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) Gonz�lez-Vacarezza N, Abad-Santos F, Carcas-Sansuan A, Dorado P, Pe�as-Lled� E, Est�vez-Carrizo F, Llerena A
Use of pharmacogenetics in bioequivalence studies to reduce sample size: an example with mirtazapine and CYP2D6.
Pharmacogenomics J. 2012 Jun 26;
In bioequivalence studies, intra-individual variability (CV(w)) is critical in determining sample size. In particular, highly variable drugs may require enrolment of a greater number of subjects. We hypothesize that a strategy to reduce pharmacokinetic CV(w), and hence sample size and costs, would be to include subjects with decreased metabolic enzyme capacity for the drug under study. Therefore, two mirtazapine studies, two-way, two-period crossover design (n=68) were re-analysed to calculate the total CV(w) and the CV(w)s in three different CYP2D6 genotype groups (0, 1 and ?2 active genes). The results showed that a 29.2 or 15.3% sample size reduction would have been possible if the recruitment had been of individuals carrying just 0 or 0 plus 1 CYP2D6 active genes, due to the lower CV(w). This suggests that there may be a role for pharmacogenetics in the design of bioequivalence studies to reduce sample size and costs, thus introducing a new paradigm for the biopharmaceutical evaluation of drug products.The Pharmacogenomics Journal advance online publication, 26 June 2012; doi:10.1038/tpj.2012.29. [PubMed Citation] [Order full text from Infotrieve]

2) Koch H, Nanev D
Important interaction between mirtazapine and ondansetron.
Afr J Psychiatry (Johannesbg). 2012 May;15(3):160.
[PubMed Citation] [Order full text from Infotrieve]

3) Baraldi S, Hepgul N, Mondelli V, Pariante CM
Symptomatic Treatment of Interferon-α-Induced Depression in Hepatitis C: A Systematic Review.
J Clin Psychopharmacol. 2012 Aug;32(4):531-43.
ABSTRACT: Despite its efficacy in treating hepatitis C, interferon-? (IFN-?) can cause depression. The purpose of this systematic review is to summarize and discuss the available and effective therapies in treating IFN-?-induced depression.Using PubMed, The Cochrane Library, Scopus, Embase, Ovid of Medline, PsycINFO, and ISI Web of Knowledge, we selected 64 articles concerning IFN-?-induced depression treatment in hepatitis C patients.Selective serotonin reuptake inhibitors can be considered the first choice for the treatment of IFN-?-induced depression, as demonstrated in open-label studies, case reports, and a randomized, double-blind, placebo-controlled trial. Also 5-hydroxytryptophan and tryptophan have been suggested to be effective as monotherapy or as augmentation of selective serotonin reuptake inhibitors. Clinical cases that show positive effects of tricyclic antidepressants, however, do not provide sufficient evidence for the use of these drugs. Two cohort studies have reported the effectiveness of amisulpride, but not of levosulpiride. Mirtazapine has been suggested to be a better choice of treatment in cases where insomnia or anorexia develop. Milnacipram can be useful in cases of concomitant medications, for the unlikely occurrence of drug-drug interactions. Psychostimulants represent an empirical treatment without controlled data to support their use. Two case reports have shown the favorable use of bupropion, particularly if sexual dysfunction or cravings for illicit drugs are present. A single case report suggests electroconvulsive therapy to be a possible choice when antidepressants are ineffective or poorly tolerated. The main limitation of our review is that the quality of the findings varied across the reviewed studies. Our observations may help clinicians with managing IFN-?-induced depression. [PubMed Citation] [Order full text from Infotrieve]

