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Effects of classic and newer antidepressants on the oxidation pathways of caffeine in rat liver. In vitro study.

Daniel WA, Kot M, Wojcikowski J.

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

Caffeine undergoes 3-N-demethylation via CYP1A2, as well as 1-N-demethylation, 7-N-demethylation and 8-hydroxylation, which may involve other CYP isoenzymes. The aim of the present study was to investigate the influence of clomipramine, desipramine, sertraline, nefazodone and mirtazapine on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated antidepressants, with an exception of mirtazapine, added in vitro to liver microsomes had an inhibitory effect on caffeine metabolism (via competitive or mixed mechanism), though their potency towards particular metabolic pathways was different. Dixon analysis of caffeine metabolism carried out in the control liver microsomes, in the absence and presence of the antidepressant drugs showed that desipramine and clomipramine exerted the most potent inhibitory effect on caffeine metabolism. Desipramine decreased the rates of 1-N-, 3-N- and 7-N-demethylations, and 8-hydroxylation of caffeine (Ki = 23.3, 36.6, 23.3 and 63.3 microM, respectively), the effect on 1-N- and 7-N-demethylation being the most pronounced. Clomipramine showed distinct inibition of 1-N- and 3-N-demethylation and 8-hydroxylation of caffeine, the effects on N-demethylations being the most pronounced (Ki = 38.6, 34.8, 45.6 microM, respectively). Its effect on 7-N-demethylation was rather weak (Ki = 97.8 microM). Sertraline decreased significantly the rate of 1-N- and 3-N-demethylation and 8-hydroxylation (Ki = 37.3, 69.3 and 64 microM, respectively), while its effect on 7-N-demethylation of caffeine was less pronounced (Ki = 92.1 microM). Nefazodone displayed clear effect on 3-N- and 7-N-demethylation (Ki = 68.8 and 66.4 microM, respectively), but was weak in inhibiting 1-N-demethylation and 8-hydroxylation of caffeine (Ki = 110 and 186 microM, respectively). In contrast to the above-tested antidepressants, mirtazapine did not decrease significantly the oxidation rates of 3-N-demethylation or 8-hydroxylation (Ki = 264 and 455 microM, respectively) and had no effect on other oxidation pathways of caffeine. In summary, we have observed intra- and inter-drug differences in the inhibitory effects of the antidepressants on the four oxidation pathways of caffeine in rat liver microsomes. The tested antidepressants (with an exception of mirtazapine) may lead to drug-drug metabolic interactions at a level of a few CYP isoforms. The obtained results provide further indirect evidence that apart from CYP1A2, other CYP isoforms are also important for the metabolism of caffeine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14730100&dopt=Abstract mirtazapine Remeron



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Therapeutic drug monitoring of the antidepressant mirtazapine and its N-demethylated metabolite in human serum.

Shams M, Hiemke C, Hartter S.

Department of Psychiatry, University of Mainz, Mainz, Germany.

Mirtazapine is a novel antidepressant that acts by enhancing serotonergic and noradrenergic neurotransmission. Because very little is known about serum concentrations in relation to clinical effects, the use of therapeutic drug monitoring is so far unclear. A rapid automated HPLC method with fluorescence detection was developed for routine quantification of mirtazapine and its demethylated metabolite N-desmethylmirtazapine in human serum. The precision of the method was suitable because the day-to-day (n = 7) coefficient of variation (CV) of mirtazapine was 9.8, 4.2, and 5.1% for concentrations of 10, 40, and 80 ng/mL, respectively, and the CV for N-desmethylmirtazapine were 11.6, 10.3, and 9.5% for 5, 20, and 40 ng/mL, respectively. The bias ranged between 0.7 and 4.2 ng/mL and between 0.9 and 2.0 ng/mL for mirtazapine and N-desmethylmirtazapine, respectively. Serum samples of 100 patients, aged between 18 and 93 years, were analyzed. There was wide interindividual variability of serum concentrations on each dose level, and the median (25th to 75th percentiles) of the mirtazapine and N-desmethylmirtazapine concentrations was 19.5 (11.0-28.7) and 9.0 (6.0-17.0) ng/mL, respectively. Women had higher dose-corrected concentrations (C/Ds, ng/mL/mg) of mirtazapine [median (25th-75th percentiles) 0.6 (0.4-0.9) vs 0.4 (0.3-0.6) and N-desmethylmirtazapine [0.4 (0.2-0.6) vs 0.2 (0.1-0.4)] than men. Patients over 60 years of age (mean age +/- SD was 72.2 +/- 7.1) had higher C/Ds of mirtazapine and N-desmethylmirtazapine [0.7 (0.4-1.2) vs 0.53 (0.4-0.8) and 0.5 (0.2-0.9) vs 0.3 (0.2-0.9), respectively] than younger patients (mean age +/- SD was 43.3. +/- 10.6). Patients with N-desmethylmirtazapine/mirtazapine ratios less than 0.4 had significantly more side effects (P < 0.05) than those having higher ratios. Comedications were assessed for drug-drug interaction, and significantly (P < 0.05) lower N-desmethylmirtazapine/mirtazapine ratios were found under concomitant medications of the antidepressant sertraline and the antipsychotic amisulpride.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14749554&dopt=Abstract mirtazapine Remeron



