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) 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.
[PubMed Citation] [Order full text from Infotrieve]

2) Giorgi M, Yun H
Pharmacokinetics of mirtazapine and its main metabolites in Beagle dogs: A pilot study.
Vet J. 2011 Jun 6;
Mirtazapine (MRT) is a human antidepressant drug mainly metabolised by the cytochrome P450 enzyme system to 8-OH mirtazapine (8-OH) and dimetilmirtazapine (DMR). The drug is usually administered to dogs with anorexia according to doses extrapolated from humans, although it could also have applications as an antidepressant and analgesic in this species. The aim of this study was to assess the pharmacokinetics of MRT and its metabolites, DMT and 8-OH. Six healthy male Beagle dogs were administered MRT orally (20mg/dog) and plasma MRT and metabolite concentrations were evaluated by high performance liquid chromatography with fluorescence detection. The pharmacokinetic profiles of MRT and DMR were similar (detected from 0.25 up to 10h), while 8-OH (detected from 0.50 up to 10h) attained the highest concentrations. The mean half-life of MRT was 6.17h with a clearance of 1193mL/h/kg. The study showed that MRT has a different pharmacokinetic profile in the dog compared to other species. [PubMed Citation] [Order full text from Infotrieve]

3) Noe KH, Locke DE, Sirven JI
Treatment of depression in patients with epilepsy.
Curr Treat Options Neurol. 2011 Aug;13(4):371-9.
OPINION STATEMENT: In this article, we review the current best evidence for the treatment of depression in patients with epilepsy. Depression is a common epilepsy comorbidity, but it is often unrecognized. The most important step in appropriately managing mood disorders in this population is making the diagnosis. Clinical vigilance and routine use of a validated screening tool can improve detection and quality of care. As is increasingly the case for the general population, persons with epilepsy are often interested in exploring alternative therapies for chronic conditions, including depression. Unfortunately, the benefit of complementary and alternative therapies for depression currently is largely unproven for persons with a seizure history, although an early study of exercise for mild depression has shown some benefit. Concerns about drug interactions, side effects, and expense may be barriers to the prescription of antidepressant medications for people requiring chronic antiepileptic drug (AED) therapy. For this reason, use of an AED with mood-stabilizing properties has appeal and may be appropriate for selected individuals with mild depressive symptoms. Undue fear of lowering seizure threshold should not preclude the prescription of an antidepressant medication, as the perceived risks are often overestimated and rarely outweigh the risk of leaving depression untreated. At present, the best evidence for efficacy and safety support the use of citalopram, sertraline, or mirtazapine as initial pharmacotherapy, whereas bupropion should be avoided. Start low, go slow, and use the lowest effective dose. Cognitive behavioral therapy is a valuable adjunct to antidepressant therapy in this population. For people with refractory partial epilepsy and refractory depression, vagus nerve stimulation has some appeal, in that it may be beneficial for both conditions, but the efficacy of vagus nerve stimulation in improving mood in patients with epilepsy remains unclear. [PubMed Citation] [Order full text from Infotrieve]

4) Sch�le C, Eser D, Baghai TC, Nothdurfter C, Kessler JS, Rupprecht R
Neuroactive steroids in affective disorders: target for novel antidepressant or anxiolytic drugs?
Neuroscience. 2011 Mar 23;
In the past decades considerable evidence has emerged that so-called neuroactive steroids do not only act as transcriptional factors in the regulation of gene expression but may also alter neuronal excitability through interactions with specific neurotransmitter receptors such as the GABA(A) receptor. In particular, 3?-reduced neuroactive steroids such as allopregnanolone or allotetrahydrodeoxycorticosterone have been shown to act as positive allosteric modulators of the GABA(A) receptor and to play an important role in the pathophysiology of depression and anxiety. During depression, the concentrations of 3?,5?-tetrahydroprogesterone and 3?,5?-tetrahydroprogesterone are decreased, while the levels of 3?,5?-tetrahydroprogesterone, a stereoisomer of 3?,5?-tetrahydroprogesterone, which may act as an antagonist for GABAergic steroids, are increased. Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) or mirtazapine apparently have an impact on key enzymes of neurosteroidogenesis and have been shown to normalize the disequilibrium of neuroactive steroids in depression by increasing 3?-reduced pregnane steroids and decreasing 3?,5?-tetrahydroprogesterone. Moreover, 3?-reduced neuroactive steroids have been demonstrated to possess antidepressant- and anxiolytic-like effects both in animal and human studies for themselves. In addition, the translacator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor, is the key element of the mitochondrial import machinery supplying the substrate cholesterol to the first steroidogenic enzyme (P450scc), which transforms cholesterol into pregnenolone, the precursor of all neurosteroids. TSPO ligands increase neurosteroidogenesis and are a target of novel anxiolytic drugs producing anxiolytic effects without causing the side effects normally associated with conventional benzodiazepines such as sedation or tolerance. [PubMed Citation] [Order full text from Infotrieve]

