Prevention of poststroke depression: 1 year randomised placebo controlled double blind trial of mianserin with 6 month follow up after therapy. (1/203)

OBJECTIVES: (1) To test whether early prophylactic antidepressive treatment by mianserin is able to prevent poststroke depression, and (2) to discover whether mianserin as an antidepressant has any beneficial influence on the outcome of ischaemic stroke. METHODS: A randomised, double blind, placebo controlled study involved 100 consecutive patients under 71 years old admitted to hospital for an acute ischaemic stroke; they were enrolled to receive 60 mg/day mianserin or placebo for 1 year. They were examined on admission, and at 2, 6, 12, and 18 months with depression, stroke, and functional outcome scales. RESULTS: According to DSM-III-R, the prevalence of major depression was 6% at the initial stage, 11% at 1 year, and 16% at 18 months. At no time point did prevalences differ between the treatment groups, nor were differences found in depression scales, although at 2 months a greater improvement from initial assessment on the Hamilton depression scale was evident in patients on mianserin (p=0.05). Some beneficial changes on the Hamilton depression scale and Beck depression inventory were found in patients older than 56 (median age) and in men treated with mianserin, but not in other subgroups. Mianserin treatment did not affect stroke outcome as measured by neurological status, nor did it have any influence on functional outcome as measured by Rankin scale or Barthel index. CONCLUSION: It was not possible to show that early initiation of antidepressant therapy can prevent poststroke depression, because the prevalence of poststroke depression remained low even in patients on placebo. In this stroke population with a low rate of depressive patients, antidepressive medical treatment failed to affect stroke outcome.  (+info)

The Norwegian naturalistic treatment study of depression in general practice (NORDEP)-I: randomised double blind study. (2/203)

OBJECTIVE: To evaluate the efficacy of emotional support and counselling combined with placebo or antidepressants with single or dual mechanism of action in the treatment of depression in primary care. DESIGN: Randomised double blind study. SETTING: Several locations in Norway. SUBJECTS: 372 patients with depression. MAIN OUTCOME MEASURES: Improvement (clinical remission) reported both by the patient (Montgomery Asberg depression rating scale) and the physician (clinical global improvement and impression scales). RESULTS: Intention to treat analyses showed 47% remission in patients randomised to placebo compared with 61% remission in patients randomised to sertraline (odds ratio 0.56, 95% confidence interval 0.33 to 0.96) and 54% in patients randomised to mianserin (0.75, 0.44 to 1.27). Women responded better than men (1.86, 1.17 to 2.96). Subgroup analyses showed that subjects with recurrent depression (n=273) responded more frequently to sertraline than to placebo (0.43, 0.23 to 0.82) than those having their first episode of depression (1.18, 0.39 to 3.61). Statistically significant interactions between type of drug treatment and history of depression were not shown by logistic regression. CONCLUSION: The combination of active drug and simple psychological treatment (counselling, emotional support, and close follow up over a 24 week period) was more effective than simple psychological treatment alone, in particular for those with recurrent depression. Overall, women may benefit more than men. If confirmed in future studies, the findings should lead to more differentiated treatment guidelines for depression in primary care.  (+info)

Isoform-selective metabolism of mianserin by cytochrome P-450 2D. (3/203)

The involvement of cytochrome P-450 (CYP) 2D isoforms in the metabolism of mianserin and the stereoselectivity of their catalytic activities were investigated by using five CYP2D isoforms (CYP2D1, 2D2, 2D3, 2D4, and 2D6). Using RS-mianserin as a substrate, we found that five CYP2D isoforms had similar levels of 8-hydroxylation activity. However, N-demethylation activity differed among the isoforms; CYP2D3 and 2D4 efficiently demethylated RS-mianserin compared with the other three isoforms. N-Oxidation activity was specific to CYP2D1 although its level was relatively low. Another metabolite, assigned as 8-hydroxy-N-desmethylmianserin by liquid chromatography/mass spectrometry analysis, was formed by CYP2D4 and 2D6. The metabolism exhibited stereoselectivity. CYP2D1 and 2D4 selectively 8-hydroxylated the R(-)-enantiomer, and CYP2D6 predominately N-demethylated R(-)-enantiomer. N-Oxidation by CYP2D1 was specific to R(-)-enantiomer. In conclusion, CYP2D isoforms are involved in several metabolic pathways of mianserin acting in an isoform-specific manner. Stereoselectivity of the catalytic activities was clearly observed in the reactions of CYP2D1, 2D4, and 2D6.  (+info)

