Mirtazapine (Remeron) Drug Interactions / Pharmacokinetics -- Neurotransmitter.net

(Updated 5/25/04)

Anttila SA, Leinonen EV.
A review of the pharmacological and clinical profile of mirtazapine.
CNS Drug Rev 2001 Fall;7(3):249-64
"The novel antidepressant mirtazapine has a dual mode of action. It is a noradrenergic and specific serotonergic antidepressant (NaSSA) that acts by antagonizing the adrenergic alpha2-autoreceptors and alpha2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission. This dual mode of action may conceivably be responsible for mirtazapine's rapid onset of action. Mirtazapine is extensively metabolized in the liver. The cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4 are mainly responsible for its metabolism. Using once daily dosing, steady-state concentrations are reached after 4 days in adults and 6 days in the elderly." [Abstract]
Timmer CJ, Sitsen JM, Delbressine LP.
Clinical pharmacokinetics of mirtazapine.
Clin Pharmacokinet 2000 Jun;38(6):461-74 [Abstract]
Stormer, Elke, von Moltke, Lisa L., Shader, Richard I., Greenblatt, David J.
Metabolism of the Antidepressant Mirtazapine In Vitro: Contribution of Cytochromes P-450 1A2, 2D6, and 3A4
Drug Metab Dispos 2000 28: 1168-1175 [Full Text]
Sitsen JM, Voortman G, Timmer CJ.
Pharmacokinetics of mirtazapine and lithium in healthy male subjects.
J Psychopharmacol 2000 Jun;14(2):172-6
"The results indicate that mirtazapine does not alter the pharmacokinetics of lithium and vice versa. In addition, the combination of mirtazapine and lithium appeared to be safe and well-tolerated. Extensive psychometric testing after the administration of mirtazapine did not reveal any differences on any tests in subjects on lithium and placebo, respectively." [Abstract]
Zoccali R, Muscatello MR, Torre DL, Malara G, Canale A, Crucitti D, D'Arrigo C, Spina E.
Lack of a pharmacokinetic interaction between mirtazapine and the newer antipsychotics clozapine, risperidone and olanzapine in patients with chronic schizophrenia.
Pharmacol Res. 2003 Oct;48(4):411-4.
"The effect of mirtazapine on steady-state plasma concentrations of the newer atypical antipsychotics clozapine, risperidone and olanzapine was investigated in 24 patients with chronic schizophrenia. In order to treat residual negative symptoms, additional mirtazapine (30 mg per day) was administered for six consecutive weeks to nine patients stabilized on clozapine therapy (200-650 mg per day), eight on risperidone (3-8 mg per day) and seven on olanzapine (10-20mg per day). There were only minimal and statistically insignificant changes in mean plasma concentrations of clozapine and its metabolite norclozapine, risperidone and its metabolite 9-hydroxyrisperidone, and olanzapine during the study period. Mirtazapine co-administration with either clozapine, risperidone or olanzapine was well tolerated. In the overall sample, a slight improvement in negative symptomatology, as assessed by the Scale for Assessment of Negative Symptoms, was observed at final evaluation (P<0.01) and six patients (two in each treatment group) were classified as responders. While double-blind, controlled studies are needed to evaluate the potential clinical benefits of mirtazapine in chronic schizophrenia, our findings indicate that mirtazapine has a negligible effect on the metabolism of clozapine, risperidone and olanzapine and can be added safely to an existing treatment with these antipsychotics." [Abstract]
Loonen AJ, Doorschot CH, Oostelbos MC, Sitsen JM.
Lack of drug interactions between mirtazapine and risperidone in psychiatric patients: a pilot study.
Eur Neuropsychopharmacol 1999 Dec;10(1):51-7 [Abstract]

