Remeron
Low-dose mirtazapine increases genioglossus activity in the anesthetized rat.

Berry RB, Koch GL, Hayward LF.

Malcom Randall VAMC/University of Florida College of Medicine, Gainesville 32610, USA. sleep_doc msn.com

STUDY OBJECTIVES: To examine the effects of mirtazapine on genioglossus and diaphragmatic electromyogram activity in the anesthetized rat. DESIGN: Parallel-group study. SUBJECTS: Sprague-Dawley adult male rats, 10 in each of 3 groups were studied. INTERVENTIONS: After anesthesia with 1.2 g/kg of urethane, a tracheostomy and bilateral vagotomy were performed. Femoral arterial and venous lines were placed, and fine wire hook electrodes were implanted into the genioglossus and diaphragm muscles. MEASUREMENTS: After a baseline period of measurement, either saline, 0.5 mg/kg of mirtazapine, or 5.0 mg/kg of mirtazapine was injected via the intraperitoneal route, and measurements were made for the next 3 hours. The average peak and tonic values of the moving time average of the genioglossus and diaphragm electromyogram for hours 1, 2, and 3 were determined and expressed as a percentage of the corresponding average value during the baseline (preinjection) monitoring period. RESULTS: At 0.5 mg/kg of mirtazapine, the peak genioglossus electromyogram was significantly higher than in control conditions over hours 2 and 3. At 5.0 mg/kg of mirtazapine, the genioglossus electromyogram was significantly lower than in control conditions for the first 2 hours of monitoring. The peak diaphragmatic electromyogram was slightly but significantly lower in the mirtazapine 5.0-mg/kg group than in controls. CONCLUSIONS: Mirtazapine, at a dose similar to one used clinically, increased genioglossus activity. We hypothesize that, at this dose, the ability of mirtazapine to increase serotonin and norepinephrine or block type-3 serotonin receptors predominated. At the higher dose of mirtazapine, the type-2 blockade effect predominated and genioglossus activity decreased.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15700723&dopt=Abstract mirtazapine Remeron



Remeron
A comparison of the physicochemical and biological properties of mirtazapine and mianserin.

Kelder J, Funke C, De Boer T, Delbressine L, Leysen D, Nickolson V.

NV Organon, Oss, The Netherlands.

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated. Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pKa value, is slightly but significantly lower than that of mianserin. The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the alpha 1-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9232538&dopt=Abstract mirtazapine Remeron



Remeron
Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine.

Berendsen HH, Broekkamp CL.

Department of Neuropharmacology, N.V. Organon, Oss, The Netherlands. h.berendsen organon.akzonobel.nl

The new antidepressant mirtazapine was tested in two experimental procedures which can reveal direct or indirect 5-HT1A receptor agonistic effects. These procedures were observation for induction of lower lip retraction in rats and comparison of stimulus properties in cross-familiarization experiments with conditioned taste aversion in mice. Mirtazapine induced lower lip retraction in rats, as did the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). However, the response to mirtazapine at doses up to 22 mg/kg remained below the maximum score obtained with 8-OH-DPAT (0.46 mg/kg). Blockade of the 5-HT1A receptors with pindolol (10 mg/kg) caused a strong reduction of the lower lip retraction induced both with mirtazapine and 8-OH-DPAT. In the cross-familiarization conditioned taste aversion experiments it was found that the conditioned taste aversion induced by mirtazapine (0.32 mg/kg) could be prevented if the mice were pre-exposed to injections with mirtazapine (0.22 and 0.46 mg/kg), 8-OH-DPAT (0.22 and 0.46 mg/kg) and after pre-exposure to the 5-HT reuptake inhibitor fluoxetine (22 mg/kg). No familiarization for the mirtazapine stimulus was obtained by pre-exposure to (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) (0.46-4.6 mg/kg) and MK212 (2.2-22 mg/kg), being agonists for the 5-HT2A and 5-HT2C receptors, respectively. With the reversed sequence, the conditioned taste aversion induced by 8-OH-DPAT (0.22 mg/kg), DOI (1.0 mg/kg) and fluoxetine could be prevented only partially by pre-exposure to mirtazapine in a dose of 1 mg/kg. The conditioned taste aversion induced by MK 212 (4.6 mg/kg) was not affected by pre-exposure to mirtazapine (0.1-1.0 mg/kg). On the basis of these results, it can be concluded that mirtazapine has indirect 5-HT1A receptor agonistic properties which may play an important role in the therapeutic effect of this compound.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9361334&dopt=Abstract mirtazapine Remeron



Remeron
Mirtazapine enhances the effect of haloperidol on apomorphine-induced climbing behaviour in mice and attenuates haloperidol-induced catalepsy in rats.

Berendsen HH, Broekkamp CL, Pinder RM.

