Research Article

Mirtazapine in combination with amitriptyline: a drug–drug interaction study in healthy subjects

  1. C. Sennef,
  2. C. J. Timmer,
  3. J. M. A. Sitsen*

Article first published online: 30 JAN 2003

DOI: 10.1002/hup.441

Issue

Human Psychopharmacology: Clinical and Experimental

Human Psychopharmacology: Clinical and Experimental

Volume 18, Issue 2, pages 91–101, March 2003

Additional Information

How to Cite

Sennef, C., Timmer, C. J. and Sitsen, J. M. A. (2003), Mirtazapine in combination with amitriptyline: a drug–drug interaction study in healthy subjects. Human Psychopharmacology: Clinical and Experimental, 18: 91–101. doi: 10.1002/hup.441

Author Information

  1. NV Organon, PO Box 20, 5340 BH Oss, The Netherlands

*NV Organon, PO Box 20, 5340 BH Oss, The Netherlands.

Publication History

  1. Issue published online: 13 FEB 2003
  2. Article first published online: 30 JAN 2003
  3. Manuscript Accepted: 1 JUL 2002
  4. Manuscript Received: 23 APR 2002

Funded by

  • NV Organon, Oss, The Netherlands

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Keywords:

  • amitriptyline;
  • mirtazapine;
  • cytochrome P450;
  • drug–drug interaction

Abstract

Objective

To assess the steady-state pharmacokinetics of mirtazapine (30 mg/day orally) and amitriptyline (75 mg/day orally) during combined administration compared with that of either drug administered alone. To evaluate the tolerability and effects on psychometric tests of acute and subchronic administration of both drugs combined and alone.

Methods

In a single-blind, three-way cross-over study, 24 (12 male and 12 female) healthy subjects were randomly assigned to six different sequences of three 9-day treatments, i.e. racemic mirtazapine (30 mg/day), amitriptyline (75 mg/day) or the combination of these drugs. To control for acute pharmacodynamic assessments, during the first treatment period, a placebo group (n = 8; 4 females and 4 males) was added. Serial blood samples were drawn for plasma level measurements that were subsequently subjected to pharmacokinetic analysis. Psychometric tests assessed attentional performance, and a computer-assisted telephone questionnaire assessed self-ratings of drowsiness/alertness and sleep quality.

Results

Amitriptyline increased the Cmax of mirtazapine (+ 36%, p < 0.05) in male subjects only. Mirtazapine altered the Cmax of amitriptyline in both male (+ 23%, p < 0.05) and female (− 23%, p < 0.05) subjects. No changes were observed for other pharmacokinetic parameters. Metabolite parameters were not affected. Changes in parent compound levels mainly resulted from effects on absorption. The psychometric test results did not reveal significant changes between combined and single drug treatments. The telephone registrations of VAMRS and LSEQ did not show clinically relevant differences between the active treatments.

Conclusion

Combined administration of mirtazapine (30 mg/day) and amitriptyline (75 mg/day) alters the pharmacokinetics of either compound to a minor extent. Adding one drug to the other and substituting one drug by the other had no major effects on tolerability. Nevertheless, caution is warranted when combining amitriptyline and mirtazapine. Copyright © 2003 John Wiley & Sons, Ltd.

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