Sitsen J, Maris F, Timmer C.
Drug-drug interaction studies with mirtazapine and carbamazepine in healthy male subjects.
Eur J Drug Metab Pharmacokinet 2001 Jan-Jun;26(1-2):109-21 [Abstract]
Morgan PE, Tapper J, Spencer EP.
Measurement of total mirtazapine and normirtazapine in plasma/serum by liquid chromatography with fluorescence detection.
J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Dec 25;798(2):211-5.
"A simple high performance liquid chromatography (HPLC) method for the measurement of the new antidepressant mirtazapine and its N-demethyl metabolite, normirtazapine, in human plasma or serum during low dose mirtazapine therapy has been developed. A Waters Spherisorb S5 SCX column was used with ammonium perchlorate (50 mmol/l) in methanol/water (95 + 5 (v/v)), apparent pH 6.7, as eluent, and fluorescence detection. Only small volumes of sample (0.2 ml) and extraction solvent are used. An interference study found no significant co-elution with drug or metabolite, although paroxetine co-elutes with the internal standard. The recovery of mirtazapine and normirtazapine (mean +/- S.D.) was 79 +/- 2, and 64 +/- 3%, respectively. The LOD was estimated as 0.5 microg/l, LLOQ was 1 microg/l, with a linear response over the concentration range 4-1000 microg/l (both analytes). The analytes were stable in serum for at least 10 months when stored at -20 degrees C. Intra- and inter-day accuracy were in the range 91-107 and 93-103%, respectively. In clinical samples (n = 14, median mirtazapine dose 45 mg per day, range 15-45 mg per day) the median (range) mirtazapine and normirtazapine concentrations were 26 (8-40) and 21 (8-32) microg/l, respectively." [Abstract]
Ptacek P, Klima J, Macek J.
Determination of mirtazapine in human plasma by liquid chromatography.
J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Sep 5;794(2):323-8.
"A rapid high-performance liquid chromatographic method for the quantitation of mirtazapine in human plasma is presented. The method is based on a liquid-liquid extraction and reversed-phase chromatography with fluorimetric detection. The separation was performed on a Luna microm C(18)(2) 50 x 4.6 mm I.D. column using an isocratic elution. Zolpidem hemitartrate was used as the internal standard. The between-day precision expressed by relative standard deviation was less than 5% and inaccuracy does not exceed 6%. A low limit of quantitation (1.5 ng/ml) and a short time of analysis (4 min) makes this assay suitable for pharmacokinetic studies." [Abstract]

[Do not assume that this information is comprehensive. See also mirtazapine research.]

Shams M, Hiemke C, Hartter S.
Therapeutic drug monitoring of the antidepressant mirtazapine and its N-demethylated metabolite in human serum.
Ther Drug Monit. 2004 Feb;26(1):78-84.
"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." [Abstract]

Anttila AK, Rasanen L, Leinonen EV.
Fluvoxamine augmentation increases serum mirtazapine concentrations three- to fourfold.
Ann Pharmacother 2001 Oct;35(10):1221-3 [Abstract]

Demers JC, Malone M.
Serotonin syndrome induced by fluvoxamine and mirtazapine.
Ann Pharmacother 2001 Oct;35(10):1217-20
"An increasing number of drugs that affect serotonin are available and are indicated for various disorders. Since there is a significant likelihood of these agents being prescribed concomitantly, clinicians must be aware of possible interactions that could lead to serotonin syndrome." [Abstract]

Sitsen JM, Maris FA, Timmer CJ.
Concomitant use of mirtazapine and cimetidine: a drug-drug interaction study in healthy male subjects.
Eur J Clin Pharmacol 2000 Aug;56(5):389-94
"Co-administration of cimetidine (800 mg b.i.d.) and mirtazapine (30 mg nocte) resulted in increased steady-state plasma levels of mirtazapine (C(ss,min) = +61%, P < 0.05; C(ss,av) = +54%, P < 0.05), probably as a result of increased bio-availability. The Cmax (+22%, P < 0.05) and AUC(0-24) (+54%, P < 0.05) also increased. Due to the variability of the mirtazapine plasma levels in patients, the clinical meaning of these increases is probably limited. Co-administration of mirtazapine did not alter cimetidine pharmacokinetics." [Abstract]

Spaans E, Van Den Heuvel MW, Schnabel PG, Peeters PA, Chin-Kon-Sung UG, Colbers EP, Sitsen JM.
Concomitant use of mirtazapine and phenytoin: a drug-drug interaction study in healthy male subjects.
Eur J Clin Pharmacol 2002 Sep;58(6):423-9
"Co-administration of mirtazapine did not alter the steady-state pharmacokinetics of phenytoin. The addition of phenytoin to an existing daily administration of mirtazapine results in a decrease of the plasma concentrations of mirtazapine by 46% on average, most likely due to induction of CYP 3A3/4." [Abstract]

