Remeron
[Mirtazapine in inpatient treatment of depressed patients]

[Article in German]

Bailer U, Praschak-Rieder N, Pezawas L, Kasper S.

Klinische Abteilung fur Allgemeine Psychiatrie, Universitatsklinik fur Psychiatrie, Wien, Osterreich.

Mirtazapine is a new antidepressant with a specific pharmacological profile which is different from all other currently available antidepressants. It is a so-called noradrenergic and specific serotonergic antidepressant (NaSSA). 46 in-patients were treated with mirtazapine. The mean dose was 56 mg mirtazapine per day (SD: 23; range: 15 to 90). The duration of treatment was 3.6 weeks (SD +/- 3.4). Patients presented with following diagnosis: 29 (= 63%) were diagnosed as having a unipolar depression, 26% (n = 12) suffered from a depression in the course of a bipolar disorder. 37% (n = 17) were moderately depressed, 52% (n = 24) were severely depressed. 2 patients (= 4%) met ICD-10 (international Classification of Diseases) criteria for a schizoaffective disorder, 2 patients (= 4%) suffered from dysthymia. 1 patient suffered from an organic depressive disorder. The efficacy of the treatment was evaluated with CGI (Clinical Global Impression), when patients were discharged from hospital. 68% of the patients were in partial or full remission (CGI 2, 3 and 4), 17% were unimproved (CGI 5 and 6), in 15% of the patients the treatment was stopped before. Our observations are indicative that mirtazapine is effective in the treatment of moderately and severely depressed patients and therefore confirm the data obtained in phase III-trials. Furthermore we found mirtazapine in either mono- or combination-therapy with various other antidepressants to be tolerated well. Side effects did not cause in a single patient a discontinuation in treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9816638&dopt=Abstract mirtazapine Remeron



Remeron
Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan.

de Boer TH, Nefkens F, van Helvoirt A, van Delft AM.

Department of Neuropharmacology, N.V. Organon, Oss, The Netherlands.

The effects of three compounds with alpha-2 adrenoceptor antagonistic properties, mirtazapine (Org 3770; Remeron), mianserin and idazoxan, were measured on hippocampal noradrenergic and serotonergic transmission in freely moving rats by using microdialysis. Dihydroxyphenylacetic acid (DOPAC) was measured as a correlate of noradrenergic presynaptic activity. Infusing 1 microM tetrodotoxin decreased extracellular serotonin (5-HT) and DOPAC by 65 and 40%, respectively. 5-Hydroxytryptophan (25 mg/kg s.c.) increased extracellular 5-HT by 500%, whereas 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (0.5 mg/kg s.c.) decreased 5-HT release by 60%. Prazosin decreased 5-HT release to 60% of base-line in agreement with an alpha-1-mediated control of 5-HT transmission, whereas it increased DOPAC release with 80%. Both mirtazapine (2 and 5 mg/kg s.c.) and idazoxan (1 mg/kg s.c.) caused a rapid increase in DOPAC by up to 80%. Mianserin slowly increased DOPAC, reaching a maximal increase of 30 and 60% at 2 and 5 mg/kg s.c., respectively. Only mirtazapine caused a concurrent increase in 5-HT, reaching up to 80% above base-line within 60 min, whereas mianserin and idazoxan failed to change 5-HT levels significantly. Mirtazapine (5 mg/kg s.c.) only slightly affected DOPAC and homovanillic acid levels in the striatum, hardly affected 5-HT release, but clearly increased 5-hydroxyindole acetic acid. Thus, the antidepressants mirtazapine and mianserin markedly differ in their effects on noradrenergic and serotonergic transmission in vivo as measured with microdialysis in freely moving rats. These differences are explained by their different modulatory effects on noradrenergic transmission.

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Remeron
Effect of the alpha-2 adrenoceptor antagonist mirtazapine on the 5-hydroxytryptamine system in the rat brain.

Haddjeri N, Blier P, de Montigny C.