4) Sung SC, Haley CL, Wisniewski SR, Fava M, Nierenberg AA, Warden D, Morris DW, Kurian BT, Trivedi MH, Rush AJ
The impact of chronic depression on acute and long-term outcomes in a randomized trial comparing selective serotonin reuptake inhibitor monotherapy versus each of 2 different antidepressant medication combinations.
J Clin Psychiatry. 2012 May 29;
OBJECTIVE: To compare sociodemographic and clinical features, acute and continuation treatment outcomes, and adverse events/side effect burden between outpatients with chronic (current episode > 2 years) versus nonchronic major depressive disorder (MDD) who were treated with combination antidepressant therapy or selective serotonin reuptake inhibitor (SSRI) monotherapy. METHOD: 663 outpatients with chronic (n = 368) or nonchronic (n = 295) moderate to severe DSM-IV-TR MDD (17-item Hamilton Depression Rating Scale score ? 16) were enrolled from March 2008 through September 2009 in a single-blind 7-month prospective randomized trial conducted at 6 primary and 9 psychiatric care sites across the United States. Participants were treated with escitalopram monotherapy plus placebo or 1 of 2 combination treatments (bupropion sustained-release [SR] + escitalopram or venlafaxine extended-release [XR] + mirtazapine). Analyses compared baseline sociodemographic and clinical characteristics, rates of remission (at least 1 of the last 2 consecutive scores on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR16] < 6, with the other < 8), and adverse events/side effect burden (Frequency, Intensity, and Burden of Side Effects Ratings) obtained at 12 and 28 weeks. RESULTS: Participants with chronic MDD were at greater socioeconomic disadvantage and had greater medical and psychiatric disease burden. The chronic and nonchronic groups did not differ in rates of remission at 12 weeks (35.9% vs 42.0%, respectively; odds ratio [OR] = 0.778, P = .1500; adjusted OR [AOR] = 0.956, P = .8130) or at 28 weeks (41.0% vs 49.8%, respectively; OR = 0.706, P = .0416; AOR = 0.837, P = .3448). Participants with chronic MDD had higher final QIDS-SR16 scores and smaller overall percent changes in QIDS-SR16 from baseline to exit, but these differences did not remain after adjusting for covariates. There were no significant differences in adverse events or side effect burden. No significant interactions were found between chronicity and type of treatment at 12 or 28 weeks. CONCLUSION: Chronicity of illness does not appear to differentially impact acute or longer-term outcomes with SSRI monotherapy or combination antidepressant medication treatment in patients with moderate to severe nonpsychotic MDD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00590863. [PubMed Citation] [Order full text from Infotrieve]

5) Tatara A, Shimizu S, Shin N, Sato M, Sugiuchi T, Imaki J, Ohno Y
Modulation of antipsychotic-induced extrapyramidal side effects by medications for mood disorders.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Aug 7;38(2):252-9.
Antipsychotic drugs are widely used not only for schizophrenia, but also for mood disorders such as bipolar disorder and depression. To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects (EPS), we examined the effects of antidepressants and mood-stabilizing drugs on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. The selective serotonin reuptake inhibitors (SSRIs), fluoxetine and paroxetine, and the tricyclic antidepressant (TCA) clomipramine, which showed no EPS by themselves, significantly potentiated HAL-induced bradykinesia and catalepsy in a dose-dependent manner. In contrast, the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine failed to augment, but rather attenuated HAL-induced bradykinesia and catalepsy. Mianserin also tended to reduce the EPS induction. In addition, neither treatment with lithium, sodium valproate nor carbamazepine potentiated HAL-induced EPS. Furthermore, treatment of animals with ritanserin (5-HT2A/2C antagonist), ondansetron (5-HT3 antagonist), and SB-258585 (5-HT6 antagonist) significantly antagonized the EPS augmentation by fluoxetine. Intrastriatal injection of ritanserin or SB-258585, but not ondansetron, also attenuated the EPS induction. The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction. In addition, 5-HT2A/2C, 5-HT3 and 5-HT6 receptors seem to be responsible for the augmentation of antipsychotic-induced EPS by serotonin reuptake inhibitors. [PubMed Citation] [Order full text from Infotrieve]

6) Zheng L, Yu Q, Miao J, Xiang J, Xu N
Bioequivalence study of two mirtazapine oral tablet formulations in healthy Chinese male volunteers.
Int J Clin Pharmacol Ther. 2012 May;50(5):368-74.
[PubMed Citation] [Order full text from Infotrieve]