Sennef C, Timmer CJ, Sitsen JM.
Mirtazapine in combination with amitriptyline: a drug-drug interaction study in healthy subjects.
Hum Psychopharmacol. 2003 Mar;18(2):91-101.
"OBJECTIVE: To assess the steady-state pharmacokinetics of mirtazapine (30 mg/day orally) and amitriptyline (75 mg/day orally) during combined administration compared with that of either drug administered alone. To evaluate the tolerability and effects on psychometric tests of acute and subchronic administration of both drugs combined and alone. METHODS: In a single-blind, three-way cross-over study, 24 (12 male and 12 female) healthy subjects were randomly assigned to six different sequences of three 9-day treatments, i.e. racemic mirtazapine (30 mg/day), amitriptyline (75 mg/day) or the combination of these drugs. To control for acute pharmacodynamic assessments, during the first treatment period, a placebo group (n = 8; 4 females and 4 males) was added. Serial blood samples were drawn for plasma level measurements that were subsequently subjected to pharmacokinetic analysis. Psychometric tests assessed attentional performance, and a computer-assisted telephone questionnaire assessed self-ratings of drowsiness/alertness and sleep quality. RESULTS: Amitriptyline increased the C(max) of mirtazapine (+ 36%, p < 0.05) in male subjects only. Mirtazapine altered the C(max) of amitriptyline in both male (+ 23%, p < 0.05) and female (- 23%, p < 0.05) subjects. No changes were observed for other pharmacokinetic parameters. Metabolite parameters were not affected. Changes in parent compound levels mainly resulted from effects on absorption. The psychometric test results did not reveal significant changes between combined and single drug treatments. The telephone registrations of VAMRS and LSEQ did not show clinically relevant differences between the active treatments. CONCLUSION: Combined administration of mirtazapine (30 mg/day) and amitriptyline (75 mg/day) alters the pharmacokinetics of either compound to a minor extent. Adding one drug to the other and substituting one drug by the other had no major effects on tolerability. Nevertheless, caution is warranted when combining amitriptyline and mirtazapine." [Abstract]

Abo-Zena RA, Bobek MB, Dweik RA.
Hypertensive urgency induced by an interaction of mirtazapine and clonidine.
Pharmacotherapy 2000 Apr;20(4):476-8 [Abstract]

Normann C, Hesslinger B, Frauenknecht S, Berger M, Walden J.
Psychosis during chronic levodopa therapy triggered by the new antidepressive drug mirtazapine.
Pharmacopsychiatry 1997 Nov;30(6):263-5
"We report the case of a patient developing psychosis after the addition of mirtazapine, a novel antidepressant enhancing serotonergic neurotransmission, to a chronic levodopa regimen. There was complete and rapid recovery upon low-dose clozapine treatment. To our knowledge, this is the first published case of a mirtazapine-levodopa interaction and the second case report of a psychosis induced by a serotonergic antidepressant in a patient with Parkinson's disease (PD). This phenomenon might be due to a postsynaptic serotonin receptor supersensitization caused by low central serotonin levels in treated PD." [Abstract]

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Recent Mirtazapine Interactions Research
1) Botts S, Diaz FJ, Santoro V, Spina E, Muscatello MR, Cogollo M, Castro FE, de Leon J
Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 May 7;
The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age >/=18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient). Smoking and concomitant carbamazepine or lamotrigine use were found to have significant effects on median plasma olanzapine concentrations. The effects of lamotrigine on plasma olanzapine concentrations were modified by smoking. After adjusting for olanzapine dose and carbamazepine intake, plasma olanzapine concentrations were 10% lower in non-smokers who were taking lamotrigine than in non-smokers who were not taking lamotrigine; olanzapine concentrations were 35% higher in smokers who were taking lamotrigine than in smokers who were not taking lamotrigine; olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine than in non-smokers who were not taking lamotrigine; and olanzapine concentrations were 11% lower in smokers who were taking lamotrigine than in non-smokers who were taking lamotrigine. After adjusting for olanzapine dose and taking carbamazepine, the correction factor comparing smokers taking lamotrigine versus non-smokers who were not taking lamotrigine was 1.3. Gender, age, and concomitant use of mirtazapine, valproic acid, lamotrigine, topiramate, lorazepam, citalopram or oxcarbazepine did not have significant effects on olanzapine concentrations. The main limitation of this clinical design is the unavoidable substantial "noise" that characterizes (uncontrolled) clinical environments, which may make it difficult to detect the effects of some variables. Other limitations were the small sample size of some drug sub-samples and the lack of testing for plasma olanzapine metabolites. [PubMed Citation] [Order full text from Infotrieve]

2) Liu CC, Liang KY, Liao SC
Antidepressant-associated mania: soon after switch from fluoxetine to mirtazapine in an elderly woman with mixed depressive features.
J Psychopharmacol. 2008 May 30;
Abstract Mirtazapine augmentation to a serotonin-reuptake inhibitor has been proposed to boost antidepressant effects and more likely to induce manic switch. Such a combined antidepressant therapy strategy should be used carefully if the patient's refractoriness is attributable to mixed depressive features. Mixed depression is more difficult to be treated by antidepressant monotherapy and related to higher risk of manic switch during treatment. We report a case with no previous history of bipolar disorder, whereas developed full-blown psychotic manic symptoms soon after switch from fluoxetine to mirtazapine. The patient's premorbid characters and clinical presentations suggested an implicit bipolarity that predisposed her to a manic switch. Her manic switch was likely to be triggered by a simulated combined effect because of complex drug interactions during shifting from fluoxetine to mirtazapine. For patients in mixed depressive states, mood stabilizers are preferable to antidepressants. [PubMed Citation] [Order full text from Infotrieve]