5) �lvarez E, Vi�as F
Mirtazapine in combination.
Actas Esp Psiquiatr. 2010 Mar;38(2):121-8.
INTRODUCTION: Depression is undoubtedly a particularly important disease in terms of personal suffering and death as well as social, family, and economic costs. Pharmacological treatment is a reasonably effective therapeutic approach;however, a delayed therapeutic response and the persistence of depressive symptoms represent serious drawbacks to clinical recovery.Although the pharmacological action of anti depressants begins a few hours after the start of treatment, an antidepressant response usually takes between 2 and 6 weeks.The persistence of depressive symptoms after the first weeks of treatment is indicative of a poor prognosis in terms of chronicity and a return to normal social function.The combination of mirtazapine with other antidepressants may significantly lessen these drawbacks.Its antagonist effect on the presynaptic receptors reduces the latency of the antidepressant response. Moreover, its robust noradrenergic effect enhances the serotoninergic effects of the most common antidepressants. In addition, the side effects of mirtazapine can be partially neutralized by the pharmacodynamic activity of other antidepressants, while mirtazapine can ameliorate the serious adverse effects, such as sexual dysfunction, of other medications. [PubMed Citation] [Order full text from Infotrieve]

6) Laux G
[Possibilities and limitations of psychopharmacological treatments in patients with psychological comorbidity].
Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2011 Jan;54(1):37-45.
Comorbid depressive and anxiety disorders are associated with chronic physical illnesses. Treatment with antidepressants and mood stabilizers require knowledge about toxicity, potential side effects, and drug interactions. According to controlled studies in comorbid cardiovascular diseases, diabetes mellitus, and cerebrovascular disorders (post-stroke depression), serotonin-selective reuptake inhibitors (SSRIs), e.g., sertraline and citalopram, are preferred. Pramipexole, reboxetine, mirtazapine, or nortriptyline showed efficacy in treatment of Parkinson depression. Chronic pain syndromes can be improved with low-dose tricyclic antidepressants. Both establishment of compliance and follow-up examinations are essential. Combined treatment with psychotherapeutic interventions, including coping strategies, should be used whenever possible. [PubMed Citation] [Order full text from Infotrieve]

7) Haduch A, Bromek E, Daniel WA
The effect of psychotropic drugs on cytochrome P450 2D (CYP2D) in rat brain.
Eur J Pharmacol. 2011 Jan 25;651(1-3):51-8.
The aim of the study was to investigate the influence of selected antidepressants and neuroleptics on the protein level and activity of cytochrome P450 2D (CYP2D) in rat brain. The obtained results showed that imipramine, fluoxetine, nefazodone, thioridazine and perazine, added to brain microsomes of control rats, inhibited CYP2D activity to a lower extent (K(i)=255-485?M) than when added to liver microsomes (K(i)=1-45?M), which may result from their stronger affinity for liver CYP2D2 (K(i)=2.7 and 1.25?M for imipramine and fluoxetine, respectively) than for brain CYP2D4 (K(i)=25 and 10?M for imipramine and fluoxetine, respectively), as well as from their high non-specific binding in brain microsomes. Two-week treatment with fluoxetine evoked decreases in the level and activity of CYP2D in the striatum and the nucleus accumbens. In contrast, fluoxetine increased CYP2D expression in the cerebellum, while nefazodone considerably enhanced the activity (but not the protein level) of CYP2D in the truncus cerebri. Imipramine and mirtazapine (active in the liver) did not affect brain CYP2D. Chronic thioridazine decreased CYP2D activity in the substantia nigra and nucleus accumbens, but significantly increased that activity in the striatum and cerebellum. Clozapine significantly enhanced CYP2D activity in the truncus cerebri. In conclusion, psychotropics influence CYP2D in the brain, but their effect is different than in the liver and depends on the cerebral structure. The observed psychotropics-brain CYP2D interactions may be important for the metabolism of neurosteroids and monoaminergic neurotransmitters, and for the local biotransformation of drugs. [PubMed Citation] [Order full text from Infotrieve]