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Mirtazapine is associated with less anxiolytic use among elderly depressed patients in long-term care facilities.

Gardner ME, Malone DC, Sey M, Babington MA.

College of Pharmacy, The University of Arizona, Tucson, AZ, USA. gardner pharmacy.arizona.edu

BACKGROUND: Depression is a common, treatable disorder among nursing facility residents. OBJECTIVE: The purpose of this study was to examine medication use and cost between two groups of patients: (1) persons treated with mirtazapine, as compared with (2) persons taking other antidepressants. DESIGN: This study was a retrospective chart review of long-term care patients. Consultant pharmacists collected data on patients who were receiving selective serotonin reuptake inhibitors (SSRIs), venlafaxine, nefazodone, or mirtazapine. SETTING: Nursing facilities that were geographically dispersed throughout the United States. PARTICIPANTS: We studied patients greater than 65 years of age with major depressive disorder or a depression-related diagnosis and receiving antidepressant treatment for at least 3 months. Patients with bipolar-induced depression were excluded as well as those receiving tricyclic antidepressants. RESULTS: The two groups were similar in terms of age, but those receiving mirtazapine had lower body weight and body mass index. Patients on mirtazapine were less likely to be taking a sedative/hypnotic (P = 0.006). This was primarily the result of fewer patients in the mirtazapine group taking lorazepam (P = 0.03). There was no difference between the two groups regarding their use of other psychotropic medications, including multiple antidepressants, antipsychotics, anticonvulsants, acetylcholinesterase inhibitors, or appetite stimulants. Monthly medication costs were less for those patients receiving mirtazapine ($82.83) as compared with other antidepressants ($97.03) (P <0.0001). CONCLUSIONS: The results of this study suggest that patients receiving mirtazapine are less likely to be on anxiolytic/hypnotic agents. The findings also suggest that medication costs are less when mirtazapine is used compared with other antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14984621&dopt=Abstract mirtazapine Remeron



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A Trilogy Case Review Highlighting the Clinical and Pharmacologic Applications of Mirtazapine in Reducing Polypharmacy for Anxiety, Agitation, Insomnia, Depression, and Sexual Dysfunction.

Barkin RL, Chor PN, Braun BG, Schwer WA.

Departments of Anesthesiology, Family Medicine, Pharmacology, and Psychiatry, Rush-Presbyterian-St. Luke's Medical Center and Rush Medical College, Chicago, Ill. Dr. Braun is in private practice in Skokie, Ill.

BACKGROUND: Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is characterized by a unique receptor-specific pharmacologic profile and tolerable side-effect profile in comparison to other antidepressants. It has been reported to have a low incidence of agitation, anxiety, and insomnia, which may be due to blockade of 5-HT(2) and 5-HT(3) receptors. This unique multireceptor-mediated clinical pharmacologic profile may reduce the need for polypharmacy in selected patients. CASE REPORTS: Three cases are presented. In case 1, mirtazapine was able to rapidly treat anxiety and agitation in a 90-year-old woman. This was confirmed with 3 consecutive challenges with mirtazapine. In case 2, both a mood disorder and insomnia were successfully treated with rapid resolution in a patient by using mirtazapine. In case 3, the patient experienced sexual dysfunction while receiving sertraline and developed insomnia with the addition of bupropion. The addition of mirtazapine and the discontinuation of sertraline and bupropion resolved the sexual dysfunction and insomnia. Polypharmacy interventions were decreased in these patients through receptor-specific events from mirtazapine. CONCLUSION: The new antidepressant mirtazapine appears to be an effective strategy for treating anxiety, agitation, and insomnia and for diminishing SSRI-related sexual dysfunction without compromising the patient's therapeutic response to the medication while decreasing the need for additional pharmacotherapies. More than 70% of patients with major depression will have anxiety symptoms. The 5-HT(2) receptor seems to play a major role in the regulation of anxiety. The anxiolytic properties of mirtazapine may be due to its antagonism of 5-HT(2) receptors and can appear as early as the first week of treatment.