3) Dvir Y, Smallwood P
Serotonin syndrome: a complex but easily avoidable condition.
Gen Hosp Psychiatry. 2008 May-Jun;30(3):284-7.
Serotonin syndrome is a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism in central and peripheral nervous system serotonergic receptors (Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-1120). Symptoms are characterized by a triad of neuron-excitatory features, which include (a) neuromuscular hyperactivity -- tremor, clonus, myoclonus, hyperreflexia and, in advanced stages, pyramidal rigidity; (b) autonomic hyperactivity -- diaphoresis, fever, tachycardia and tachypnea; (c) altered mental status -- agitation, excitement and, in advanced stages, confusion (Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 2005;95:434-441). It arises when pharmacological agents increase serotonin neurotransmission at postsynaptic 5-hydroxytryptamine 1A and 5-hydroxytryptamine 2A receptors through increased serotonin synthesis, decreased serotonin metabolism, increased serotonin release, inhibition of serotonin reuptake or direct agonism of the serotonin receptors (Houlihan D. Serotonin syndrome resulting from coadministration of tramodol, venlafaxine, and mirtazapine. Ann Pharmacother 2004;38:411-413). The etiology is often the result of therapeutic drug use, intentional overdosing of serotonergic agents or complex interactions between drugs that directly or indirectly modulate the serotonin system (Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-1120). Due to the increasing availability of agents with serotonergic activity, physicians need to more aware of serotonin syndrome. The following case highlights the complex nature in which serotonin syndrome can arise, as well as the proper recognition and treatment of a potentially life-threatening yet easily avoidable condition. [PubMed Citation] [Order full text from Infotrieve]

4) Kang RH, Choi MJ, Paik JW, Hahn SW, Lee MS
Effect of serotonin receptor 2A gene polymorphism on mirtazapine response in major depression.
Int J Psychiatry Med. 2007;37(3):315-29.
The 5-HTR2A gene is a candidate gene for influencing the clinical response to treatment with antidepressants. The purpose of this study was to determine the relationship between the -1438A/G polymorphism of the 5-HTR2A gene and the response to mirtazapine in a Korean population with major depressive disorder. Mirtazapine was administered for eight weeks to the 101 patients who completed the study, during which we evaluated the clinical outcome using repeated-measures ANCOVA. A main effect of genotype or an effect of genotype-time interactions on the decrease in HAMD score during the eight-week follow-up was not found, which suggests that the 5-HTR2A -1438A/G polymorphism does not affect the clinical outcome to mirtazapine administration. However, significant effects of genotype and allele carriers on the decrease in the sleep score over the eight weeks were found (genotype: F = 4.093, p = 0.017; allele: F = 4.371, p = 0.037), whereas no effect of genotype-time interactions on the decrease in the HAMD score over the eight-week follow-up was found. These observations suggest that the -1438A/G polymorphism on the sleep improvement at each time period revealed significant differences in the sleep scores after two weeks of mirtazapine administration. The sleep scores were lower for carriers of the A+ allele than of the A- allele after two weeks of mirtazapine administration (p = 0.041), which means that the -1438GG genotype is associated with less improvement in sleep, and suggests that the effect of mirtazapine on improving the sleep quality differs with the 5-HTR2A -1438A/G polymorphism within two weeks of mirtazapine treatment. In conclusion, although the -1438A/G polymorphism affects the sleep improvement resulting from the administration of mirtazapine to Korean patients with major depressive disorder, our results do not support the hypothesis that this polymorphism of the 5-HTR2A gene is involved in the therapeutic response to mirtazapine. [PubMed Citation] [Order full text from Infotrieve]

5) Wille SM, Cooreman SG, Neels HM, Lambert WE
Relevant issues in the monitoring and the toxicology of antidepressants.
Crit Rev Clin Lab Sci. 2008;45(1):25-89.
This review provides specific information concerning the interpretation and usefulness of antidepressant drug monitoring. Fifteen antidepressants (ADs) were selected based on their importance in the 7 major markets (Japan, USA, France, United Kingdom, Italy, Spain, Germany) according to the Cognos Plus Study #11. Literature data were reviewed concerning monitoring of the tricyclic ADs amitriptyline, clomipramine, imipramine, and new generation antidepressants such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, mianserin, mirtazapine, bupropion, and milnacipran. In addition, St.-John's Wort was added as this natural antidepressant is very popular in Europe. The objectives of therapeutic drug monitoring (TDM) for old and new generation ADs differs, as older ADs have narrow therapeutic windows with higher risks of severe drug interactions, while the new ADs have a wide therapeutic range, but an unclear plasma concentration-effect relationship. Therefore, the purpose of TDM for new-generation ADs leads more to the monitoring of patient compliance and special patient groups such as the elderly, patients with liver and kidney impairment, patients with poor metabolism by CYP 450 and comedication with inhibitors and inducers of those enzymes. [PubMed Citation] [Order full text from Infotrieve]