8) Desmarais JE, Beauclair L, Margolese HC
Switching from Brand-Name to Generic Psychotropic Medications: A Literature Review.
CNS Neurosci Ther. 2010 Nov 30;
Generic medications do not undergo the rigorous approval process required of original medications. Their effectiveness and safety is expected to be equal to that of their more expensive counterparts. However, several case reports and studies describe clinical deterioration and decreased tolerability with generic substitution. Pubmed was searched from January 1, 1974 to March 1, 2010. The MeSH term "generic, drugs" was combined with "anticonvulsants,"mood stabilizers,"lithium,"antidepressants,"antipsychotics,"anxiolytics," and "benzodiazepines." Additional articles were obtained by searching the bibliographies of relevant references. Articles in English, French, or Spanish were considered if they discussed clinical equivalence of generic and brand-name medications, generic substitution, or issues about effectiveness, tolerability, compliance, or economics encountered with generics. Clinical deterioration, adverse effects, and changes in pharmacokinetics are described with generic substitution of several anticonvulsants/mood stabilizers (carbamazepine, valproate, lamotrigine, gabapentin, topiramate, lithium), antidepressants (amitriptyline, nortriptyline, desipramine, fluoxetine, paroxetine, citalopram, sertraline, venlafaxine, mirtazapine, bupropion), antipsychotics (risperidone, clozapine), and anxiolytics (clonazepam, alprazolam). Generics do not always lead to the anticipated monetary savings and also raise compliance issues. Although the review is limited by publication bias and heterogeneity of the studies in the literature, we believe there is enough concern to advise generic switching on an individual basis with close monitoring throughout the transition. Health professionals should be aware of the stakes around generic substitution especially when health economics promote universal use of generics. [PubMed Citation] [Order full text from Infotrieve]

9) Graves SM, Napier TC
Mirtazapine alters cue-associated methamphetamine seeking in rats.
Biol Psychiatry. 2011 Feb 1;69(3):275-81.
[PubMed Citation] [Order full text from Infotrieve]

10) von Eichborn J, Murgueitio MS, Dunkel M, Koerner S, Bourne PE, Preissner R
PROMISCUOUS: a database for network-based drug-repositioning.
Nucleic Acids Res. 2011 Jan;39(Database issue):D1060-6.
The procedure of drug approval is time-consuming, costly and risky. Accidental findings regarding multi-specificity of approved drugs led to block-busters in new indication areas. Therefore, the interest in systematically elucidating new areas of application for known drugs is rising. Furthermore, the knowledge, understanding and prediction of so-called off-target effects allow a rational approach to the understanding of side-effects. With PROMISCUOUS we provide an exhaustive set of drugs (25,000), including withdrawn or experimental drugs, annotated with drug-protein and protein-protein relationships (21,500/104,000) compiled from public resources via text and data mining including manual curation. Measures of structural similarity for drugs as well as known side-effects can be easily connected to protein-protein interactions to establish and analyse networks responsible for multi-pharmacology. This network-based approach can provide a starting point for drug-repositioning. PROMISCUOUS is publicly available at http://bioinformatics.charite.de/promiscuous. [PubMed Citation] [Order full text from Infotrieve]

11) Quimby JM, Gustafson DL, Samber BJ, Lunn KF
Studies on the pharmacokinetics and pharmacodynamics of mirtazapine in healthy young cats.
J Vet Pharmacol Ther. 2011 Aug;34(4):388-96.
Quimby, J. M., Gustafson, D. L., Samber, B. J., Lunn, K. F. Studies on the pharmacokinetics and pharmacodynamics of mirtazapine in healthy young cats. J. vet. Pharmacol. Therap.34, 388-396. Mirtazapine pharmacokinetics was studied in 10 healthy cats. Blood was collected before, and at intervals up to 72 h after, oral dose of 3.75 mg (high dose: HD) or 1.88 mg (low dose: LD) of mirtazapine. Liquid chromatography coupled to tandem mass spectrometry was used to measure mirtazapine, 8-hydroxymirtazapine and glucuronide metabolite concentrations. Noncompartmental pharmacokinetic modeling was performed. Median half-life was 15.9 h (HD) and 9.2 h (LD). Using Mann-Whitney analysis, a statistically significant difference between the elimination half-life, clearance, area under the curve (AUC) per dose, and AUC(?) /dose of the groups was found. Mirtazapine does not appear to display linear pharmacokinetics in cats. There was no significant difference in glucuronidated metabolite concentration between groups. Pharmacodynamics was studied in 14 healthy cats administered placebo, LD and HD mirtazapine orally once in a crossover, blinded trial. In comparison with placebo, cats ingested significantly more food when mirtazapine was administered. No difference in food ingestion was seen between HD and LD, but significantly more behavior changes were seen with the HD. Limited serum sampling during the pharmacodynamic study revealed drug exposure comparable with the pharmacokinetic study, but no correlation between exposure and food consumed. Mirtazapine (LD) was administered daily for 6 days with no drug accumulation detected. [PubMed Citation] [Order full text from Infotrieve]