7) Pligoropoulou H, Vonaparti A, Panderi I
Hydrophilic interaction liquid chromatography/positive ion electrospray mass spectrometry for the quantification of deferasirox, an oral iron chelator, in human plasma.
J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Apr 15;893-894:114-20.
A rapid hydrophilic interaction liquid chromatography/positive ion electrospray mass spectrometric assay (HILIC/ESI-MS) was developed, validated and applied to the determination of deferasirox, in human plasma. The sample preparation process involved liquid-liquid extraction of 50 ?L plasma sample using ethyl acetate as an extraction solvent. Chromatographic separation was performed on an XBridge-HILIC analytical column (150.0 mm � 2.1 mm i.d., particle size 3.5 ?m, 135 ?) under isocratic elution. The mobile phase was composed of a 10% 8.0 mM ammonium acetate water solution pH=5.0, adjusted with formic acid, in a binary mixture of acetonitrile/methanol (50:50, v/v) and pumped at a flow rate of 0.20 mL/min. Quantitation of deferasirox was performed with selected ion monitoring (SIM) in positive ionization mode using electrospray ionization interface. The assay was found to be linear in the concentration range of 0.20-120.0 ?g/mL for deferasirox. Intermediate precision was found less than 3.9% over the tested concentration ranges. A run time of less than 6.0 min for each sample made it possible to analyze a large number of human plasma samples per day. The method can be used to support a wide range of clinical studies concerning deferasirox monitoring and it was applied to the analysis of human plasma samples obtained from patients with ?-thalassemia major. [PubMed Citation] [Order full text from Infotrieve]

8) Patil AS, Kuller JA, Rhee EH
Antidepressants in pregnancy: a review of commonly prescribed medications.
Obstet Gynecol Surv. 2011 Dec;66(12):777-87.
Perinatal depression is an increasingly common comorbidity of pregnancy and is associated with adverse birth outcomes. Newer classes of antidepressants have been developed with a variety of mechanisms and improved side effect profiles. There is increasing use of these medications in reproductive-aged women. Medical providers have to balance the need to prevent relapse of maternal depressive symptoms with the need to minimize fetal exposure to medications. We review the literature on 10 of the most commonly used antidepressant medications: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, duloxetine, bupropion, and mirtazapine. The pharmacokinetic properties of the medications are detailed, as well as practical considerations for their use in pregnant and lactating women. Guidance on counseling and management of pregnancies complicated by perinatal depression is discussed. TARGET AUDIENCE: Obstetricians & Gynecologists and Family Physicians. LEARNING OBJECTIVes: After completing this CME activity, physicians should be better able to differentiate the current classes of medications utilized commonly for perinatal depression, evaluate the reported adverse effects of antidepressant medications on the patient and developing fetus and choose the appropriate antidepressant medications for a depressed patient who is breast-feeding. [PubMed Citation] [Order full text from Infotrieve]

9) Spina E, Trifir� G, Caraci F
Clinically significant drug interactions with newer antidepressants.
CNS Drugs. 2012 Jan 1;26(1):39-67.
After the introduction of selective serotonin reuptake inhibitors (SSRIs), other newer antidepressants with different mechanisms of action have been introduced in clinical practice. Because antidepressants are commonly prescribed in combination with other medications used to treat co-morbid psychiatric or somatic disorders, they are likely to be involved in clinically significant drug interactions. This review examines the drug interaction profiles of the following newer antidepressants: escitalopram, venlafaxine, desvenlafaxine, duloxetine, milnacipran, mirtazapine, reboxetine, bupropion, agomelatine and vilazodone. In general, by virtue of a more selective mechanism of action and receptor profile, newer antidepressants carry a relatively low risk for pharmacodynamic drug interactions, at least as compared with first-generation antidepressants, i.e. monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). On the other hand, they are susceptible to pharmacokinetic drug interactions. All new antidepressants are extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes, and therefore may be the target of metabolically based drug interactions. Concomitant administration of inhibitors or inducers of the CYP isoenzymes involved in the biotransformation of specific antidepressants may cause changes in their plasma concentrations. However, due to their relatively wide margin of safety, the consequences of such kinetic modifications are usually not clinically relevant. Conversely, some newer antidepressants may cause pharmacokinetic interactions through their ability to inhibit specific CYPs. With regard to this, duloxetine and bupropion are moderate inhibitors of CYP2D6. Therefore, potentially harmful drug interactions may occur when they are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index. The other new antidepressants are only weak inhibitors or are not inhibitors of CYP isoforms at usual therapeutic concentrations and are not expected to affect the disposition of concomitantly administered medications. Although drug interactions with newer antidepressants are potentially, but rarely, clinically significant, the use of antidepressants with a more favourable drug interaction profile is advisable. Knowledge of the interaction potential of individual antidepressants is essential for safe prescribing and may help clinicians to predict and eventually avoid certain drug combinations. [PubMed Citation] [Order full text from Infotrieve]