6) Kot M, W�jcikowski J, Daniel WA
Caffeine metabolism during prolonged treatment of rats with antidepressant drugs.
Pharmacol Rep. 2007 Nov-Dec;59(6):727-33.
Our previous studies showed that some of the tested antidepressants (tricyclics, SSRIs, mirtazapine, nefazodone) directly inhibited the metabolism of caffeine when added in vitro to liver microsomes. The aim of the present study was to investigate a possible indirect effect of prolonged in vivo administration of these antidepressants on the rate of caffeine oxidative metabolism: 1-N-, 3-N- and 7-N-demethylation and 8-hydroxylation in rat liver. The reactions were studied in liver microsomes of rats treated intraperitoneally (ip) for one day or two weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone at 10 mg/kg; desipramine, fluoxetine, sertraline at 5 mg/kg; mirtazapine at 3 mg/kg), in the absence of the antidepressants in vitro. One-day treatment with imipramine and amitriptyline decreased, while fluoxetine accelerated the metabolism of caffeine. Nefazodone stimulated 1-N-demethylation only. Fluoxetine given chronically increased exclusively 7-N-demethylation, while imipramine showed only such tendency. Sertraline and mirtazapine enhanced the rates of all caffeine oxidation pathways. We conclude that the tested antidepressant drugs may affect the metabolism of caffeine not only in a direct way (binding to the enzyme), but also indirectly via inducing CYP1A2 (sertraline and mirtazapine) and CYP2C isoforms (fluoxetine, sertraline, mirtazapine) after prolonged administration. In addition, the presented data provide further experimental evidence for the importance of the subfamily CYP2C for the 7-N-demethylation of caffeine in the rat. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

7) Mandrioli R, Raggi MA
Electrodriven methods for the enantioseparation of second-generation antidepressant drugs: an update.
Electrophoresis. 2008 Jan;29(1):252-9.
Second-generation antidepressant drugs are increasingly prescribed world-wide by psychiatrists and primary care physicians. Generally speaking, they seem to be safer than traditional tricyclic antidepressant drugs, especially in overdose. However, most of them possess stereogenic centers, thus they can exist as enantiomeric couples. Since enantiomers can have even dramatically different pharmacokinetic and pharmacodynamic properties, the study of antidepressant chirality is of great importance. In fact, the application of enantioselective analytical techniques can be useful both for the quality control of enantiomerically pure formulations and for the pharmacovigilance and therapeutic monitoring of patients undergoing treatment with these drugs. The high efficiency and inexpensiveness of electrodriven methods makes them a very attractive alternative to the usual chromatographic methods. This review is an update (2004-2007) of a previously published paper on recent electrodriven methods for the enantioseparation of second-generation antidepressants. In particular, the focus has been put on selective serotonin reuptake inhibitors such as citalopram and sertraline, noradrenergic and specific serotonergic antidepressants, such as mirtazapine and tetracyclic antidepressants such as mianserin, as well as on multianalyte methods. [PubMed Citation] [Order full text from Infotrieve]

8) Kang RH, Hahn SW, Choi MJ, Lee MS
Relationship between G-protein beta-3 subunit C825T polymorphism and mirtazapine responses in Korean patients with major depression.
Neuropsychobiology. 2007;56(1):1-5.
AIMS: This study aimed to determine the relationship between the C825T polymorphism in the G-protein beta 3 subunit (GNB3) gene and the response to mirtazapine in a Korean population with major depressive disorder (MDD). METHOD: Mirtazapine was administered for 8 weeks to the 101 MDD patients who completed this study. All subjects were examined using the Structured Clinical Interview for DSM-IV, and the severity of depression was assessed using the 21-item Hamilton Depression Rating (HAMD-21) scale. RESULTS: There was a significant main effect of time on the decrease in the HAMD-21 score during the 8-week study period. However, a main effect of or an interaction of genotype with time on the decrease in the HAMD-21 score during the 8-week study period was not found. ANOVA revealed no significant effects of the GNB3 C825T polymorphism on the decrease in the HAMD-21 score at each time period. CONCLUSION: Although the C825T polymorphism of the GNB3 gene may affect the pathogenesis of MDD, our results do not support the hypothesis that this polymorphism is involved in the therapeutic response to mirtazapine in Korean patients with MDD. [PubMed Citation] [Order full text from Infotrieve]

