Remeron
Drug-induced stimulation and suppression of action monitoring in healthy volunteers.

de Bruijn ER, Hulstijn W, Verkes RJ, Ruigt GS, Sabbe BG.

Nijmegen Institute for Cognition and Information (NICI), Nijmegen, The Netherlands. ellendb nici.kun.nl

RATIONALE: Action monitoring has been studied extensively by means of measuring the error-related negativity (ERN). The ERN is an event-related potential (ERP) elicited immediately after an erroneous response and is thought to originate in the anterior cingulate cortex (ACC). Although the ACC has a central role in the brain, only a few studies have been performed to investigate directly the effects of drugs on action monitoring. A recent theory argues that the mesencephalic dopamine system carries an error signal to the ACC, where it generates the ERN. METHODS: ERPs and behavioral measurements were obtained from 12 healthy volunteers performing an Eriksen Flankers task. On each of the 4 test days, the stimulant D-amphetamine, the sedative lorazepam, the antidepressant mirtazapine, or a placebo was orally administered in a double-blind, four-way crossover design. RESULTS: The indirect dopamine agonist amphetamine led to a strong enlargement of ERN amplitudes without affecting reaction times. Lorazepam and mirtazapine both showed slowing of responses, but only lorazepam led to reduced ERN amplitudes. CONCLUSIONS: Administration of amphetamine leads to stimulated action monitoring, reflected in increased ERN amplitudes. This result provides evidence for dopaminergic involvement in action monitoring and is in line with differences in ERN amplitude found in neuropsychiatric disorders also suggesting dopaminergic involvement. The different effects for lorazepam and mirtazapine are probably caused by the neurobiological characteristics of these two types of sedation. Action monitoring is suppressed after administration of lorazepam, because the GABAergic pathways directly inhibit ACC functioning, whereas the histaminergic pathways of mirtazapine do not innervate the ACC directly.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15578258&dopt=Abstract mirtazapine Remeron



Remeron
Effects of antidepressant mirtazapine on fibromyalgia symptoms.

Samborski W, Lezanska-Szpera M, Rybakowski JK.

Department of Physiotherapy and Rheumatology, University of Medical Sciences, Poznan, Poland.

PURPOSE: Fibromyalgia syndrome (FS) is a form of non-articular rheumatism. The main criteria are the widespread musculoskeletal pain and tender points at multiple characteristic sites which are associated with several vegetative and functional symptoms. Depression is the most frequent psychiatric concomitant of FS. Etiology is unknown, connection between disturbances of serotonin metabolism and pathogenesis is postulated. Pharmacological therapy with analgetic and nonsteroidal antiinflammatory drugs is not very effective. Positive effects were reported in some patients treated with antidepressant drugs, especially serotonergic agents. MATERIAL AND METHODS: In the study a novel antidepressant drug mirtazapine was used characterized by selective blockade of 5-HT2 and 5-HT3 receptors. In an open trial participated 29 patients with FS, who met 1990 ACR criteria for fibromyalgia. All were treated with mirtazapine for 6 weeks. Intensity of pain, sleep disturbances, fatigue and other symptoms were measured using visuale analogue scale, severity of depression was evaluated with HDRS and BDI. RESULTS: An open trial completed 26 patients, the majority of them experienced a clinical improvement at the end of the study as a consequence of > or = 40% reduced intensity of fibromyalgia symptoms as well as reduced severity of depression. The significant correlation between reduction in depression after 6 weeks of mirtazapine treatment with the reduction on all four main symptoms of FS suggests a common pathophysiology of depression and symptoms of fibromyalgia. The data thus far obtained indicate the blockade of 5-HT2 and 5-HT3 receptors with mirtazapine as an effective and promising method in FS. CONCLUSIONS: Further double-blind placebo-controlled study are required to confirm our results.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15631355&dopt=Abstract mirtazapine Remeron



Remeron
Effects of chronic treatment with classic and newer antidepressants and neuroleptics on the activity and level of CYP2D in the rat brain.

