Remeron
Chiral determination of mirtazapine in human blood plasma by high-performance liquid chromatography.

Dodd S, Burrows GD, Norman TR.

Department of Psychiatry, University of Melbourne, Austin & Repatriation Medical Centre, Heidelberg, Victoria, Australia.

A method is described for the determination of the two enantiomers of mirtazapine in human blood plasma by high-performance liquid chromatography. Measurements were performed on drug free plasma spiked with mirtazapine and used to prepare and validate standard curves. Levels of enantiomers of mirtazapine were also measured in patients being treated for depression with racemic mirtazapine. Mirtazapine was separated from plasma by solid-phase extraction using CERTIFY columns. Chromatographic separation was achieved using a Chiralpak AD column and pre-column and compounds were detected by their absorption at 290 nm. Imipramine was used as an internal standard. The assay was validated for each analyte in the concentration range 10-100 ng/ml. The coefficient of variance was 16% and 5.5% for(+)-mirtazapine for 10 and 100 ng/ml control specimens respectively and 15% and 7.3% for mirtazapine for 10 and 100 ng/ml control specimens respectively. This assay is appropriate for use in the clinical range. The range of plasma mirtazapine concentrations from eleven patients taking daily doses of 30-45 mg of racemate was <5 to 69 ng/ml for (+)-mirtazapine and 13-88 ng/ml for (-)-mirtazapine for blood specimens collected 10-17.5 h after taking the dose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11087086&dopt=Abstract mirtazapine Remeron



Remeron
Determination of mirtazapine in tablets by UV spectrophotometric and derivative spectrophotometric methods.

Karasen N, Altinoz S.

Department of Analytical Chemistry, Faculty of Pharmacy, University of Hacettepe, Ankara, Turkey.

Mirtazapine, 1, 2, 3, 4, 10, 14b-hexahydro-2-methyl-pyrazino [2, 1-a] pyrido [2, 3-c] [G.L. Stimmel, J.A. Dopheide and S.M. Stahl, Pharmacotheraphy 17(1) (1997) 10] benzazepine, is a new and well tolerated antidepressant. It blocks pre-synaptic alpha2-adrenergic receptors and postsynaptic serotonin type 2 and type 3 receptors. The drug is rapid and completely absorbed after oral administration. Mirtazapine was analyzed by HPLC and gas chromatography with nitrogen-sensitive detection. In this study, mirtazapine was analyzed by using UV spectrophotometry, first and second order derivative spectrophotometry. The type of solvent, the degree of derivation, range of wavelength and n value were chosen in order to optimize the conditions. The concentration of mirtazapine in its methanolic solutions were determined between the wavelength range of 225-360 nm in the linearity range of 1-100, 2-100 and 1-120 microg ml(-1) by using the values obtained from UV. first-order derivative (n = 5, delta lambda = 17.5 nm) and second-order derivative (n = 9, delta lambda = 31.5 nm) spectrum of the substance, respectively. The developed UV Spectrophotometric, first-order and second-order derivative spectrophotometric methods were applied to a pharmaceutical preparation as tablet form. Developed UV and derivative UV spectrophotometric method in this study are accurate, sensitive, precise, reproducible and can be directly and easily applied to the pharmaceutical preparations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11108534&dopt=Abstract mirtazapine Remeron



Remeron
Inhibition of stress- or anxiogenic-drug-induced increases in dopamine release in the rat prefrontal cortex by long-term treatment with antidepressant drugs.

Dazzi L, Spiga F, Pira L, Ladu S, Vacca G, Rivano A, Jentsch JD, Biggio G.

Department of Experimental Biology 'B. Loddo', Chair of Pharmacology, University of Cagliari, Cagliari, Italy. dazzi vaxca1.unica.it

The effects of long-term treatment with imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, on the response of cortical dopaminergic neurons to foot-shock stress or to the anxiogenic drug FG7142 were evaluated in freely moving rats. As expected, foot shock induced a marked increase (+ 90%) in the extracellular concentration of dopamine in the prefrontal cortex of control rats. Chronic treatment with imipramine or mirtazapine inhibited or prevented, respectively, the effect of foot-shock stress on cortical dopamine output. Whereas acute administration of the anxiogenic drug FG7142 induced a significant increase (+ 60%) in cortical dopamine output in control rats, chronic treatment with imipramine or mirtazapine completely inhibited this effect. In contrast, the administration of a single dose of either antidepressant 40 min before foot shock, had no effect on the response of the cortical dopaminergic innervation to stress. These results show that long-term treatment with imipramine or mirtazapine inhibits the neurochemical changes elicited by stress or an anxiogenic drug with an efficacy similar to that of acute treatment with benzodiazepines. Given that episodes of anxiety or depression are often preceded by stressful events, modulation by antidepressants of the dopaminergic response to stress might be related to the anxiolytic and antidepressant effects of these drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11181840&dopt=Abstract mirtazapine Remeron



Remeron
Following long-term training with citalopram, both mirtazapine and mianserin block its discriminative stimulus properties in rats.

