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Pharmacopsychiatry 2003; 36(3): 98-104
DOI: 10.1055/s-2003-39983
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Therapeutic Drug Monitoring of Tricyclic Antidepressants: How Does it Work under Clinical Conditions?

M. J. Müller1 , A. Dragicevic1 , M. Fric3 , I. Gaertner2 , K. Grasmäder4 , S. Härtter1 , E. Hermann5 , H. J. Kuss6 , G. Laux3 , W. Oehl5 , M. L. Rao4 , N. Rollmann1 , H. Weigmann1 , M. Weber-Labonte5 , C. Hiemke1
  • 1Department of Psychiatry, University of Mainz, Mainz, Germany
  • 2Department of Psychiatry and Psychotherapy, University of Tübingen, Germany
  • 3Bezirksklinikum Gabersee, Wasserburg/Inn, Germany
  • 4Department of Psychiatry, University of Bonn, Bonn, Germany
  • 5St. Valentinus-Krankenhaus, Kiedrich/Rheingau, Germany
  • 6Department of Psychiatry, University of Munich, Munich, Germany
This research work was supported in part by the Bundesministerium für Bildung und Forschung (BMBF). It was a subproject (3.8) of the Competence-Net Depression/Suicidality (Grant 01GI9924)
Further Information

Publication History

Received: 6.2.2002 Revised: 11.4.2002

Accepted: 8.8.2002

Publication Date:
13 June 2003 (online)

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Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCA) is established in the treatment of depression to optimize outcome and safety. However, there are few reports on TDM under naturalistic clinical conditions. In the present study, we investigated a TDM group (TDM) and a randomly assigned parallel group without TDM (no-TDM) while on TCA treatment. Serum levels were analyzed in both cohorts, but feedback and dose recommendation were only provided for the TDM group. Serum levels of TCA were assessed by high-performance liquid chromatography (HPLC). The outcome was measured weekly using the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impressions Scale (CGI), and the UKU side-effect scale. 84 patients with depressive disorder according to DSM-IV were recruited in three centers (TDM, n = 43; no-TDM, n = 41; mean age 49.9 ± 13.2 years, 63.1 % female). Patients were treated with either amitriptyline (n = 69) or doxepin (n = 15); the mean dosage at endpoint was 126 ± 35 mg and 155 ± 47 mg, respectively. The mean study duration was 21 ± 8 days. Both groups improved according to HAMD (from 25.2 ± 8.4 at baseline to 12.0 ± 7.4 at endpoint) and CGI scores (68 % responders). Moderately severe or severe side effects occurred in 16 % of patients. Adequate dose adjustment was significantly higher in the TDM group (60 % vs. 46 %, p < 0.05); this led to a significantly higher rate of therapeutic serum levels in the TDM group (58 % vs. 44 %, p < 0.05). Direct effects of TDM were not found for effectiveness. Therapeutic TCA serum levels over weeks one to three, however, were associated with significantly better outcome at endpoint (p < 0.05) as measured with changes in the HAMD or CGI response rates from baseline to endpoint. Finally, considerable side effects occurred significantly more often when serum levels were above the therapeutic range (27 % vs. 11 %; p < 0.01). We conclude that treating depression with TCA can be optimized by early TDM, which is superior to clinical judgment on its own. Since the psychiatrists in charge were less than completely ”compliant” to the recommendations provided together with serum levels, the effect could be more pronounced than this study shows. The results encourage further studies in order to optimize antidepressant pharmacotherapy when using TDM appropriately.

