Therapeutic Drug Monitoring of Mirtazapine in a Routine Outpatient Setting in Asian Psychiatric Patients

• Abstract
• Introduction
• Materials and Methods
• Samples and subjects
• Assessment of the clinical outcome
• Determination of mirtazapine concentration
• Statistical analysis
• Results
• Clinical and demographic characteristics
• Mirtazapine concentration
• Factors associated with mirtazapine concentration
• Association between mirtazapine concentration and responsiveness
• Discussion
• Author Contributions
• References

Abstract

Introduction:  Mirtazapine is an antidepressant that acts by enhancing serotonergic and noradrenergic neurotransmission. This study aimed to evaluate mirtazapine pharmacokinetic data from Korean psychiatric patients and to identify the potential factors affecting its steady-state concentration.

Methods:  A total of 337 samples of steady-state mirtazapine concentrations from 188 adult psychiatric outpatients were retrospectively evaluated. Serum mirtazapine concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry.

Results:  Median mirtazapine concentration was 43.6 μg/L (164.37 nmol) at a daily dosage range of 7.5–60 mg. At the steady state, mirtazapine dose had a positive correlation with the drug concentration. Mean concentration-to-dose (C/D) ratio was 1.48 μg/L/mg/day (5.58 nmol/mg/day), which was higher than that in a previous study in Caucasian subjects. Age and paroxetine co-medication were positively associated with C/D ratio. Initial mirtazapine concentration and C/D ratio did not show an association with responsiveness in depressive patients.

Discussion:  This study presented the therapeutic drug monitoring data for mirtazapine and pharmacokinetic variations of mirtazapine in an Asian population. A further study could be helpful for clinical decision making based on the characteristics of patients.

Introduction

Mirtazapine has a unique pharmacological profile combining dual action on both the noradrenergic and serotonergic neurotransmitter systems in the central nervous system (CNS), since it is an antagonist of presynaptic alpha 2-adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin (5-HT) presynaptic axons and is a potent antagonist of postsynaptic 5-HT2 and 5-HT3 receptors [1].

Mirtazapine is increasingly used for the treatment of major depression due to its enhanced therapeutic efficacy in comparison with that of other antidepressants [2]; it is likely to have a faster onset of action and to be more effective than selective serotonin reuptake inhibitors (SSRIs) during the acute-phase treatment [3]. In terms of adverse events, mirtazapine is likely to cause weight gain or increased appetite and somnolence; however, it is less likely to cause nausea or vomiting and sexual dysfunction than SSRIs [4].

Mirtazapine shows linear pharmacokinetics over a dose range of 15–75 mg/d [5]. Elimination half life of mirtazapine ranges from 20–40 h, and it is dependent on age and gender; females and the elderly show higher plasma concentrations than males and young adults [6]. The biotransformation is mainly mediated by cytochrome P450 (CYP) 2D6, CYP3A4, and CYP1A2 [7] [8]. One major metabolite, N-desmethylmirtazapine is pharmacologically active, and it has a 5- to 10-fold lower activity than the parent compound [9]. Inhibitors of these isoenzymes, such as paroxetine and fluoxetine, cause modestly increased mirtazapine plasma concentrations [10].

There are a few reports on the pharmacokinetic (PK) data and influence of various clinical factors on mirtazapine pharmacokinetics in a naturalistic setting [11] [12] [13] [14]. In addition, the differences in plasma concentrations of antidepressants between Asian and Caucasians has been demonstrated [15]. The higher occurrence of CYP2D6*10 that causes decreased CYP2D6 activity and the almost absent frequency of ultra-rapid metabolizers in the Asian population may influence the racial difference [16]. However, PK studies of mirtazapine have not been conducted in the Asian population despite this discrepancy. In addition, little is known about the relationship between serum concentrations of mirtazapine and clinical effects, and therefore, the use of therapeutic drug monitoring is so far unclear [12].

This study aimed to evaluate mirtazapine PK data from Korean psychiatric patients on mirtazapine treatment in a naturalistic setting, and to identify the potential factors affecting its steady-state concentration in a clinical setting. In addition, we tried to determine the association between mirtazapine concentration and responsiveness.

