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Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram.

Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A, Dekeyne A, Nicolas JP, Lejeune F.

Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125, Chemin de Ronde, 78290, Croissy-sur-Seine, Paris, France.

Mirtazapine displayed marked affinity for cloned, human alpha2A-adrenergic (AR) receptors at which it blocked noradrenaline (NA)-induced stimulation of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]-GTPgammaS) binding. Similarly, mirtazapine showed high affinity for cloned, human serotonin (5-HT)2C receptors at which it abolished 5-HT-induced phosphoinositide generation. Alpha2-AR antagonist properties were revealed in vivo by blockade of UK-14,304-induced antinociception, while antagonist actions at 5-HT2C receptors were demonstrated by blockade of Ro 60 0175-induced penile erections and discriminative stimulus properties. Mirtazapine showed negligible affinity for 5-HT reuptake sites, in contrast to the selective 5-HT reuptake inhibitor, citalopram. In freely moving rats, in the dorsal hippocampus, frontal cortex (FCX), nucleus accumbens and striatum, citalopram increased dialysate levels of 5-HT, but not dopamine (DA) and NA. On the contrary, mirtazapine markedly elevated dialysate levels of NA and, in FCX, DA, whereas 5-HT was not affected. Citalopram inhibited the firing rate of serotonergic neurons in dorsal raphe nucleus, but not of dopaminergic neurons in the ventral tegmental area, nor adrenergic neurons in the locus coeruleus. Mirtazapine, in contrast, enhanced the firing rate of dopaminergic and adrenergic, but not serotonergic, neurons. Following 2 weeks administration, the facilitatory influence of mirtazapine upon dialysate levels of DA and NA versus 5-HT in FCX was maintained, and the influence of citalopram upon FCX levels of 5-HT versus DA and NA was also unchanged. Moreover, citalopram still inhibited, and mirtazapine still failed to influence, dorsal raphe serotonergic neurons. In conclusion, in contrast to citalopram, mirtazapine reinforces frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission. These actions reflect antagonist properties at alpha2A-AR and 5-HT2C receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10762339&dopt=Abstract mirtazapine Remeron



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Effects of the co-administration of mirtazapine and paroxetine on serotonergic neurotransmission in the rat brain.

Besson A, Haddjeri N, Blier P, de Montigny C.

Neurobiological Psychiatry Unit, McGill University, 1033 Pine Avenue, West Montreal, Quebec, Canada.

The alpha(2)-adrenoreceptor antagonist mirtazapine, which is also a 5-HT(2), 5-HT(3) and H(1) receptors antagonist and the selective serotonin (5-HT) reuptake inhibitor paroxetine are effective antidepressant drugs which enhance 5-HT neurotransmission via different mechanisms. The present studies were undertaken to determine whether the mirtazapine-paroxetine combination could induce an earlier and/or a greater effect on the 5-HT system than either drug alone. Using in vivo electrophysiological paradigms, the firing activity of dorsal raphe 5-HT neurons was decreased by 70% in rats treated with paroxetine (10 mg/kg/day, s.c.) for 2 days and was back to normal after 21 days. In contrast, a 2-day treatment with mirtazapine (5 mg/kg/day, s.c.) did not alter the firing of 5-HT neurons whereas it was increased by 60% after 21 days of treatment. A low dose of mirtazapine (5 mg/kg/day, s.c.x2 days) failed to offset the decremental effect of paroxetine on the 5-HT neuron firing activity, but a higher dose (10 mg/kg/day, s.c.x2 days) did attenuate the decremental effect of paroxetine. In the dorsal hippocampus, neither mirtazapine (5 mg/kg/day, s.c.) nor a paroxetine (10 mg/kg/day, s.c.) treatment altered the responsiveness of 5-HT(1A) receptors to microiontophoretically-applied 5-HT. Both in controls and in rats treated for 2 days with paroxetine alone, the administration of the 5-HT(1A) antagonist WAY 100635 (25-100 microg/kg, i.v.) did not change the firing activity of dorsal hippocampus CA(3) pyramidal neurons. However, WAY 100635 increased significantly the firing activity of these neurons in rats treated with mirtazapine alone but to a greater extent with both mirtazapine and paroxetine for 2 days. After 21 days of treatment, WAY 100635 increased to a greater degree the firing rate of CA(3) pyramidal neurons in rats which received the combination over rats given either drug alone. It is concluded that the mirtazapine-paroxetine combination shortened the delay in enhancing the tonic activation of postsynaptic 5-HT(1A) receptors and produced a greater activation of the postsynaptic 5-HT(1A) receptors than either drug given alone. The present results suggested that mirtazapine may have a faster onset of action than a SSRI, and that the co-administration of mirtazapine and paroxetine may accelerate the antidepressant response and as well as being more effective than either drug alone.

