Anttila SA, Leinonen EV.
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]
CJ, Sitsen JM, Delbressine LP.
Clinical pharmacokinetics of mirtazapine.
Clin Pharmacokinet 2000 Jun;38(6):461-74 [Abstract]
Elke, von Moltke, Lisa L., Shader, Richard I., Greenblatt, David J.
of the Antidepressant Mirtazapine In Vitro: Contribution of Cytochromes P-450
1A2, 2D6, and 3A4
Drug Metab Dispos 2000 28: 1168-1175
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]
R, Muscatello MR, Torre DL, Malara G, Canale A, Crucitti D, D'Arrigo C, Spina
Lack of a pharmacokinetic interaction between mirtazapine and
the newer antipsychotics clozapine, risperidone and olanzapine in patients with
Pharmacol Res. 2003 Oct;48(4):411-4.
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."
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.
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.
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."
Ptacek P, Klima J, Macek J.
of mirtazapine in human plasma by liquid chromatography.
Chromatogr B Analyt Technol Biomed Life Sci. 2003 Sep 5;794(2):323-8.
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."
[Do not assume that this information is comprehensive. See also
M, Hiemke C, Hartter S.
Therapeutic drug monitoring of the antidepressant
mirtazapine and its N-demethylated metabolite in human serum.
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."
Anttila AK, Rasanen L, Leinonen EV.
augmentation increases serum mirtazapine concentrations three- to fourfold.
Ann Pharmacother 2001 Oct;35(10):1221-3 [Abstract]
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
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
E, Van Den Heuvel MW, Schnabel PG, Peeters PA, Chin-Kon-Sung UG, Colbers EP, Sitsen
Concomitant use of mirtazapine and phenytoin: a drug-drug interaction
study in healthy male subjects.
Eur J Clin Pharmacol 2002
"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."
C, Timmer CJ, Sitsen JM.
Mirtazapine in combination with amitriptyline:
a drug-drug interaction study in healthy subjects.
"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.
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
Psychosis during chronic levodopa therapy triggered by the new
antidepressive drug mirtazapine.
"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."