Materials and Methods

Samples and subjects

A total of 337 samples of mirtazapine concentrations from 188 patients (from May 2005 to December 2012) were included in this study. Inclusion criteria were as follows: (i) dosing history of mirtazapine was available; and (ii) time since last dose adjustment was at least 14 days, so that the steady state was achieved [11]. The samples showing significant hepatic impairment or that were proved to be below the limit of quantification of mirtazapine (1.5 μg/L) were excluded. We retrospectively collected the data including clinical and demographic data, mirtazapine dosing history, drug responsiveness, and concurrent medications.

Mirtazapine was given once daily at night and samples were taken in the morning (12 h after dosing) in the fasting state. Median duration of mirtazapine treatment was 125.5 days (interquartile range: 42–307). Among the total 188 patients, therapeutic drug monitoring (TDM) was performed more than once in 83 patients, and 67 patients provided multiple samples at a constant dose during the study period. For the evaluation of the inter-individual variation, the latest TDM value was selected for each patient.

Assessment of the clinical outcome

Clinical outcome was evaluated based on the treatment in patients with major depressive disorder. Treatment response was assessed using the 17-item Hamilton rating scale for depression (HAM-D) by a single trained rater every 2 weeks. The rater was blinded to the mirtazapine concentration. Responders were defined as at least 50% decrease in the HAM-D score at 6 weeks from baseline [15].

Determination of mirtazapine concentration

Serum mirtazapine concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS). Analyses were performed on an API 4000 tandem mass spectrometer (Applied Biosystems, Foster City, CA, USA) equipped with an Agilent Technologies Series 1200 HPLC system (Agilent Technologies, Santa Clara, CA, USA). The Cadenza column was used (2.1×150 mm, 5 um). The mobile phases A and B were water with 2 mM ammonium acetate and acetonitrile, respectively, both containing 0.1% formic acid. After simple protein precipitation with ZnSO₄, the serum samples were mixed with an internal standard (I.S.; bromoperidol) and centrifuged for 4 min. Quantitative analysis was performed in multiple reaction-monitoring mode (m/z 266.0→195.0 for mirtazapine; 422.0→165.1 for I.S.) with a total run time of 180 s for each sample. The linear assay range was 1.5–400 μg/L (R-square>0.99). Intra- and inter-day coefficients of variation were less than 10%.

Statistical analysis

Continuous variables with non-normal distribution are presented as the median value with interquartile range, and quartile coefficient of dispersion (the interquartile range divided by the sum of the first and third quartiles) was employed to measures dispersion. Spearman correlation test was used to test the association between concentration-to-dose (C/D) ratio and continuous variables. For group comparisons, the Wilcoxon ranksum test was used. Median regression analysis was used to investigate the combined effect of patient characteristics on C/D ratio. Results were considered significant at a 2-tailed threshold of p<0.05. Statistical analysis was performed using STATA 10.0 (StataCorp, College Station, TX).

Results

Clinical and demographic characteristics

A summary of the patient population is provided in [Table 1]. Most of our patients were elderly (72.3% of patients were aged ≥ 60 years, median=60, interquartile range: 60–70). The diagnosis in the majority of patients was major depressive disorder (166, 88.3%) and the diagnoses in the remaining patients were dysthymia (11, 5.9%), anxiety disorder (5, 2.6%), somatoform disorder (4, 2.1%), and bipolar affective disorder (2, 1.1%). Among the 337 samples of mirtazapine concentrations, 216 samples (64.1%) were obtained from the patients with no co-medication. The most frequently used co-medication was benzodiazepine (124, 36.8%).