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Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex.

Devoto P, Flore G, Pira L, Longu G, Gessa GL.

B.B. Brodie Department of Neuroscience, University of Cagliari, SS 554 km 4,5, 09042 Monserrato (CA), Italy. pdevoto unica.it

The novel antidepressant mirtazapine has been shown to increase extracellular noradrenaline and dopamine in the medial prefrontal cortex. Our previous studies indicate that extracellular dopamine in the cerebral cortex originates largely from noradrenergic terminals, such release being controlled by alpha(2)-adrenoceptors. Because mirtazapine inhibits alpha(2)-adrenoceptors, the possibility that it might corelease dopamine and noradrenaline was investigated. By means of microdialysis, the effect of mirtazapine on extracellular dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and noradrenaline in the medial prefrontal cortex, densely innervated by dopaminergic and noradrenergic neurons, and in the occipital cortex, receiving equal noradrenergic but scarce dopaminergic projections, was compared. Basal extracellular concentration of noradrenaline was similar in both cortices, while dopamine in the occipital cortex was only about 50% lower than in the medial prefrontal cortex, reflecting noradrenergic rather than dopaminergic projections. The intraperitoneal (i.p.) administration of mirtazapine (5 and 10 mg/kg) increased extracellular dopamine, DOPAC and noradrenaline to approximately the same extent in both cortices, an effect totally suppressed by the alpha(2)-adrenoceptors agonist clonidine (0.15 mg/kg, i.p.). To exclude the possibility that mirtazapine-induced increase in dopamine might result from reduced dopamine removal from extracellular space, noradrenaline and dopamine uptake mechanisms were blocked by perfusing 100 microM desipramine into either cortex. The combined i.p. administration of mirtazapine (5 mg/kg) and the local perfusion of desipramine produced an additional increase in extracellular dopamine, DOPAC and noradrenaline in the medial prefrontal cortex and occipital cortex compared with the increase produced by either drug given alone. The results suggest that mirtazapine by inhibiting alpha(2)-adrenoceptors produces a corelease of noradrenaline and dopamine from noradrenergic terminals in the cerebral cortex.

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Are selective serotonin re-uptake inhibitors associated with an increased risk of self-harm by antidepressant overdose?

Bateman DN, Chick J, Good AM, Kelly CA, Masterton G.

Scottish Poisons Information Bureau (NPIS Edinburgh), Royal Infirmary of Edinburgh, 51 Little France Crescent, EH10 4SA Edinburgh, Scotland. spib luht.scot.nhs.uk

OBJECTIVE: To investigate likelihood of self-harm by overdose with antidepressant drugs of different types by examining hospital admission data and poisons inquiries and relating them to prescribing. DESIGN: Retrospective analysis of prospectively collected data on overdose admissions, poisons inquiries and prescribing of antidepressants in Edinburgh and Scotland. SETTING: Poisons treatment unit of the Royal Infirmary of Edinburgh and its surrounding catchment for overdose cases and Scotland for poisons inquiries. PARTICIPANTS: All patients admitted to the Royal Infirmary of Edinburgh between 1 January 2000 and 31 December 2002 with an overdose involving an antidepressant. MAIN OUTCOME MEASURES: Overdose admissions (patients) in relation to prescribing in Edinburgh and poisons inquiries in relation to prescription rates in Scotland. RESULTS: There were 1656 admissions involving 1343 patients. The likelihood of admission for an individual patient in relation to volume of prescribing (likelihood ratio: 95%CI) in the catchment was somewhat smaller for amitriptyline (0.83:0.74-0.92) and sertraline (0.79:0.63-0.99), and somewhat greater for mirtazapine (1.99:1.57-2.51), trazadone (1.30:1.09-1.54) and venlafaxine (1.33:1.13-1.55). For poisons inquiries in Scotland, the excess for venlafaxine and mirtazapine was confirmed and likelihood of an inquiry lowest for selective serotonin re-uptake inhibitors (SSRIs). CONCLUSIONS: There was no evidence of an excess likelihood of presentation with overdose with SSRIs, and the likelihood was reduced with sertraline. There was a small excess of both admissions and poisons inquiries for mirtazapine and venlafaxine. This is a concern in view of the increased toxicity of venlafaxine in overdose in comparison with SSRIs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15083251&dopt=Abstract mirtazapine Remeron