Dekeyne A, Iob L, Millan MJ.

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, Paris, France. anne.dekeyne fr.netgrs.com

RATIONALE: The discriminative stimulus (DS) properties of the selective serotonin (5-HT) uptake inhibitor (SSRI), citalopram, are mediated by 5-HT2C receptors. Interestingly, the "atypical" antidepressants, mianserin and mirtazapine, behave as antagonists at 5-HT2C receptors. OBJECTIVE: Herein, we evaluated the influence of mianserin and mirtazapine upon the DS effects of citalopram. METHODS: In a two-lever drug discrimination procedure, rats initially trained to discriminate citalopram (2.5 mg/kg, i.p.) from saline were retrained with a lower dose of citalopram (0.63 mg/kg, i.p.). Subsequently, generalization and antagonist studies were conducted with mianserin and mirtazapine. RESULTS: Both dose-dependently blocked, but did not generalize to, the DS properties of citalopram without markedly disrupting response rates. Their effective dose50s were 0.1 and 1.4 mg/kg, s.c., respectively. CONCLUSION: These observations are consistent with a role of 5-HT2C receptors in mediation of the interoceptive properties of SSRIs and suggest that the DS effects of citalopram are not related to its "antidepressant" properties per se. Finally, they underline the distinctive nature of mirtazapine and mianserin as compared to antidepressant agents which interact with 5-HT uptake sites.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11271412&dopt=Abstract mirtazapine Remeron



Remeron
Acute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission.

Haddjeri N, Blier P, de Montigny C.

Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

Mirtazapine (ORG 3770, Remeron) is a new alpha 2-adrenoceptor antagonist which has been shown to be an effective antidepressant drug. The aims of the studies were to assess, using an in vivo electrophysiological paradigm in the rat, the effects of acute and long-term treatment with mirtazapine on pre- and postsynaptic alpha 2-adrenoceptors and to determine whether this drug could modulate serotonin (5-HT) neurotransmission. Acute administration of mirtazapine produced a transient increase of the firing activity of dorsal raphe 5-HT neurons. This effect was mediated via norepinephrine (NE) neurons because it was abolished in NE-lesioned rats. In fact, this increased firing rate of 5-HT neurons was due to their activation by the enhanced release of NE resulting from the blockade of alpha 2-adrenergic autoreceptors of locus coeruleus neurons. Furthermore, acute mirtazapine injection transiently enhanced the firing activity of locus coeruleus NE neurons and attenuated the suppressant effect of the alpha 2-adrenoceptor agonist clonidine on these NE neurons. Sustained administration of mirtazapine for 21 days (5 mg/kg/day, s.c., using minipumps) lead to a marked increase in the firing rate of 5-HT neurons (75%) but a more modest increase in the firing rate of NE neurons (30%), as well as to a desensitization of alpha 2-adrenergic heteroreceptors on 5-HT terminals in the hippocampus. The desensitization of these heteroreceptors, resulting from an increased synaptic availability of NE induced by mirtazapine would free 5-HT terminals from the inhibitory influence of NE on 5-HT release. These modifications of 5-HT neurons lead to an increased tonic activation of postsynaptic 5-HT1A receptors. The latter conclusion was based on the capacity of the selective 5-HT1A receptor antagonist WAY 100635 to enhance the firing activity of dorsal hippocampus CA3 pyramidal neurons in mirtazapine-treated rats but not in controls. This enhanced 5-HT neurotransmission may underlie to the antidepressant effect of mirtazapine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10333981&dopt=Abstract mirtazapine Remeron



Remeron
Does mirtazapine have a more rapid onset than SSRIs?

Quitkin FM, Taylor BP, Kremer C.

Department of Therapeutics, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, NY, USA. Quitkin Pl.CPMC.Columbia.edu

BACKGROUND: A single study utilizing a cross-sectional analysis of scores on the Hamilton Rating Scale for Depression (HAM-D) suggested that mirtazapine has a more rapid onset than selective serotonin reuptake inhibitors (SSRIs). Analysis based on the HAM-D may favor drugs with sleep-producing effects. The purpose of the present study was to determine if a review of all studies comparing an SSRI with mirtazapine, utilizing persistent improvement as the dependent variable, would suggest that mirtazapine had a more rapid onset than SSRIs. METHOD: All double-blind studies comparing mirtazapine with SSRIs were analyzed. Included in the analysis to determine speed of onset were 298 patients taking mirtazapine and 285 taking an SSRI. Pattern analysis, which has been described and used by other researchers, was employed to study speed of onset. RESULTS: At the end of each of the 3 studies, the total number of responders for each of the drugs did not differ. However, the proportion of responders with onset of persistent improvement in week 1 was greater for mirtazapine (13%, 38/298) than for the SSRIs (6%, 18/285; chi2 = 6.95, df = 1, p = .008). CONCLUSION: These data support the possibility that mirtazapine may have a more rapid onset than SSRIs. This observation should be considered preliminary because of the retrospective nature of the analysis and the absence of a placebo group.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11411818&dopt=Abstract mirtazapine Remeron