Mirtazapine concentration

Median mirtazapine concentration in the 337 samples from 188 patients was 43.6 μg/L (164.37 nmol, range: 1.5–199.3 μg/L) at a daily dosage range from 7.5–60 mg ([Table 1]). Most of the patients took a conventional maintenance dose of 15–45 mg/day, but a few patients took a reduced dose of 7.5 mg/day for drug tapering. At the steady state, mirtazapine dose had a positive correlation with the drug concentration (rho=0.49, p<0.0001). Median C/D ratio was 1.48 (interquartile range: 0.93–2.08). Individual C/D ratios ranged from 0.06–5.22. A subgroup of patients (n=67), in whom the mirtazapine concentration was measured more than twice at a constant daily dose, was investigated for intra-individual variability; Maximum concentration to minimum concentration ratio ranged from 1.00–12.03 fold (quartile coefficient of dispersion=0.32).

Factors associated with mirtazapine concentration

On investigating the influence of individual characteristics on mirtazapine C/D ratio, we observed that older patients showed a significantly higher C/D ratio than younger patients (rho=0.21, p<0.0001, [Table 2]). However, the correlation of sex and body weight with C/D ratio did not reach statistical significance. Among the co-medications used, a statistically significant difference in C/D ratio was observed only between the use of paroxetine and the non-use of paroxetine (p<0.0001). All other co-medication did not have a significant association with C/D ratio.

Next, we conducted a regression analysis for assessing the association between C/D ratio and the independent variables (age, sex, and paroxetine co-medication). Age had a positive association with C/D ratio (regression coefficient=0.02, 95% confidence interval [CI]=0.01–0.03, p<0.001, [Table 3]). The patients with paroxetine co-medication showed a higher C/D ratio than the patients without paroxetine co-medication (regression coefficient=0.69, 95% CI=0.26–1.12, p<0.01, [Table 3]).

Association between mirtazapine concentration and responsiveness

Among the 166 patients with MDD, we could retrospectively collect the HAM-D data from 106 patients (63.8%). Their median baseline HAM-D score was 18 (interquartile range: 17–21.5), which is consistent with moderately severe depression. 74 out of 106 patients responded to mirtazapine, and the response rate was 69.8%. Initial mirtazapine concentration (p=0.93) and C/D ratio (p=0.22) did not show a significant association with responsiveness. In addition, we did not find any correlation between initial mirtazapine concentration (p=0.55), C/D ratio (p=0.24) and HAM-D score reduction.

Discussion

In the present study, we evaluated mirtazapine TDM data from Korean psychiatric patients on mirtazapine treatment. We found an association between age, paroxetine co-medication, and mirtazapine C/D ratio. A high inter- and intra-individual variability in mirtazapine PK was noted in a clinical setting. However, the responsiveness to mirtazapine was not significantly associated with the mirtazapine concentration.

In the present study, the C/D ratios were higher than those in the other studies which targeted depressive patients in a naturalistic setting. A previous study in a Caucasian ethnic group showed a lower C/D ratio (males: 0.4–0.86, females: 0.6–0.99) than that in our study (males: 1.39, females: 1.55) in both sexes [11] [12]. Considering that women and elderly patients show a higher C/D ratio, this result might be partly explained by the different demographics of the patients. Another possible explanation might be the difference in ethnicity. It has been known that clinical therapeutic levels could be reached by using much lower dosages in Asians [17]. This result implied that the discrepancy of therapeutic dose of mirtazapine could arise from pharmacokinetic differences rather than pharmacodynamic causes. One speculative explanation could be interethnic differences in genotypes of drug metabolizing enzymes [18]. Despite the fact that low functional CYP2D6 alleles are not frequent in Asian populations; the CYP2D6*10 allele that causes intermediate enzyme activity is commonly present in the Asian population [19] [20]. Another possible reason for the difference in ethnicity could be the lower clearance of mirtazapine in the Asian population [10]. A further study on genotype data and renal clearance of mirtazapine will be helpful to clarify this difference [21].

Reis et al. reported that the intra-individual variation was low in contrast to the inter-individual variation, which indicated a stable metabolism within individual patients [11]. In contrast, marked inter-individual and intra-individual variations in the C/D ratio of mirtazapine were observed in our results. Considering that no major change in co-medication was reported in the patients in whom the ratio exceeded the upper 90 percentile, the large intra-individual variability in the present study possibly resulted from non-compliance, although we excluded the obviously non-compliant patients from our analysis. In this regard, TDM might be useful at least in a situation in which the cause of the change in the clinical picture (e. g., poor response, relapse, or recurrence) is difficult to determine in a patient; however, the usefulness of routine TDM of mirtazapine might be questionable due to negative results for the correlation between serum concentration and clinical response [22].