Tissue distribution of mirtazapine (Remeron) in postmortem cases. (4/203)

Mirtazapine (Remeron) is a member of the relatively new class of tetracyclic antidepressants. There are published cases of mirtazapine's detection as an incidental finding in postmortem cases; however, case reports with associated tissue concentrations and interpretations are not available. This report documents the tissue distribution of mirtazapine in eight postmortem cases in which it was identified but did not contribute to the cause or manner of death. The following mean mirtazapine concentrations (milligrams per liter or milligrams per kilogram) were found: heart blood 0.12 (range, < 0.01-0.33, n = 7); peripheral blood 0.09 (< 0.01-0.14, n = 4); urine 0.61 (0.01-3.2, n = 7); liver 0.88 (0.04-3.6, n = 6), kidney 0.21 (0.02-0.48, n = 5); and bile 0.62 (0.11-1.6, n = 6). In each case, the mirtazapine concentration in heart blood was approximately equal to that of peripheral blood, indicating that postmortem redistribution was not a factor in evaluating postmortem blood concentrations in these cases. However, because the liver mirtazapine concentrations were 5-30 times the blood concentrations, the potential for postmortem redistribution cannot be excluded. Additionally, because urine concentrations of the parent compound were consistently greater than the blood concentrations, urine is an adequate screening specimen for mirtazapine.  (+info)

Distribution of mirtazapine (Remeron) in thirteen postmortem cases. (5/203)

Mirtazapine is a new antidepressant agent that entered the United States market in April 1996. To date, the literature provides limited information about therapeutic blood concentrations and virtually no information about postmortem levels. The Los Angeles County Coroner's Toxicology Laboratory has encountered 13 cases where postmortem tissue distributions of mirtazapine were determined. The analysis of mirtazapine from postmortem specimens (2-mL sample size) consisted of an n-butylchloride basic extraction procedure with identification and quantitation on a gas chromatograph-nitrogen-phosphorus detector. Linearity was achieved from 0.025 mg/L to 3.0 mg/L with a limit of quantitation of 0.025 mg/L. Confirmation of mirtazapine was performed on a gas chromatograph-mass spectrometer by comparison with a pure analytical standard. The tissue distribution of mirtazapine are in the following concentration ranges: heart blood 0.03-0.57 mg/L (13 cases), femoral blood 0.04-0.24 mg/L (9 cases), vitreous 0.06-0.10 mg/L (3 cases), liver 0.32-2.1 mg/kg (12 cases), bile 0.40-6.6 mg/L (7 cases), urine 0.12-2.5 mg/L (11 cases), kidney 0.23 mg/kg (1 case), spleen 0.17 mg/kg (1 case), and gastric 0.001-2.7 mg total (9 cases). Mirtazapine was not implicated in the cause of death in any of the 13 cases studied. These cases are being presented to aid the forensic toxicologist in the evaluation of postmortem mirtazapine levels.  (+info)

Serotonin-induced spike narrowing in a locomotor pattern generator permits increases in cycle frequency during accelerations. (6/203)

During serotonin-induced swim acceleration in the pteropod mollusk Clione limacina, interneurons of the central pattern generator (CPG) exhibit significant action potential narrowing. Spike narrowing is apparently necessary for increases in cycle frequency during swim acceleration because, in the absence of narrowing, the combined duration of the spike and the inhibitory postsynaptic potential (IPSP) of a single cycle is greater than the available cycle duration. Spike narrowing could negatively influence synaptic efficacy in all interneuron connections, including reciprocal inhibitory connections between the two groups of antagonistic CPG interneurons as well as the interneuron-to-motoneuron connections. Thus compensatory mechanisms must exist to produce the overall excitatory behavioral change of swim acceleration. Such mechanisms include 1) a baseline depolarization of interneurons, which brings them closer to spike threshold, 2) enhancement of their postinhibitory rebound, and 3) direct modulation of swim motoneurons and muscles, all through inputs from serotonergic modulatory neurons.  (+info)

Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2, 2D6, and 3A4. (7/203)

The metabolism of the antidepressant mirtazapine (MIR) was investigated in vitro using human liver microsomes (HLM) and recombinant enzymes. Mean K(m) values (+/-S.D., n = 4) were 136 (+/-44) microM for MIR-hydroxylation, 242 (+/-34) microM for N-demethylation, and 570 (+/-281) microM for N-oxidation in HLM. Based on the K(m) and V(max) values, MIR-8-hydroxylation, N-demethylation, and N-oxidation contributed 55, 35, and 10%, respectively, to MIR biotransformation in HLM at an anticipated in vivo liver MIR concentration of 2 microM. Recombinant CYP predicted a 65% contribution of CYP2D6 to MIR-hydroxylation at 2 microM MIR, decreasing to 20% at 250 microM. CYP1A2 contribution increased correspondingly from 30 to 50%. In HLM, quinidine and alpha-naphthoflavone reduced MIR-hydroxylation to 75 and 45% of control, respectively, at 250 microM MIR. A >50% contribution of CYP3A4 to MIR-N-demethylation at <1 microM MIR was indicated by recombinant enzymes. In HLM, ketoconazole (1 microM) reduced N-desmethylmirtazapine formation rates to 60% of control at 250 microM. Twenty percent of MIR-N-oxidation was accounted for by CYP3A4 at 2 microM MIR, increasing to 85% at 250 microM, while CYP1A2 contribution decreased from 80 to 15%. Ketoconazole reduced MIR-N-oxidation to 50% of control at 250 microM. MIR did not substantially inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP1E2, and CYP3A4 activity in vitro. Induction/inhibition or genetic polymorphisms of CYP2D6, CYP1A2, and CYP3A4 may affect MIR metabolism, but involvement of several enzymes in different metabolic pathways may prevent large alterations in in vivo drug clearance.  (+info)

Scaling drug biotransformation data from cDNA-expressed cytochrome P-450 to human liver: a comparison of relative activity factors and human liver abundance in studies of mirtazapine metabolism. (8/203)

The present study represents a comparison of three approaches to transform recombinant cytochrome P-450 (rCYP) enzyme kinetic data to human liver activity using mirtazapine (MIR) biotransformation as a model. MIR metabolite rCYP formation rates were corrected using I) relative activity factors (RAFs) determined on site, II) RAFs based on activity data provided by the rCYP manufacturer, and III) immunologically determined human liver abundance of CYP isoforms reported in the literature. For 2.5, 25, and 250 microM MIR, predictions of 1) the relative contribution of CYP isoforms to a particular reaction, 2) absolute metabolite formation rates, 3) the relative contribution of each pathway to net MIR biotransformation, and 4) the relative contribution of CYP isoforms to net MIR biotransformation were generated, and the results were compared with data obtained with human liver microsomes (HLM). We found that RAFs determined on site most accurately predict the results observed in HLM. Estimations based on liver abundance systematically underestimated CYP1A2 and overestimated CYP3A and CYP2C9 contributions to MIR metabolism and, therefore, seem less suitable to predict CYP isoform involvement in a particular reaction. Normalized RAFs calculated from the manufacturer activity data fell within the range of RAFs determined on site and lead to similar results for CYP isoform contribution to metabolic reactions and to net MIR biotransformation. Considering the time and resource-intensive step of RAF determination, manufacturer RAFs are an alternative to RAFs determined on site for the transformation of rCYP enzyme kinetic data; both of them provide more accurate estimations than immunologically determined human liver CYP isoform content.  (+info)