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Distribution pattern of mirtazapine and normirtazapine in blood and CSF

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Abstract

Rationale

The aim of this study was to investigate the distribution pattern of mirtazapine and its metabolite normirtazapine (N-desmethylmirtazapine) in blood and cerebrospinal fluid (CSF).

Objectives and methods

Concentrations of mirtazapine were measured in blood serum and CSF of 16 patients treated with daily doses of 7.5–60 mg. Daily doses were correlated with serum and CSF concentrations as well as serum levels with those in CSF.

Results

Serum levels of mirtazapine and normirtazapine showed a strong relation to the daily dose of mirtazapine of r = +0.631 and r = +0.732, respectively (p < 0.01). Between the daily doses and the CSF levels of both mirtazapine and normirtazapine, we only found a trend-wise correlation (r = +0.535, p = 0.060). The correlation between mirtazapine and normirtazapine in serum and CSF was highly significant (r = +0.664, p = 0.005 and r = +0.885, p < 0.001, respectively). High discrepancies between (total) mirtazapine levels in serum and CSF indicate a low penetration into CSF with regard to the total serum concentration as the mean of the calculated penetration ratio was 0.16 (SD = 0.11). By correcting the penetration ratio for the plasma protein binding, the mean CSF/serum ratio for the unbound fraction was 1.05 (SD 0.72, range 0.56–3.19) indicating a high passage into CSF.

Conclusions

Findings indicate a good ability of mirtazapine and normirtazapine to overcome the blood-cerebrospinal fluid barrier and suggest a high ability to enter the brain with sufficient drug levels at the target sites within the brain contributing to clinical efficacy.

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Abbreviations

BCSFB:

Blood-cerebrospinal fluid barrier

BBB:

Blood-brain barrier

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

NaSSA:

Noradrenergic and specific serotonergic antidepressant

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Acknowledgments

The authors wish to thank Anette Rieger-Gies, Sandra Heller, and Gaby Stroba from the Institute of Clinical Chemistry and Laboratory Medicine at the University Medical Center at Mainz for the determination of mirtazapine and normirtazapine for this investigation. Appreciation is also given to Dr. Karsten Henkel of the Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University for collecting blood and CSF samples and Dr. Ingo Vernaleken of the Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University for his always fruitful thought-provoking impulses.

Conflict of interest

Dr. Paulzen, Dr. Groppe, Dr. Tauber and Dr. Veselinovic have no financial interests to declare.

Dr. Gründer has served as a consultant for Bristol-Myers Squibb (New York, NY, USA), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, IN, USA), Forest Laboratories (New York, NY, USA), Lundbeck (Copenhagen, Denmark), Otsuka (Rockville, MD, USA), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Bristol-Myers Squibb, Eli Lilly, Gedeon Richter (Budapest, Hungary), Otsuka, Roche, and Servier. He has received grant support from Alkermes, Eli Lilly, and Roche. He is co-founder of Pharma-Image Molecular Imaging Technologies GmbH, Düsseldorf, and Brainfoods UG, Düsseldorf.

Dr. Hiemke has served as a consultant for Servier (Paris, France) and Janssen-Cilag (Beerse, Belgium). He has served on the speakers’ bureau of Bristol-Myers Squibb, Eli Lilly, Pfizer, and Servier. He is the managing director of psiac GmbH, Mainz, which provides an internet based drug interaction program for psychoactive drugs.

Authorship contributions

MP, GG, and CH participated in research design. MP, SCT, and TV conducted experiments. CH contributed analytic tools. MP and SEG performed data analysis. MP, SEG, SCT, TV, CH, and GG wrote or contributed to the writing of the manuscript.

Financial support

This work was done without financial support.

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Authors and Affiliations

  1. Department of Psychiatry, Psychotherapy and Psychosomatics and JARA–Translational Brain Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany

    Michael Paulzen, Gerhard Gründer, Tanja Veselinovic & Sarah E. Groppe

  2. Department of Neurology, RWTH Aachen University, Aachen, Germany

    Simone C. Tauber

  3. Department of Psychiatry and Psychotherapy and Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany

    Christoph Hiemke

Authors
  1. Michael Paulzen
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  2. Gerhard Gründer
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  3. Simone C. Tauber
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  5. Christoph Hiemke
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  6. Sarah E. Groppe
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Correspondence to Michael Paulzen.

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Paulzen, M., Gründer, G., Tauber, S.C. et al. Distribution pattern of mirtazapine and normirtazapine in blood and CSF. Psychopharmacology 232, 807–813 (2015). https://doi.org/10.1007/s00213-014-3717-9

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  • DOI: https://doi.org/10.1007/s00213-014-3717-9

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