10) Ranjan OP, Shavi GV, Nayak UY, Arumugam K, Averineni RK, Meka SR, Sureshwar P
Controlled release chitosan microspheres of mirtazapine: in vitro and in vivo evaluation.
Arch Pharm Res. 2011 Nov;34(11):1919-29.
The purpose of the study was to formulate and evaluate controlled release chitosan microspheres of mirtazapine (MTZ) to improve the bioavailability by altering the pharmacokinetic profiles of the drug. Chitosan microspheres were prepared to prolong the release of the drug into the systemic circulation. Microspheres were prepared by a single water in oil (w/o) emulsion technique varying the chitosan/drug ratio, stirring speed and concentration of the crosslinking agent (glutaraldehyde). Drug-polymer compatibility studies were carried out using fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The microspheres were evaluated for encapsulation efficiency, particle size, surface morphology, swelling index, in vitro release, as well as erosion and in vivo studies in rats. The FT-IR and DSC studies revealed no interaction between drug and polymer. The encapsulation efficiency of different formulation varied from 53 � 1.2% to 78 � 1.5%. The mean particle size of the optimized formulation F-14 was 106.4 � 0.5 ?m. Surface morphology revealed that chitosan microspheres were discrete and spherical in shape with a porous surface. The release of MTZ from chitosan microspheres was rapid up to 4 h, and then it was continuously and slowly released up to 48 h. Optimized formulation (F-14) was found to be stable under accelerated storage conditions based on International Conference on Harmonisation guidelines. Pharmacokinetic studies revealed that the optimized formulation showed significant increases in systemic exposure (AUC = 177.70 � 7.39 ?g�h/mL), half-life (4.72 � 0.46 h) and reduced clearance (0.009 � 0.0001 L/h) compared to pure drug administration. Hence, the present study demonstrates that controlled release formulation of MTZ microspheres using chitosan can improve pharmacokinetic profiles of MTZ. [PubMed Citation] [Order full text from Infotrieve]

11) Miguel C, Albuquerque E
Drug interaction in psycho-oncology: antidepressants and antineoplastics.
Pharmacology. 2011;88(5-6):333-9.
[PubMed Citation] [Order full text from Infotrieve]

12) Linden M, Westram A
What do psychiatrists talk about with their depressed patients parallel to prescribing an antidepressant?
Int J Psychiatry Clin Pract. 2011 Mar;15(1):35-41.
[PubMed Citation] [Order full text from Infotrieve]

13) Colfax GN, Santos GM, Das M, Santos DM, Matheson T, Gasper J, Shoptaw S, Vittinghoff E
Mirtazapine to reduce methamphetamine use: a randomized controlled trial.
Arch Gen Psychiatry. 2011 Nov;68(11):1168-75.
[PubMed Citation] [Order full text from Infotrieve]

14) Quimby JM, Gustafson DL, Lunn KF
The pharmacokinetics of mirtazapine in cats with chronic kidney disease and in age-matched control cats.
J Vet Intern Med. 2011 Sep-Oct;25(5):985-9.
[PubMed Citation] [Order full text from Infotrieve]

15) Sikka P, Kaushik S, Kumar G, Kapoor S, Bindra VK, Saxena KK
Study of antinociceptive activity of SSRI (fluoxetine and escitalopram) and atypical antidepressants (venlafaxine and mirtazepine) and their interaction with morphine and naloxone in mice.
J Pharm Bioallied Sci. 2011 Jul;3(3):412-6.
[PubMed Citation] [Order full text from Infotrieve]

