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Comprehensive Survey of the Relationship Between Serum Concentration and Therapeutic Effect of Amitriptyline in Depression

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Abstract

The relationship between serum concentration (Cs) of amitriptyline and its therapeutic effect in depression has been investigated frequently over the last 3 decades; however, the results were controversial and no consensus was reached. Therefore, we have performed a comprehensive survey and meta-analysis of the subject. All relevant literature was included, and the design of studies on the serum concentration-therapeutic effect relationship (SCTER) of amitriptyline was evaluated. Pooled original data from SCTER studies with adequate design were analysed by various statistical methods: regression analysis of therapeutic effect and Cs; comparison of the mean therapeutic effect in various ranges of Cs; dichotomisation of outcome and analysis according to sensitivity of receiver operation curves; frequency of responders and nonresponders in ranges determined by points of sensitivity; analysis of the distribution of Cs in responders and nonresponders; logistic regression of responders and nonresponders with Cs and other independent variables; calculation of effect size (g) and mean effect size (gm).

Forty-five SCTER studies of amitriptyline were identified, and 27 studies met the minimum criteria of adequate study design. Inadequate study design predicted the finding of no SCTER. Analysis of the pooled data from studies with adequate design confirmed a therapeutic window of the sum of Cs of amitriptyline and its active metabolite nortriptyline of about 80 to 200 µg/L. A moderate and significant positive gm (0.538, 95% confidence interval 0.167 to 0.909) was calculated for treatment with Cs within the therapeutic window in comparison with treatment with Cs outside the therapeutic window (19 studies with adequate design and original data available, n = 583).

In conclusion, the evidence for a biphasic SCTER of amitriptyline in depression is considerably improved, and the results may help to find a consensus in the future. However, the clinical benefit of therapeutic drug monitoring of amitriptyline can only be demonstrated in a controlled and randomised study. Furthermore, the results provide further evidence that antidepressants at optimum Cs are superior to placebo in the treatment of depression.

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Acknowledgements

This paper is dedicated to Professor F.P. Meyer on the occasion of his 65th birthday and retirement as the head of the Institute of Clinical Pharmacology, Otto-von-Guericke University, Magdeburg, Germany. This work was supported by the Bundesministerium für Bildung, Forschung und Technologie of Germany under the code number 01ZZ9510. The authors thank Dr. Zhaoheng Ge, Institute of Pharmacology and Toxicology, Beijing, China, for the translation of Chinese references, and Dr. Slavomir Vosika, International Commission for the Protection of the River Elbe, Magdeburg, for the translation of Czech references.

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  1. Institute of Clinical Pharmacology, University Hospital, Magdeburg, Germany

    Sven Ulrich

  2. Institute of Biometry and Medical Informatics, University Hospital, Otto-von-Guericke University, Magdeburg, Germany

    Jürgen Läuter

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Ulrich, S., Läuter, J. Comprehensive Survey of the Relationship Between Serum Concentration and Therapeutic Effect of Amitriptyline in Depression. Clin Pharmacokinet 41, 853–876 (2002). https://doi.org/10.2165/00003088-200241110-00004

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