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

Mirtazapine ([(+/-)-MIR], Remeron, ORG 3770) is an alpha-2 adrenoceptor antagonist endowed with antidepressant activity in humans. The aim of the present study was to assess the effects of (+/-)-MIR and of its (-)enantiomer [(-)-MIR] on pre- and postsynaptic alpha-2 adrenoceptors and to characterize their putative modulation of 5-HT neurotransmission. (+/-)-MIR (25 micrograms/kg i.v.) enhanced the effectiveness of the electrical stimulation of the ascending 5-HT pathway by blocking both alpha-2 adrenergic auto- and heteroreceptors. (-)-MIR (10 micrograms/kg i.v.) enhanced the effectiveness of these stimulations due to a selective action of (-)-MIR on the alpha-2 heteroreceptors located on 5-HT terminals. Both (+/-)- and (-)-MIR (500 micrograms/kg i.v.) blocked the suppressant effect of microiontophoretically applied norepinephrine (NE) on the firing activity of CA3 dorsal hippocampus pyramidal neurons, indicating their antagonistic effects on postsynaptic alpha-2 adrenoceptors. (+/-)-MIR (10- 250 micrograms/kg i.v.) enhanced dose-dependently the firing activity of the 5-HT neurons in naive rats, but not in 6-hydroxydopamine-pretreated rats. (+/-)-MIR also significantly increased the firing activity of locus ceruleus NE neurons. In contrast, (-)-MIR (10-250 micrograms/kg i.v.) failed to change the firing rate of dorsal raphe 5-HT neurons. In conclusion, these results suggest that both (+/-)-MIR and (-)-MIR are antagonists at postsynaptic alpha-2 adrenergic receptors, that (+/-)-MIR is an antagonist of somatodendritic as well as terminal alpha-2 adrenergic auto- and heteroreceptors, whereas (-)-MIR is a selective antagonist at alpha-2 adrenergic heteroreceptors. Furthermore, the inhibitory effect of (-)-MIR on locus ceruleus NE neurons appears to be mediated via 5-HT neurons because it is abolished by a 5,7-dihydroxytryptamine pretreatment.

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Remeron
Effects of long-term treatment with the alpha 2-adrenoceptor antagonist mirtazapine on 5-HT neurotransmission.

Haddjeri N, Blier P, de Montigny C.

Neurobiological Psychiatry Unit, McGill University, Montreal, Quebec, Canada.

Mirtazapine (ORG 3770, Remeron) is a nonselective alpha 2-adrenoceptor antagonist with antidepressant activity in major depression. The aim of the present study was to assess, using an in vivo electrophysiological paradigm, the effect of long-term treatment with mirtazapine on pre- and postsynaptic alpha 2-adrenoceptors and on 5-HT neurotransmission in male Sprague-Dawley rats. A 21-day treatment with mirtazapine (5 mg/kg/day, s.c., using osmotic minipumps) increased the spontaneous firing activity of locus coeruleus noradrenaline (NA) neurons. Their firing activity was back to normal 48 h after removing the minipump. However, this treatment did not modify the dose-response curve of the suppressant effect of the alpha 2-adrenoceptor agonist clonidine on the firing activity of NA neurons. The spontaneous firing activity of dorsal raphe 5-HT neurons was also markedly increased in mirtazapine-treated rats, and was back to normal 48 h after removing of the minipump. The dose-response curve of the suppressant effect of clonidine on the firing activity of 5-HT neurons was altered in mirtazapine-treated rats. Furthermore, it was further shifted to the left after a 48-h washout. Long-term mirtazapine treatment did not modify the suppressant effects of microiontophoretically-applied NA and 5-HT on the firing activity of CA3 dorsal hippocampus pyramidal neurons. However, this mirtazapine treatment antagonized both the enhancing effect of a low dose (10 micrograms/kg, i.v.) and the reducing effect of a high dose (100 micrograms/kg, i.v.) of the alpha 2-adrenoceptor agonist clonidine on the effectiveness of the electrical stimulation of the ascending 5-HT pathway in suppressing the firing activity of dorsal hippocampus CA3 pyramidal neurons. After a 48-h washout, only the effect of the high dose of clonidine was attenuated, suggesting a desensitization of the terminal alpha 2-adrenergic heteroreceptor, but not of the terminal alpha 2-adrenergic autoreceptor. The decrease in the effectiveness of the stimulation upon increasing its frequency from 1 to 5 Hz (due to the activation of terminal 5-HT autoreceptors) was unaltered after the long-term mirtazapine treatment. In conclusion, the tonic activation of postsynaptic 5-HT receptor is enhanced by a 21-day treatment with mirtazapine, as a result of a sustained increase in 5-HT neuron firing activity in the presence of decreased function of alpha 2-adrenergic heteroreceptors located on 5-HT terminals in the dorsal hippocampus.

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Remeron
Designing a new generation of antidepressant drugs.

Pinder RM.

NV Organon, Oss, The Netherlands.

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9265946&dopt=Abstract mirtazapine Remeron



Remeron
Mirtazapine: pharmacology in relation to adverse effects.

Nutt D.

School of Medical Sciences, University of Bristol, United Kingdom.

Mirtazapine is a new antidepressant that falls into the general class of receptor-blocking drugs rather than being an uptake or enzyme inhibitor. It can be described as a noradrenergic and specific serotonergic antidepressant (NaSSA). The unique pharmacology of mirtazapine means that it has a very different side effect profile from the tricyclic antidepressants, producing less alpha 1 adrenergic and muscarinic blockade, and the selective serotonin reuptake inhibitors (SSRIs) and the serotonin-noradrenaline reuptake inhibitors (SNRIs), causing much less nausea and sexual dysfunction by virtue of its blockade of 5-HT2 and 5-HT3 receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9265949&dopt=Abstract mirtazapine Remeron