Department of Neuropharmacology, N.V. Organon, Oss, The Netherlands. h.berendsen organon.oss.akzonobel.nl

Activation of 5-HT1A receptors has been shown to attenuate catalepsy induced by typical antipsychotic compounds. Since mirtazapine (Remeron; Org 3770) has indirect 5-HT1A receptor stimulating properties as well as antagonist properties at alpha2-adrenoceptors and 5-HT2 receptors, it was of interest to investigate how the compound could modulate the effect of haloperidol on apomorphine-induced climbing behaviour in mice and haloperidol-induced catalepsy in rats. In the apomorphine climbing test, it was found that mirtazapine (2.2-22 mg/kg) did not change the climbing behaviour of mice induced by 1 mg/kg of apomorphine. However, when given as a co-treatment with haloperidol, mirtazapine (1 and 10 mg/kg) dose-dependently augmented the inhibiting effect of haloperidol on this climbing behaviour. Co-treatment with the 5-HT1A receptor agonist 8-OH-DPAT (0.1 mg/kg) also augmented the effect of haloperidol. Catalepsy induced by haloperidol (4.6 mg/kg) was attenuated by mirtazapine (2.2-22 mg/kg). The strongest effect was seen at 90 min after haloperidol treatment. The results obtained in these experiments suggest that co-treatment with mirtazapine may enhance the antipsychotic effect of haloperidol and reduce its extrapyramidal side effects, thereby widening its therapeutic window.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9498732&dopt=Abstract mirtazapine Remeron



Remeron
Mirtazapine, a mixed-profile serotonin agonist/antagonist, suppresses sleep apnea in the rat.

Carley DW, Radulovacki M.

Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

Serotonin enhancing drugs, including L-tryptophan and, more recently, fluoxetine and paroxetine, have been tested as pharmacologic treatments for sleep apnea syndrome. Although some patients have demonstrated reduced apnea expression after treatment with these compounds, this improvement has been restricted to nonrapid eye movement (NREM) sleep, with some patients showing no improvement. This study reports the effects of mirtazapine, an antidepressant with 5-HT(1) agonist as well as 5-HT(2) and 5-HT(3) antagonist effects, on sleep and respiration in an established animal model of central apnea. We studied nine adult male Sprague-Dawley rats chronically instrumented for sleep staging. In random order on separate days, rats were recorded after intraperitoneal injection of: (1) saline, (2) 0.1 mg/kg +/- mirtazapine (labeled as Remeron), (3) 1 mg/kg mirtazapine, or (4) 5 mg/ kg mirtazapine. With respect to saline injections, mirtazapine at all three doses reduced apnea index during NREM sleep by more than 50% (p < 0.0001) and during REM sleep by 60% (p < 0.0001) for at least 6 h. In association with this apnea suppression normalized inspiratory minute ventilation increased during all wake/sleep states (p < 0.001 for each state). The duration of NREM sleep was unaffected by any dose of mirtazapine (p = 0.42), but NREM EEG delta power was increased by more than 30% at all doses (p = 0.04), indicating improved NREM sleep consolidation after mirtazapine injection. We conclude that mirtazapine, over a 50-fold dose range, significantly reduces central apnea expression during NREM and REM sleep in the rat. The efficacy of this compound to suppress apnea in all sleep stages most probably arises from its mixed agonist/antagonist profile at serotonin receptors. The implications of these findings for the management of sleep apnea syndrome must be verified by appropriate clinical trials.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10588592&dopt=Abstract mirtazapine Remeron



Remeron
Neurochemical effects of the enantiomers of mirtazapine in normal rats.

McGrath C, Burrows GD, Norman TR.

Department of Psychiatry, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia. c.mcgrath medicine.unibelb.edu.au

The present study was designed to examine the neurochemical effects of (+/-)-mirtazapine (10 mg kg(-1) i.p.) and its enantiomers in rats. Male Sprague-Dawley rats received either (+)-mirtazapine, (-)-mirtazapine, (+/-)-mirtazapine or vehicle, by intraperitoneal injection for two weeks. Maximum change in temperature from baseline, following a single dose of the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.15 mg kg(-1) s.c.), was used to assess the function of the 5-HT1A receptors. Chronic drug treatment potentiated this response, with (+/-)-mirtazapine > (-)-mirtazapine > (+)-mirtazapine. Receptor changes were also observed with a slight decrease in beta1-adrenoceptor density, although this failed to reach significance. A significant decrease in beta1-adrenoceptor affinity was observed following (-)-mirtazapine treatment. All drugs tested significantly reduced the density of the 5-HT2 receptors. Results of the present study suggest that in so far as alterations in these receptor populations are important for the therapeutic action of antidepressants, neither of the enantiomers appear to be more active than the racemic mixture.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9774241&dopt=Abstract mirtazapine Remeron