16) Phan SV, Kreys TJ
Adjunct mirtazapine for negative symptoms of schizophrenia.
Pharmacotherapy. 2011 Oct;31(10):1017-30.
Negative symptoms of schizophrenia are characterized by affective flattening, alogia, avolition, and anhedonia and are often nonresponsive to antipsychotic therapy. Because negative symptoms are predictive of poor occupational and social functioning, as well as poor global outcomes, numerous studies evaluating adjunct therapy to antipsychotics have been conducted. This review focuses on the use of the antidepressant mirtazapine as adjunct therapy to antipsychotics for the treatment of negative symptoms of schizophrenia. A literature search of the MEDLINE database (from inception-March 2011) identified eight relevant articles: six were randomized, double-blind, placebo-controlled trials, and two were open-label trials. Of the six randomized trials reviewed, four studies assessed add-on mirtazapine to second-generation antipsychotics, whereas two studies examined add-on mirtazapine to first-generation antipsychotics. Five of the six randomized trials supported the use of mirtazapine for negative symptoms of schizophrenia. Of the two open-label trials, one naturalistic study demonstrated that mirtazapine add-on therapy to clozapine was not associated with improvements in negative symptoms; however, this study focused primarily on improvements in cognition, not negative symptoms. An open-label extension phase to a randomized controlled trial showed that mirtazapine continued to produce significant improvement in negative symptoms over a longer duration of time, when added to first-generation antipsychotic therapy. Overall, mirtazapine appears to be well tolerated and associated with few drug interactions. Although adjunct mirtazapine to antipsychotics has been shown to be effective at doses of 30 mg/day in most of the trials, limitations of these studies include short study duration and small sample sizes. To improve generalizability, larger multicenter studies with broader inclusion criteria should be conducted. In addition, studies of longer duration that use different mirtazapine dosages are needed to further assess the benefits of mirtazapine for negative symptoms of schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

17) Molden E, Spigset O
[Interactions between metoprolol and antidepressants].
Tidsskr Nor Laegeforen. 2011 Sep 20;131(18):1777-9.
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18) Schelleman H, Brensinger CM, Bilker WB, Hennessy S
Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study.
PLoS One. 2011;6(6):e21447.
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19) Shah KM, Rank MA, Dav� SA, Oslie CL, Butterfield JH
Predicting which medication classes interfere with allergy skin testing.
Allergy Asthma Proc. 2010 Nov-Dec;31(6):477-82.
Medications often interfere with allergy skin test interpretation. This study was performed to determine which medications interfere with allergy skin tests. We retrospectively reviewed skin-prick test results from patients who had discontinued H(1)-antagonists, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), benzodiazepines, atypical antidepressants, antipsychotics, hypnotics, sedatives, proton pump inhibitors (PPIs), and H(2)-antagonists between 0 and 7 days before allergy skin testing. Ninety-seven subjects had taken second-generation H(1)-antihistamines within 7 days of skin testing; all patients who had stopped 3 days before testing had positive histamine controls. Two hundred sixty-eight skin tests performed on patients taking a single medication of interest showed that patients had the following percentages of a positive histamine control: TCAs, 56.5%; SNRIs, 100%; H(2)-blockers, 100%; SSRIs, 97%; PPIs, 97%; benzodiazepines, 85.7%; and atypical antidepressants/sedatives, 92.6%. The 580 patients taking multiple medications of interest showed that the odds ratio and 95% confidence intervals of a negative histamine test for patients taking TCAs were 6.33 (2.11-20.5), for H(1)-blockers were 4.95 (1.78-15.1), for benzodiazepines were 5.01 (1.72-15.80), for atypical antidepressants/sedatives were 3.11 (1.09-9.61), and for H(2)-blockers were 2.91 (0.97-9.37). The odds of a negative histamine test for SSRIs, SNRIs, or PPIs were not significantly increased. SSRIs, SNRIs, and PPIs are unlikely to interfere with skin testing. TCAs, H(1)-blockers, benzodiazepines, quetiapine, and mirtazapine should be discontinued temporarily if clinically able. H(2)-antagonists, bupropion, eszopiclone, trazodone, or zolpidem showed minimal interference with immediate hypersensitivity skin test histamine response. [PubMed Citation] [Order full text from Infotrieve]

20) Kilic FS, Dogan AE, Baydemir C, Erol K
The acute effects of mirtazapine on pain related behavior in healthy animals.
Neurosciences (Riyadh). 2011 Jul;16(3):217-23.
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