We found that the age of the patients was associated with the C/D ratio. This result is similar to that in a previous study [11] [12]. Reis et al. and Shams et al. showed that the elderly patients had an approximately 30% higher C/D ratio compared with their younger counterparts [11]. It is likely that this result was due to the physiological age-related lower clearance. In addition, our results showed that paroxetine co-medication was significantly associated with a high C/D ratio. It was consistent with the previous study showing an increase of plasma concentrations of mirtazapine when paroxetine was co-administered in healthy subjects [23], and the pharmacokinetic property of paroxetine that inhibits CYP 2D6, which is involved in the metabolism of mirtazapine [24]. These results imply that clinicians should be careful when using paroxetine as a combination treatment especially in the elderly patients. The main limitation of this study is its retrospective design. We could not control the co-medications used by patients. In addition, this study was carried out in outpatients in a naturalistic setting; therefore, we could not confirm the compliance of the patients. Lack of data on the major metabolite of mirtazapine (N-desmethylmirtazapine) that could have an effect on the treatment response should be mentioned as one of the limitations of this study [9]. In addition, CYP genotype and smoking history should be considered in any future study [14]. Nevertheless, our study results could be meaningful since this was the first report on TDM data in Asian psychiatric patients.

In summary, we evaluated mirtazapine TDM data and the potential factors affecting its steady-state concentration in Korean psychiatric patients on mirtazapine treatment. A further study in this area could be helpful for clinical decision making based on the characteristics of patients.

Author Contributions

Each author’s contribution was as follows: Woojae Myung and Ja-Hyun Jang were involved in writing the manuscript; Woojae Myung, Ja-Hyun Jang, Hyeyeon Yoon, Soo-Youn Lee, and Doh Kwan Kim were involved in planning the study. Woojae Myung and Ja-Hyun Jang performed the statistical analyses and interpreted the data; Soo-Youn Lee and Doh Kwan Kim edited the manuscript and supervised in interpreting the data.

Conflict of Interest

The authors declare that they have no potential competing interests with respect to the research, authorship, and/or publication of this article.

Acknowledgements

This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A110339).

^* These individuals contributed equally to this article as co-first authors.

^# These individuals contributed equally to this article as co-corresponding authors.