9) Gon�alves Silva BJ, Costa Queiroz RH, Costa Queiroz ME
Simultaneous determination of nontricyclic antidepressants in human plasma by solid-phase microextraction and liquid chromatography (SPME-LC).
J Anal Toxicol. 2007 Jul-Aug;31(6):313-20.
A sensitive, selective, and reproducible solid-phase microextraction and liquid chromatographic (SPME-LC) method for simultaneous determination of mirtazapine, citalopram, paroxetine, fluoxetine, and sertraline in human plasma was developed, validated, and further applied to analyze plasma samples obtained from patients with depression. Important factors in the optimization of SPME efficiency are discussed, including the fiber coating, extraction time, pH, ionic strength, influence of plasma proteins, and desorption conditions. The limit of quantitation of the nontricyclic antidepressants in plasma varied from 25 to 50 ng/mL with a coefficient of variation lower than 5%. The response of the SPME-LC method for most of the drugs was linear over a dynamic range of 50 to 500 ng/mL, with all of them having correlation coefficients greater than 0.9970. The performance of the SPME-LC method allowed the nontricyclic antidepressants analyses in therapeutic levels. [PubMed Citation] [Order full text from Infotrieve]

10) Yilmaz I, Sezer Z, Kayir H, Uzbay TI
Mirtazapine does not affect pentylenetetrazole- and maximal electroconvulsive shock-induced seizures in mice.
Epilepsy Behav. 2007 Aug;11(1):1-5.
Mirtazapine is an antidepressant exhibiting both noradrenergic and serotonergic activity. We have investigated the effects of mirtazapine on pentylenetetrazole (PTZ)- and maximal electroconvulsive shock (MES)-induced seizures in mice. Mirtazapine (1.25-20mg/kg) or saline was administered, and locomotor activity was evaluated for 30 min. One hour after administration of mirtazapine (1.25-5mg/kg) or saline, PTZ (80 mg/kg) was injected intraperitoneally into the mice. Immediately afterward, times of onset of the first myoclonic jerk (FMJ), generalized clonic seizures (GCS), and tonic extension (TE) were recorded. In the MES groups, we used the MES protocol to induce convulsions characterized by tonic hindlimb extension. Similarly, 1h after mirtazapine or saline administration, an electroshock was evoked by ear-clip electrodes to induce convulsion. Mirtazapine, at 10 and 20 mg/kg, depressed locomotor activity. Doses of 1.25-5mg/kg had no significant effect on the time of onset of FMJ, GCS, or TE induced by PTZ; on the duration of GCS and TE; or on the latency to reinstatement of the righting reflex after MES administration. Our results suggest that mirtazapine neither aggravates nor alleviates PTZ- or MES-induced seizures in mice. [PubMed Citation] [Order full text from Infotrieve]

11) Levy RH, Collins C
Risk and predictability of drug interactions in the elderly.
Int Rev Neurobiol. 2007;81:235-51.
The issue of drug-drug interactions is particularly relevant for geriatric patients with epilepsy because they are often treated with multiple medications for concurrent diseases such as cardiovascular disease and psychiatric disorders (e.g., dementia and depression). The antidepressants with the least potential for altering antiepileptic drug (AED) metabolism are citalopram, escitalopram, venlafaxine, duloxetine, and mirtazapine. The use of established AEDs with enzyme-inducing properties, such as carbamazepine, phenytoin, and phenobarbital, may be associated with reductions in the levels of drugs such as donepezil, galantamine, and particularly warfarin. Carbamazepine, phenytoin, and phenobarbital have been reported to decrease prothrombin time in patients taking oral anticoagulants, although with phenytoin, an increase in prothrombin time has also been reported. Drugs associated with increased risk of bleeding in patients taking oral anticoagulants include selective serotonin reuptake inhibitors (especially fluoxetine), gemfibrozil, fluvastatin, and lovastatin. Other drugs affected by enzyme inducers include cytochrome P450 3A4 substrates, such as calcium channel blockers (e.g., nimodipine, nilvadipine, nisoldipine, and felodipine) and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors atorvastatin, lovastatin, and simvastatin. Although there have been no reports of AEDs altering ticlopidine metabolism, ticlopidine coadministration can result in carbamazepine and phenytoin toxicity. Also, there is a significant risk of elevated levels of carbamazepine when diltiazem and verapamil are administered. In addition, there are case reports of phenytoin toxicity when administered with diltiazem. Drugs with a lower potential for metabolic drug interactions include (1) cholinesterase inhibitors (although the theoretical possibility of a reduction in donepezil and galantamine levels by enzyme-inducing AEDs should be considered) and the N-methyl-D-aspartate receptor antagonist memantine and (2) antihypertensives such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, hydrophilic beta-blockers, and thiazide diuretics. There is a moderate risk that enzyme-inducing AEDs will decrease levels of lipophilic beta-blockers. Newer AEDs have a lower potential for drug interactions. In particular, levetiracetam and gabapentin have not been reported to alter enzyme activity. In summary, there is a significant potential for drug interactions between AEDs and drugs commonly prescribed in geriatric patients with epilepsy. [PubMed Citation] [Order full text from Infotrieve]