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Behavioral and memory improving effects of mirtazapine in rats.

Nowakowska E, Chodera A, Kus K.

Department of Pharmacology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.

These experiments examined the effects of the antidepressant mirtazapine in several behavioral and memory tests. The tests were carried out on male Wistar rats weighing about 200 g. The drugs were injected 30 min before the tests. The aim of the locomotor activity test was to select a dose which had no influence on the motility of the animals and, at the same time, was active at least in one behavioral test. The chosen dose was 2.5 mg/kg. In the two-compartment exploratory test, 2.5 mg/kg of mirtazapine had a distinct anxiolytic effect after the first treatment, after 7 days the effect was weaker but still significant and it disappeared after 14 days. In the forced swimming test, the immobility time was shortened only after 14 days of administering the drug. In the maze test, mirtazapine shortened the food finding time (it improved memory) and counteracted memory loss induced by scopolamine. In the conditioned avoidance responses test (CARs), mirtazapine improved memory only after its earlier impairment by scopolamine. The authors cohclude, contrary to some published data, that after proper dose (adequate for other tests but not for the locomotor activity test), mirtazapine has a distinct memory improving activity or a memory restoring effect after scopolamine treatment.

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Acute effects of mirtazapine on sleep continuity and sleep architecture in depressed patients: a pilot study.

Winokur A, Sateia MJ, Hayes JB, Bayles-Dazet W, MacDonald MM, Gary KA.

Department of Psychiatry, Dartmouth Medical School, Hanover, New Hampshire, USA.

BACKGROUND: Mirtazapine, a clinically effective antidepressant, acts by antagonizing central alpha2-adrenergic and 5-HT2/5-HT3 receptors. No data are available regarding mirtazapine's effects on sleep architecture in patients with major depressive disorder. METHODS: Six patients meeting criteria for major depressive disorder and scoring > or =4 on the three Hamilton Depression Rating Scale sleep items were studied. Polysomnographic evaluations were performed at baseline and after 1 (15 mg at bedtime) and 2 weeks (30 mg at bedtime) of open-label mirtazapine treatment. RESULTS: Mirtazapine significantly decreased sleep latency and significantly increased total sleep time and sleep efficiency from baseline levels during week 1, with similar results observed after week 2. Mirtazapine did not significantly alter rapid eye movement sleep parameters. Clinically, Hamilton Depression Rating Scale and sleep disturbance ratings improved after treatment. CONCLUSIONS: Mirtazapine significantly improves sleep continuity in major depressive disorder patients with poor sleep quality at weeks 1 and 2 of treatment, while preserving sleep architecture.

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

Stormer E, von Moltke LL, Shader RI, Greenblatt DJ.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts, USA.

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.

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Economic impact of using mirtazapine compared to amitriptyline and fluoxetine in the treatment of moderate and severe depression in the UK.

Borghi J, Guest JF.

CATALYST Health Economics Consultants Ltd., The Folly, Pinner Hill Road, Pinner, Middlesex, HA5 3YQ, UK.

This study modelled the economic impact of mirtazapine, compared to amitriptyline and fluoxetine, in the management of moderate and severe depression in the UK, as well as the costs related to discontinuation of antidepressant treatment. Decision models of the management of moderate and severe depression were developed from clinical trial data, resource use obtained from interviews with general practitioners and psychiatrists, and published literature, and were used to estimate the expected direct National Health Service (NHS) costs of managing a patient with moderate or severe depression. The expected cost of healthcare resource use attributable to managing a patient suffering from moderate or severe depression who discontinues antidepressant treatment, irrespective of the initial treatment, was estimated to be pounds sterling 206 (range pounds sterling 50 to pounds sterling 504) over five months. Using mirtazapine instead of amitriptyline for seven months increases the proportion of successfully treated patients by 21% (from 19.2 to 23.2%) and reduces the expected direct NHS cost by pounds sterling 35 per patient (from pounds sterling 448 to pounds sterling 413). Using mirtazapine instead of fluoxetine for six months increases the proportion of successfully treated patients by 22% (from 15.6 to 19.1%), albeit for an additional cost to the NHS of pounds sterling 27 per patient (from pounds sterling 394 to pounds sterling 420). In conclusion, this study suggests that mirtazapine is a cost-effective antidepressant compared to amitriptyline and fluoxetine in the management of moderate and severe depression in the UK.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11004733&dopt=Abstract mirtazapine Remeron