• References

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Correspondence

• References

• 1 De Boer T, Nefkens F, Van Helvoirt A. The alpha 2-adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo. Eur J Pharmacol 1994; 253: R5-R6
  CrossrefPubMedSearch in Google Scholar
• 2 Watanabe N, Omori IM, Nakagawa A et al. Mirtazapine versus other antidepressants in the acute-phase treatment of adults with major depression: systematic review and meta-analysis. J Clin Psychiatry 2008; 69: 1404-1415
  CrossrefPubMedSearch in Google Scholar
• 3 Thase ME, Nierenberg AA, Vrijland P et al. Remission with mirtazapine and selective serotonin reuptake inhibitors: a meta-analysis of individual patient data from 15 controlled trials of acute phase treatment of major depression. Int Clin Psychopharmacol 2010; 25: 189-198
  CrossrefPubMedSearch in Google Scholar
• 4 Watanabe N, Omori IM, Nakagawa A et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev 2011; CD006528
  PubMedSearch in Google Scholar
• 5 Timmer CJ, Lohmann AAM, Mink CPA. Pharmacokinetic dose-proportionality study at steady state of mirtazapine from Remeron^® tablets. Hum Psychopharmacol 1995; 10: S97-S106
  CrossrefPubMedSearch in Google Scholar
• 6 Timmer CJ, Paanakker JE, Van Hal HJM. Pharmacokinetics of mirtazapine from orally administered tablets: influence of gender, age and treatment regimen. Hum Psychopharmacol 1996; 11: 497-509
  CrossrefPubMedSearch in Google Scholar
• 7 Dodd S, Boulton DW, Burrows GD et al. In vitro metabolism of mirtazapine enantiomers by human cytochrome P450 enzymes. Hum Psychopharmacol 2001; 16: 541-544
  CrossrefPubMedSearch in Google Scholar
• 8 Dahl ML, Voortman G, Alm C et al. In vitro and in vivo studies on the disposition of mirtazapine in humans. Clin Drug Invest 1997; 13: 37-46
  CrossrefPubMedSearch in Google Scholar
• 9 Delbressine LP, Vos RM. The clinical relevance of preclinical data: mirtazapine, a model compound. J Clin Psychopharmacol 1997; 17 (Suppl. 01) 29S-33S
  CrossrefPubMedSearch in Google Scholar
• 10 Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet 2000; 38: 461-474
  CrossrefPubMedSearch in Google Scholar
• 11 Reis M, Prochazka J, Sitsen A et al. Inter- and intraindividual pharmacokinetic variations of mirtazapine and its N-demethyl metabolite in patients treated for major depressive disorder: a 6-month therapeutic drug monitoring study. Ther Drug Monit 2005; 27: 469-477
  CrossrefPubMedSearch in Google Scholar
• 12 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; 26: 78-84
  CrossrefPubMedSearch in Google Scholar
• 13 Meineke I, Kress I, Poser W et al. Therapeutic drug monitoring of mirtazapine and its metabolite desmethylmirtazapine by HPLC with fluorescence detection. Ther Drug Monit 2004; 26: 277-283
  CrossrefPubMedSearch in Google Scholar
• 14 Lind A-B, Reis M, Bengtsson F et al. Steady-state concentrations of mirtazapine, N-desmethylmirtazapine, 8-hydroxymirtazapine and their enantiomers in relation to cytochrome P450 2D6 genotype, age and smoking behaviour. Clinical pharmacokinetics 2009; 48: 63-70
  CrossrefPubMedSearch in Google Scholar
• 15 Hong Ng NC, Norman TR, Naing KO et al. A comparative study of sertraline dosages, plasma concentrations, efficacy and adverse reactions in Chinese versus Caucasian patients. Int Clin Psychopharmacol 2006; 21: 87-92
  CrossrefPubMedSearch in Google Scholar
• 16 Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol 2004; 44: 1083-1105
  CrossrefPubMedSearch in Google Scholar
• 17 Fabrega HJ. Cultural challenges to the psychiatric enterprise. Compr Psychiatry 1995; 36: 377-383
  CrossrefPubMedSearch in Google Scholar
• 18 Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance. Clin Pharmacokinet 2009; 48: 761-804
  CrossrefPubMedSearch in Google Scholar
• 19 Yoo HD, Lee SN, Kang HA et al. Influence of ABCB1 genetic polymorphisms on the pharmacokinetics of risperidone in healthy subjects with CYP2D6*10/*10. Br J Pharmacol 2011; 164: 433-443
  CrossrefPubMedSearch in Google Scholar
• 20 Johansson I, Oscarson M, Yue QY et al. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994; 46: 452-459
  PubMedSearch in Google Scholar
• 21 Grasmader K, Verwohlt PL, Kuhn KU et al. Population pharmacokinetic analysis of mirtazapine. Eur J Clin Pharmacol 2004; 60: 473-480
  CrossrefPubMedSearch in Google Scholar
• 22 Hiemke C, Baumann P, Bergemann N et al. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry 2011; 44: 195-235
  Search in Google Scholar
• 23 Ruwe FJ, Smulders RA, Kleijn HJ et al. Mirtazapine and paroxetine: a drug-drug interaction study in healthy subjects. Hum Psychopharmacol 2001; 16: 449-459
  CrossrefPubMedSearch in Google Scholar
• 24 Sproule BA, Naranjo CA, Brenmer KE et al. Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence. Clin Pharmacokinet 1997; 33: 454-471
  CrossrefPubMedSearch in Google Scholar