12) Fusar-Poli P, Lazzaretti M, Ceruti M, Hobson R, Petrouska K, Cortesi M, Pozzi E, Politi P
Depression after lung transplantation: causes and treatment.
Lung. 2007 Mar-Apr;185(2):55-65.
During the postoperative course of lung transplantation, patients may experience depressive symptoms that negatively influence their ability to cope with the new organ, their adherence to rehabilitation and pharmacologic therapy, and their overall quality of life (QoL). To date, no review has explored the causes of depression following transplantation or the efficacy and safety of therapeutic interventions in this patient group. We conducted a comprehensive 1966-2006 MEDLINE, EMBASE, and PsycINFO search for studies of the causes and treatments of depression in lung transplant recipients. We identified 25 studies of variable methodologic quality. Depression rates are high among candidates for lung transplantation. In the short term, after surgery depressive symptoms remain low with an improvement in QoL, whereas in the long term (>3 years), the decline of functional status is associated with a dramatic increase in such symptomatology. Personality disorders, coping strategies, stressful life events, physical complications, corticosteroid medications, age, gender, and psychosocial support all play a central role in causing depressive states in lung transplant recipients. Serotonin reuptake inhibitors (SSRIs) and new-generation antidepressants (mirtazapine) represent the best therapeutic choices for this group of patients. The risk of serious drug-drug interactions should be carefully monitored by experienced clinicians. Complementary therapies and psychoeducational intervention also help recipients to strengthen their coping strategies, offering further advantages after transplantation. Additional well-conducted randomized controlled trials are needed to clarify the epidemiologic course of depression following lung transplantation and to tailor effective pharmacologic or psychological interventions accordingly. [PubMed Citation] [Order full text from Infotrieve]

13) Brockm�ller J, Meineke I, Kirchheiner J
Pharmacokinetics of mirtazapine: enantioselective effects of the CYP2D6 ultra rapid metabolizer genotype and correlation with adverse effects.
Clin Pharmacol Ther. 2007 May;81(5):699-707.
Enantiomerically pure drugs and genotyping are promising approaches to achieve optimization in antidepressant therapy. Mirtazapine is a mixed noradrenergic serotoninergic antidepressant used as a racemate. We analyzed pharmacokinetics of its enantiomers in relation to CYP2D6 genotype and in relation to its adverse effects. Mirtazapine was enantioselectively absorbed from the gut with a rate constant of 0.2 min-1 for S+, but 0.08 min-1 for R- mirtazapine. Kinetics of R- mirtazapine was only marginally dependent on CYP2D6 genotype, but total clearance of the S+ enantiomer were 1.3, 2.3, and 3.4 L min-1 in poor, extensive, and ultrarapid metabolizers of CYP2D6 substrates with apparent substantial first-pass metabolism in rapid and ultrarapid metabolizers. Mirtazapine effects on heart rate and blood pressure correlated much more strongly with R- then with S+ concentrations, whereas sedation correlated similarly with both enantiomers. At least concerning some adverse effects, it might be worthwhile to study further mirtazapine enantiospecifically. [PubMed Citation] [Order full text from Infotrieve]

14) Varia I, Venkataraman S, Hellegers C, Gersing K, Doraiswamy PM
Effect of mirtazapine orally disintegrating tablets on health-related quality of life in elderly depressed patients with comorbid medical disorders: a pilot study.
Psychopharmacol Bull. 2007;40(1):47-56.
BACKGROUND: There is a need for additional studies on the quality of life (QOL) of elderly depressed subjects with medical comorbidity. METHOD:We conducted a 10-week, open trial of mirtazapine orally disintegrating tablets in 16 elderly subjects with major depressive disorder and one or more serious medical illnesses. Quality of life was measured by the Medical Outcomes Study Short Form-36 Health Status Survey (SF- 36). RESULTS: Treatment with mirtazapine was associated with significant reductions in clinical global impressions-severity of illness scale (CGI-S) score, the Hamilton rating scale for anxiety (HAM-A) total score, the 17-item Hamilton rating scale for depression (HAM-D) total score and the Beck depression inventory (BDI) total scores. The SF-36 "physical functioning", "role limitation physical", "vitality", "social functioning", "role limitation emotional", and "mental health" domains improved significantly. The mean mirtazapine dose at endpoint was 35 mg per day. The drug was relatively well tolerated except for three subjects who dropped out because of side effects. No drug-drug interactions or significant changes in blood pressure or heart rate occurred. CONCLUSION: Mirtazapine orally disintegrating tablets may improve depression, insomnia, anxiety, somatic symptoms, and certain quality-of-life measures in elderly depressed subjects with medical disorders. A randomized, placebo-controlled study is warranted to confirm these promising findings. [PubMed Citation] [Order full text from Infotrieve]