12) Hsueh KL, Lin PY
Treatment-resistant depression prior to the diagnosis of cryptococcal meningitis: a case report.
Gen Hosp Psychiatry. 2010 Sep-Oct;32(5):560.e9-10.
Comorbidity of chronic infectious disorders is one of the common causes of treatment-resistant depression. Depression may alter some aspects of immunity that can contribute to the development of infection. Here we describe an elderly male with treatment-resistant depression. Ten months after antidepressants were administered, he was found to have cryptococcal meningitis. After successful treatment of the central nervous system infection, his depressive symptoms improved apparently. A possible interaction between depression and cellular immunity was discussed. Physicians should be cautious about the risk of opportunistic infection in patients with depression, especially in immunocompromised condition. [PubMed Citation] [Order full text from Infotrieve]

13) Rawlings NB, Norbury R, Cowen PJ, Harmer CJ
A single dose of mirtazapine modulates neural responses to emotional faces in healthy people.
Psychopharmacology (Berl). 2010 Dec;212(4):625-34.
[PubMed Citation] [Order full text from Infotrieve]

14) Launiainen T, Rasanen I, Vuori E, Ojanper� I
Fatal venlafaxine poisonings are associated with a high prevalence of drug interactions.
Int J Legal Med. 2011 May;125(3):349-58.
Venlafaxine (VEN) is an antidepressant found to possess a higher fatal toxicity index (FTI, i.e., deaths in proportion to consumption) than other newer antidepressants and selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to elucidate using post-mortem cases whether the apparent high toxicity of VEN is associated with adverse drug interactions, pharmacogenetic factors and/or the manner of death. Within a 2-year period, a comprehensive post-mortem database and death certificates were searched for cases with laboratory findings of VEN, findings of other drugs, associated background information and the cause and manner of death. In 123 cases, the concentrations of VEN and its two metabolites, O-desmethylvenlafaxine (O-VEN) and N-desmethylvenlafaxine (N-VEN), and the CYP2D6 genotype were determined in post-mortem blood. The median concentrations of VEN, O-VEN and N-VEN were 560, 420 and 49��g/l, respectively. A prominent feature of the VEN-positive cases was the high abundance of interacting drugs (46%), being more common with higher VEN concentrations. Compared to other common antidepressants, VEN-positive cases showed the highest suicide frequency, but also the proportion of suicidal VEN poisonings of all suicides was substantially higher than that of mirtazapine or SSRIs. Relative CYP2D6 activity did not predispose to high VEN concentrations, and the frequency of the extreme phenotypes followed the general population. In conclusion, the high suicide potential of VEN in combination with the high prevalence of drugs causing adverse interactions could be the reason for the observed high FTI. [PubMed Citation] [Order full text from Infotrieve]

15) Oliver P, Lubomirov R, Carcas A
Genetic polymorphisms of CYP1A2, CYP3A4, CYP3A5, pregnane/steroid X receptor and constitutive androstane receptor in 207 healthy Spanish volunteers.
Clin Chem Lab Med. 2010 May;48(5):635-9.
[PubMed Citation] [Order full text from Infotrieve]

16) Summers KM, Martin KE, Watson K
Impact and clinical management of depression in patients with coronary artery disease.
Pharmacotherapy. 2010 Mar;30(3):304-22.
The rates of major adverse coronary events, including recurrent ischemic events and death, in patients with coronary artery disease (CAD) have been shown to be significantly increased in patients with depression. In addition, health care costs are higher and health-related quality of life is lower in depressed patients with CAD. Several pathophysiologic mechanisms have been proposed for the association of increased events seen in this population. Studies have focused on antidepressants (specifically, selective serotonin reuptake inhibitors and mirtazapine), psychotherapy (cognitive behavioral therapy and interpersonal psychotherapy), and a wide range of other nonpharmacologic interventions. Pharmacologic and nonpharmacologic treatments are known to improve depressive symptoms in patients with CAD, but their effects on outcomes such as mortality and hospital admissions remain controversial. If treatment of depression is warranted, strategies should include sertraline or citalopram, with or without cognitive behavioral therapy, based on the known efficacy and safety of the drugs in this population. Nonpharmacologic therapy such as aerobic exercise has been shown to improve not only depression but also cardiovascular health. When selecting an appropriate antidepressant, clinicians should consider their patients' comorbid conditions and the potential for drug interactions, and treatment should be frequently monitored. Screening for depression in patients with cardiac disease should be instituted on a routine basis by using either case-finding or symptom-triggered approaches. Based on the high prevalence of depression and its known adverse effects in patients with CAD, future research is needed to help determine the role of antidepressants and nonpharmacologic strategies in improving outcomes in patients with both comorbidities. [PubMed Citation] [Order full text from Infotrieve]