Haduch A, Wojcikowski J, Daniel WA.

Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Krakow, Poland.

The aim of the present work was to study the effect of chronic treatment with pharmacological doses of selected antidepressants (imipramine, mirtazapine) and neuroleptics (thioridazine, risperidone) on the activity and level of CYP2D in the rat brain. Our previous studies carried out on the liver showed that after chronic treatment with psychotropics, the activity of CYP2D was significantly decreased by imipramine, thioridazine and risperidone, but increased by mirtazapine. Our preliminary results suggest that the same may happen in the brain, where similar tendencies in changes in CYP2D activity were observed. Imipramine, thioridazine and risperidone diminished, while mirtazapine tended to accelerate the rate of ethylmorphine O-deethylation, a specific reaction for measurement of CYP2D activity. In the case of thioridazine, the observed decrease in the enzyme activity was the most pronounced and statistically significant. The level of brain CYP2D4 was not substantially changed by the prolonged administration of the investigated drugs (imipramine 136.3 +/- 14.9%, thioridazine 121.9 +/- 3.5%, risperidone 113.5 +/- 7.8%, mirtazapine 80.3 +/- 1.5% of the control), and did not correspond positively with the measured CYP2D activity. This may imply that the observed changes in the CYP2D activity were not caused by the involvement of those psychotropics in the regulation of CYP2D4. In conclusion, our preliminary results suggest that the effects of prolonged treatment with antidepressants and neuroleptics on the activity of CYP2D found in our previous study in the liver also occur in the brain, which may have an impact on the pharmacological and clinical profile of those drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15662101&dopt=Abstract mirtazapine Remeron



Remeron
Mirtazapine acutely inhibits salivary cortisol concentrations in depressed patients.

Laakmann G, Hennig J, Baghai T, Schule C.

Department of Psychiatry, University of Munich, Nussbaumstr. 7, 80336 Munich, Germany. Prof.Laakmann psy.med.uni-muenchen.de.

Mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the current study, the impact of mirtazapine treatment on salivary cortisol secretion was investigated in 12 patients with major depression (DSM-IV criteria). Patients were treated with mirtazapine for 3 weeks, receiving 15 mg of mirtazapine on day 0, 30 mg on day 1, and 45 mg per day from day 2 to the end of the study (day 21). Response to mirtazapine treatment was defined by a reduction of at least 50% in the Hamilton Rating Scale for Depression after 3 weeks of therapy. Salivary cortisol concentrations were measured before treatment (day -1), at the beginning of treatment (day 0), after 1 week (day 7), and after 3 weeks (day 21) of treatment with mirtazapine. Saliva samples were collected hourly from 8 am to 8 pm. A significant reduction in cortisol concentrations was already noted after 1 day of mirtazapine treatment which was comparable in responders and in nonresponders. Mirtazapine therefore appears to be an effective in decreasing hypercortisolism in depression. However, the importance of the acute inhibitory effects of mirtazapine on cortisol secretion for its antidepressant efficacy has to be further clarified.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15677428&dopt=Abstract mirtazapine Remeron



Remeron
Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain.

Bomholt SF, Mikkelsen JD, Blackburn-Munro G.

Department of Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750, Ballerup, Denmark; Department of Molecular Anatomy and Physiology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750, Ballerup, Denmark.