15) Prospero-Garcia KA, Torres-Ruiz A, Ramirez-Bermudez J, Velazquez-Moctezuma J, Arana-Lechuga Y, Teran-Perez G
Fluoxetine-mirtazapine interaction may induce restless legs syndrome: report of 3 cases from a clinical trial.
J Clin Psychiatry. 2006 Nov;67(11):1820.
[PubMed Citation] [Order full text from Infotrieve]

16) Fusar-Poli P, Matteo L, Luca de M, Politi P, Cortesi M, Carboni V
Anxiety and depression after lung transplantation: Mirtazapine as a first-choice agent?
J Psychosom Res. 2007 Jan;62(1):101.
[PubMed Citation] [Order full text from Infotrieve]

17) Meineke I, Steinmetz H, Kirchheiner J, Brockm�ller J
Therapeutic drug monitoring of mirtazapine, desmethylmirtazapine, 8-hydroxymirtazapine, and mirtazapine-N-oxide by enantioselective HPLC with fluorescence detection.
Ther Drug Monit. 2006 Dec;28(6):760-5.
The tetracyclic antidepressant mirtazapine has been in clinical use for several years as a racemic drug. Because of a relatively narrow therapeutic index, therapeutic drug monitoring may be helpful to individually optimize therapy with mirtazapine. An enantioselective high-performance liquid chromatography (HPLC) method with fluorescence detection has been developed for the quantification of mirtazapine, desmethyl mirtazapine, 8-hydroxy mirtazapine, and mirtazapine N-oxide. The method is suitable for the analysis of plasma and urine samples in the range from 1 to 100 ng/mL with precision (coefficient of variation, or CV) between 12% and 19%. The sample preparation step comprises a liquid-solid extraction procedure with good recoveries, between 85% and 99%. Patient samples for therapeutic drug monitoring as well as concentration-time series were assayed and the resulting enantiomer ratios analyzed. Typical trough levels were between 1 and 100 ng/mL, with enantiomer ratios of approximately 0.42 (S/R). In concentration-time series, enantiomer ratios distinctively greater than 1 were observed at early time points. Because the enantiomers of mirtazapine and desmethyl mirtazapine have different pharmacological properties, the method is believed to be helpful in understanding the concentration-effect relationships in the former. [PubMed Citation] [Order full text from Infotrieve]

18) Harrison G, Dilley JW, Loeb L, Nelson K
Priapism and quetiapine: a case report.
Psychopharmacol Bull. 2006;39(1):117-9.
Priapism is a "persistent erection not accompanied by sexual desire or stimulation, usually lasting more than six hours and typically involving only the corpora cavernosa." Here we report on a gay male patient from our HIV/AIDS mental health clinic who developed serious priapism on quetiapine and recreational amphetamine. Gay men are at high risk for amphetamine use, and as such, this potential association between priapism, quetiapine, and amphetamine use should be considered in making prescription decisions with these patients. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

19) Johnson M, Markham-Abedi C, Susce MT, Murray-Carmichael E, McCollum S, de Leon J
A poor metabolizer for cytochromes P450 2D6 and 2C19: a case report on antidepressant treatment.
CNS Spectr. 2006 Oct;11(10):757-60.
Scientific literature has never described a poor metabolizer for both the cytochrome P450 (CYP) 2D6 and the CYP 2C19. They are expected to be rare (<1% in different ethnic groups) and prone to adverse drug reactions with many antidepressants. In an ongoing pharmacogenetic study, after genotyping 1,576 subjects in three Kentucky state hospitals we have found one poor metabolizer for both CYP 2D6 and CYP 2C19, which corresponds to a prevalence of 0.06% (95% CI 0.01 to 0.36). The naturalistic antidepressant treatment of this poor metabolizer for both enzymes is described in this article. As genotyping reaches clinical practice, it will be interesting to prospectively establish whether mirtazapine is a reasonable choice as an antidepressant for these patients, as the data and this case suggest. [PubMed Citation] [Order full text from Infotrieve]

20) K�nig G, D�twyler S, Eschen A, Schreiter Gasser U
Unrecognised long-lasting tramadol-induced delirium in two elderly patients. A case report.
Pharmacopsychiatry. 2006 Sep;39(5):194-9.
We present the cases of two elderly patients with intermittent long-term tramadol intake against chronic back pain. Over a period of more than two years they experienced fluctuating confusional states and cognitive deficits, reversible only after discontinuation of tramadol. According to the DSM IV-criteria, an unrecognised recurrent tramadol-induced delirium can be diagnosed in both cases. Although tramadol may represent a well established safe therapy for chronic non-malignant pain in the elderly, these cases demonstrate that it should be applied with caution even in healthy subjects. [PubMed Citation] [Order full text from Infotrieve]