Effects of Pharmacokinetic Gene Variation on Therapeutic Drug Levels
                    and Antidepressant Treatment Response

Maike Scherf-Clavel; Heike Weber; Catherina Wurst; Saskia Stonawski; Leif Hommers; Stefan Unterecker; Christiane Wolf; Katharina Domschke; Nicolas Rost; Tanja Brückl; Susanne Lucae; Manfred Uhr; Elisabeth B. Binder; Andreas Menke; Jürgen Deckert

doi:10.1055/a-1872-0613

Pharmacopsychiatry, Table of Contents

CC BY-NC-ND 4.0 · Pharmacopsychiatry 2022; 55(05): 246-254
DOI: 10.1055/a-1872-0613

Original Paper

Effects of Pharmacokinetic Gene Variation on Therapeutic Drug Levels and Antidepressant Treatment Response

Authors

Maike Scherf-Clavel^*

¹Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
Heike Weber^*

¹Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
Catherina Wurst

¹Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany

²Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Würzburg, Germany

³Comprehensive Heart Failure Center (CHFC), University Hospital of Würzburg, Würzburg, Germany
Saskia Stonawski

¹Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany

²Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Würzburg, Germany

³Comprehensive Heart Failure Center (CHFC), University Hospital of Würzburg, Würzburg, Germany
Leif Hommers

¹Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany

²Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Würzburg, Germany

³Comprehensive Heart Failure Center (CHFC), University Hospital of Würzburg, Würzburg, Germany
Stefan Unterecker

¹Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
Christiane Wolf

¹Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
Katharina Domschke

⁴Department of Psychiatry and Psychotherapy, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Nicolas Rost

⁵Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

⁶International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany
Tanja Brückl

⁵Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
Susanne Lucae

⁷Max Planck Institute of Psychiatry, Munich, Germany
Manfred Uhr

⁷Max Planck Institute of Psychiatry, Munich, Germany
Elisabeth B. Binder^†

⁵Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
Andreas Menke^†

¹Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany

⁸Department of Psychosomatic Medicine and Psychotherapy, Medical Park Chiemseeblick, Bernau, Germany

⁹Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
Jürgen Deckert^†

¹Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany

Abstract

Introduction Pharmacogenetic testing is proposed to minimize adverse effects when considered in combination with pharmacological knowledge of the drug. As yet, limited studies in clinical settings have investigated the predictive value of pharmacokinetic (pk) gene variation on therapeutic drug levels as a probable mechanism of adverse effects, nor considered the combined effect of pk gene variation and drug level on antidepressant treatment response.

Methods Two depression cohorts were investigated for the relationship between pk gene variation and antidepressant serum concentrations of amitriptyline, venlafaxine, mirtazapine and quetiapine, as well as treatment response. For the analysis, 519 patients (49% females; 46.6±14.1 years) were included.

Results Serum concentration of amitriptyline was associated with CYP2D6 (higher concentrations in poor metabolizers compared to normal metabolizers), of venlafaxine with CYP2C19 (higher concentrations in intermediate metabolizers compared to rapid/ultrarapid metabolizers) and CYP2D6 (lower metabolite-to-parent ratio in poor compared to intermediate and normal metabolizers, and intermediate compared to normal and ultrarapid metabolizers). Pk gene variation did not affect treatment response.

Discussion The present data support previous recommendations to reduce starting doses of amitriptyline and to guide dose-adjustments via therapeutic drug monitoring in CYP2D6 poor metabolizers. In addition, we propose including CYP2C19 in routine testing in venlafaxine-treated patients to improve therapy by raising awareness of the risk of low serum concentrations in CYP2C19 rapid/ultrarapid metabolizers. In summary, pk gene variation can predict serum concentrations, and thus the combination of pharmacogenetic testing and therapeutic drug monitoring is a useful tool in a personalized therapy approach for depression.

Key words

pharmacogenetics - depressive disorder - serum concentrations - pharmacokinetics

Full Text

References

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