The effects of acute, systemic administration of amitriptyline, duloxetine and mirtazapine (antidepressant drugs that variously affect extracellular noradrenaline and serotonin levels) and the selective serotonin reuptake inhibitor (SSRI) citalopram were compared in rat models of experimental pain. None of the drugs (all 3-30 mg/kg, i.p.) affected acute nociceptive responses as measured in the tail flick test. In the hot plate test, duloxetine and mirtazapine significantly increased (P<0.05) the nociceptive response latency, whereas amitriptyline and citalopram were ineffective. In the formalin test, duloxetine and citalopram significantly attenuated, whereas amitriptyline and mirtazapine increased, second phase flinching behaviour (all P<0.05). However, amitriptyline and mirtazapine reduced second phase licking behaviour. In the chronic constriction injury model of neuropathic pain, thermal hyperalgesia of the injured hindpaw was significantly attenuated by all four drugs (P<0.05); only amitriptyline and duloxetine fully reversed thermal hypersensitivity. None of the drugs tested attenuated mechanical allodynia. In contrast amitriptyline, duloxetine and mirtazapine significantly reduced mechanical hyperalgesia (P<0.05); citalopram was ineffective. No drug-related effects on motor performance in the rotarod test were observed. These results (a) highlight the difficulty in correlating antinociceptive effects of drugs from different antidepressant classes across a range of animal pain models and (b) suggest that antidepressants that variously affect both noradrenaline and serotonin levels have more potent and efficacious antinociceptive effects than SSRIs (as exemplified by citalopram), against a range of pain-like behaviours in an animal model of neuropathic pain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15695164&dopt=Abstract mirtazapine Remeron



Remeron
Comparison of the effects of mirtazapine and fluoxetine in severely depressed patients.

Versiani M, Moreno R, Ramakers-van Moorsel CJ, Schutte AJ, Antidepressants Study Group CE.

Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

INTRODUCTION: Depression is a major global problem associated with large medical, sociological and economic burdens. Mirtazapine (Remeron((R)), Organon NV, The Netherlands) is an antidepressant with a unique mechanism of action that has similar or superior efficacy to TCAs and SSRIs in moderate-to-severe depression. However, this agent has not yet been tested in patients with severe depression alone.OBJECTIVE: To compare the antidepressant efficacy and tolerability of mirtazapine and fluoxetine and their effects on anxiety and quality of life in patients with severe depression (>/=25 points on the first 17 items of the Hamilton Depression Rating Scale [HDRS-17]).METHODS: In this double-blind study, 297 severely depressed patients were randomised to receive mirtazapine 15-60 mg/day (n = 147) or fluoxetine 20-40 mg/day (n = 152) for 8 weeks. 294 subjects were actually treated and 292 included in the intent-to-treat population. Symptom severity was measured by the HDRS-17, Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI) rating scale. Quality of life was self-assessed by patients using the Leeds Sleep Evaluation Questionnaire and the Quality of Life, Enjoyment and Satisfaction Questionnaire. Adverse events were recorded throughout the study.RESULTS: No statistically significant differences were noted between the two groups in change from baseline HDRS-17 score at any time point; both treatments were associated with large (~15 points) decreases by study end. However, more mirtazapine-treated patients tended to exhibit a >/=50% decrease in HDRS score (significant at day 7; 9.0% vs 0.7%, p = 0.002). Significant differences in favour of mirtazapine were also observed at day 14 for changes in MADRS scores (-10.9 vs -8.5, p = 0.006) and the proportion of patients with >/=50% decrease in MADRS score (21.4% vs 10.9%, p = 0.031). On the CGI, the proportion of 'much/very much improved' patients tended to be greater with mirtazapine (significant at day 7; 9.7% vs 3.4%, p = 0.032). No significant between-group differences were observed for the majority of quality-of-life measures. However, mirtazapine produced significantly better improvements on 'sleeping assessment 1' (14.9 +/- 5.2 vs 13.7 +/- 5.4, p = 0.028) and 'sleeping assessment 2' (p = 0.013) than fluoxetine. Both agents were generally well tolerated but mirtazapine-treated patients experienced a mean weight gain of 0.8 +/- 2.7kg compared with a mean decrease in weight of 0.4 +/- 2.1kg for fluoxetine-treated patients (p < 0.001).CONCLUSIONS: Mirtazapine is as effective and well tolerated as fluoxetine in the treatment of patients with severe depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15697327&dopt=Abstract mirtazapine Remeron