17) Desmarais JE, Looper KJ
Interactions between tamoxifen and antidepressants via cytochrome P450 2D6.
J Clin Psychiatry. 2009 Dec;70(12):1688-97.
[PubMed Citation] [Order full text from Infotrieve]

18) de Santana FJ, Jabor VA, Cesarino EJ, Lanchote VL, Bonato PS
Enantioselective analysis of mirtazapine, demethylmirtazapine and 8-hydroxy mirtazapine in human urine after solid-phase microextraction.
J Sep Sci. 2010 Feb;33(2):268-76.
A selective and reproducible off-line solid-phase microextraction procedure was developed for the simultaneous enantioselective determination of mirtazapine (MRT), demethylmirtazapine and 8-hydroxymirtazapine in human urine. CE was used for optimization of the extraction procedure whereas LC-MS was used for method validation and application. The influence of important factors in the solid-phase microextraction efficiency is discussed, such as the fiber coatings, extraction time, pH, ionic strength, temperature and desorption time. Before extraction, human urine samples were submitted to enzymatic hydrolysis at 37 degrees C for 16 h. Then, the enzyme was precipitated with trichloroacetic acid and the pH was adjusted to 8 with 1 mol/L pH 11 phosphate buffer solution. In the extraction, the analytes were transferred from the aqueous solution to the polydimethylsiloxane-divinylbenzene fiber coating and then desorbed in methanol. The mean recoveries were 5.4, 1.7 and 1.0% for MRT, demethylmirtazapine and 8-hydroxymirtazapine enantiomers, respectively. The method was linear over the concentration range of 62-1250 ng/mL. The within-day and between-day assay precision and accuracy were lower than 15%. The method was successfully employed in a preliminary cumulative urinary excretion study after administration of racemic MRT to a healthy volunteer. [PubMed Citation] [Order full text from Infotrieve]

19) Papakostas GI
Managing partial response or nonresponse: switching, augmentation, and combination strategies for major depressive disorder.
J Clin Psychiatry. 2009;70 Suppl 6:16-25.
Despite the multitude of agents approved for the treatment of major depressive disorder, approximately 50% of patients experience no response to treatment with a first-line antidepressant. Clinicians have 4 broad pharmacologic strategies to choose from for treating antidepressant nonresponders: increasing the dose of the antidepressant, switching to a different antidepressant, augmenting the treatment regimen with a nonantidepressant agent, and combining the original antidepressant with a second antidepressant. To date, the most comprehensively studied treatment strategy for nonresponse or partial response to antidepressants is augmentation with atypical antipsychotic agents, including aripiprazole, olanzapine, quetiapine, and risperidone. However, augmentation or combination with other agents such as mirtazapine, mianserin, and omega-3 fatty acids is also supported by considerable efficacy data. Lithium, desipramine, triiodothyronine, and modafinil have mixed data. While more studies are needed, agents such as bupropion, desipramine, mecamylamine, and testosterone look promising. Switching antidepressants, especially to the newer agents, including selective serotonin reuptake inhibitors, bupropion, mirtazapine, and venlafaxine, is also supported by considerable efficacy data. Clinicians should carefully reevaluate patients with major depressive disorder who are nonresponders to treatment, particularly those who have had several adequate trials. When choosing the best treatment strategy for antidepressant nonresponders, clinicians should take into account the efficacy and tolerability of treatment as well as patient preference and treatment history. Finally, the risk of potential loss of partial therapeutic benefit from the first-line antidepressant, as well as the risk of withdrawal symptoms, should be taken into account when considering switching antidepressants, while the risk of drug interactions and poor adherence should be taken into account when considering combination and augmentation treatments. [PubMed Citation] [Order full text from Infotrieve]

20) Rodriguez-Pecci MS, Fuente-Aguado Jde L, Montero-Tinnirello J, Fernandez-Fernandez FJ
[Mirtazapine-associated hepatotoxicity].
Med Clin (Barc). 2010 Nov 6;135(13):625-6.
[PubMed Citation] [Order full text from Infotrieve]