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Nortriptyline serum concentration as a predictor for cardiac risk in amitriptyline-treated patients

  • Maike Scherf-ClavelEmail author
  • Jasper Zebner
  • Leif Hommers
  • Jürgen Deckert
  • Andreas Menke
  • Stefan Unterecker
Pharmacokinetics and Disposition

Abstract

Purpose

Tricyclic antidepressants have been shown to affect electrocardiogram (ECG) parameters, but there is limited evidence in relation to the serum concentrations. Therefore, we aimed to evaluate a prediction of cardiac risk in amitriptyline- and doxepin-treated patients by serum concentrations.

Patients and methods

The association between serum concentrations of amitriptyline (n = 100) and doxepin (n = 71) and ECG parameters was retrospectively examined using linear regression analysis. Mann-Whitney U tests were applied to evaluate differences in QTc intervals in patients with serum concentrations above and below the upper limit of the therapeutic reference range, as well as the alert level of each target drug.

Results

The sum serum concentration of amitriptyline and the nortriptyline serum concentration were significantly associated with an increased PQ interval (p = 0.020, p = 0.007), as well as with increased QTcB (p = 0.012, p < 0.001) and QTcF intervals (p = 0.025, p < 0.001). The nortriptyline concentration was significantly associated with the QRS interval (p = 0.003). In patients with active moiety concentrations above the alert level (300 ng/ml) and nortriptyline concentrations above the reference range (170 ng/ml), the QTcB interval was significantly prolonged (p = 0.032, p = 0.007). No significant association with any ECG parameter was detected for doxepin serum concentrations.

Conclusion

The effect of amitriptyline on ECG parameters may be explained by nortriptyline alone. Accordingly, with increasing nortriptyline concentrations, the potential risk for an atrioventricular block, a bundle branch block, and prolongation of QTc interval may increase significantly.

Keywords

Cardiac risk Serum concentration Amitriptyline Doxepin ECG parameters 

Notes

Acknowledgments

We are very grateful to the staff of the participating TDM laboratory at the Psychiatric Department of the University Hospital of Würzburg, Rainer Burger (medical-technical assistant), Margit Burger (medical-technical assistant), Kerstin Balcioglu (medical-technical assistant), Marion Weyer (medical-technical assistant), and Renate Keil (typist) for processing patient samples.

Authors’ contribution

M. Scherf-Clavel has substantially contributed to the data analysis and interpretation, drafted the work, did a final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. J. Zebner did the data acquisition, revised the work critically, did a final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. L. Hommers has substantially contributed to the data interpretation, revised the work critically, did a final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. J. Deckert and A. Menke have substantially contributed to the conception of the work, revised the work critically, did a final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. S. Unterecker has substantially contributed to the conception and design of the work and data interpretation, revised the work critically, did a final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Compliance with ethical standards

Conflict of interest

J. Deckert is the co-recipient of a grant of the Bavarian State Government to BioVariance and an investigator in a European grant to P1Vital. A. Menke has given talks for the health insurance company AOK, Servier, Recordati, and Medice. M. Scherf-Clavel, J. Zebner, L. Hommers, and S. Unterecker have no conflicts of interest.

Ethical approval

All procedures performed in the analysis involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study (retrospective analysis with anonymous naturalistic data), formal consent is not required.

Supplementary material

228_2019_2766_MOESM1_ESM.pdf (48 kb)
ESM 1 (PDF 48 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental HealthUniversity Hospital of WürzburgWürzburgGermany

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