721 Szeged, Semmelweis u. 6, Hungary. palotas nepsy.szote.u-szeged.hu

Antidepressants are widely used in the treatment of mood disorders associated with dementia, however little information is available on their effect at the molecular level. We have demonstrated that gene expression profiles of lymphocytes from patients with Alzheimer dementia differ from that seen with controls, with alpha(2)-adrenoceptor being the most highly repressed transcript. To address this issue in light of antidepressant treatment, we used lymphocytes derived from Alzheimer patients and control individuals to assess the impact of mirtazapine, the novel antidepressant with alpha(2)-adrenoceptor antagonistic activities, on gene expression using a cDNA microarray representing 3200 distinct human genes. Sequences that are differentially regulated after treatment with mirtazapine were identified and categorized based on similarities in biological functions. This analysis revealed that selected biological processes, including protein metabolism, cytoskeleton integrity, immune response, cellular plasticity, and neurotransmission, are involved in early phases of administration of this antidepressant. In addition, although it was possible to identify common targets, the expression profiles of Alzheimer lymphocytes differed mainly in their magnitude from those seen with controls. These results confirm the usefulness of the gene array approach for studying Alzheimer-specific changes in the periphery and suggest that the expression of genes of Alzheimer lymphocytes is modulated differently by mirtazapine, which correlates with the pathology.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15336942&dopt=Abstract mirtazapine Remeron