References

  • 1 Banger M, Hermes B, Härtter S, Hiemke C. Monitoring serum concentrations of clomipramine and metabolites: Fuorescence polarization immunoassay versus high performance liquid chromatography.  Pharmacopsychiat. 1997;  30 128-132
    PubMedGoogle Scholar
  • 2 Burke M J, Preskorn S H. Therapeutic drug monitoring of antidepressants.  Clin Pharmacokinetics. 1999;  37 147-165
    PubMedGoogle Scholar
  • 3 Collegium Internationale Psychiatriae Scalarum  (CIPS). Internationale Skalen für Psychiatrie. Weinheim; Beltz Verlag 1998
    Google Scholar
  • 4 Cramer J A, Rosenheck R. Compliance with medication regimens for mental and physical disorders.  Psychiatr Serv. 1998;  49 196-201
    PubMedGoogle Scholar
  • 5 Dahl M L, Sjovist F. Pharmacogenetic methods as a complement to therapeutic monitoring of antidepressants and neuroleptics.  Ther Drug Monit. 2000;  22 114-117
    CrossrefPubMedGoogle Scholar
  • 6 Demyttenaere K, Enzlin p, Dewe W, Boulanger B, De Bie J, De Troyer W, Mesters p. Compliance with antidepressants in a primary care setting, 1: Beyond lack of efficacy and adverse events.  J Clin Psychiatry. 2001;  62 Suppl 22 30-33
    CrossrefPubMedGoogle Scholar
  • 7 Dunner D L. Acute and maintenance treatment of chronic depression.  J Clin Psychiatry. 2001;  62 Suppl 6 10-16
    Google Scholar
  • 8 Ensom M H, Chang T K, Patel p. Pharmacogenetics: The Therapeutic Drug Monitoring of the Future.  Clin Pharmacokinet. 2001;  40 783-802
    PubMedGoogle Scholar
  • 9 Fraser A D. Experience with a specific request form for antidepressant drug monitoring.  Ther Drug Monit. 1985;  7 299-302
    PubMedGoogle Scholar
  • 10 Glassman A, and the task force on the use of laboratory tests in p sychiatry. Tricyclic antidepressants - blood level measurements and clinical outcome: an APA task force report.  Am J Psychiatry. 1985;  142 155-162
    PubMedGoogle Scholar
  • 11 Hackett L P, Dusci L J, Ilett K F. A comparison of high-performance liquid chromatography and fluorescence polarization immunoassay for therapeutic drug monitoring of tricyclic antidepressants.  Ther Drug Monit. 1998;  20 30-34
    CrossrefPubMedGoogle Scholar
  • 12 Hamilton M. A rating scale for depression.  J Neurol Neurosurg Psychiatry. 1960;  23 56-62
    CrossrefPubMedGoogle Scholar
  • 13 Härtter S, Hiemke C. Column switching and high-performance liquid chromatography in the analysis of amitriptyline, nortripyline and hydroxylated metabolites in human serum or serum.  J Chromatogr B. 1992;  578 232-278
    PubMedGoogle Scholar
  • 14 Hiemke C, Weigmann H, Härtter S, Mann K. Therapeutisches Drug Monitoring von Psychopharmaka.  Neurotransmitter. 2000;  11 52-55
    PubMedGoogle Scholar
  • 15 Hodgkiss A D, McCarthy P T, Sulke A N, Bridges P K. High dose tertiary amine tricyclic antidepressants in the treatment of severe refractory depression: the central role of serum concentration estimations.  Human Psychopharmacology. 1995;  10 407-415
    PubMedGoogle Scholar
  • 16 Hollister L E. Monitoring tricyclic antidepressant serum concentrations.  JAMA. 1979;  241 2530-2553
    CrossrefPubMedGoogle Scholar
  • 17 Hollister L E. Serum concentrations of tricyclic antidepressants in clinical practice.  J Clin Psychiatry. 1982;  43 66-69
    PubMedGoogle Scholar
  • 18 Hollister L E, Pfefferbaum A, Davis K L. Monitoring nortriptyline serum concentrations.  Am J Psychiatry. 1980;  137 485-486
    PubMedGoogle Scholar
  • 19 Isacsson G, Bergman U, Wasserman D, Redfors I, Sjoqvist F. The use of antidepressants and therapeutic drug monitoring by general practitioners and psychiatrists: findings from a questionnaire survey in two Swedish areas.  Ann Clin Psychiatry. 1996;  8 153-160
    CrossrefPubMedGoogle Scholar
  • 20 Kuss H J. Application of HPLC for Analysis of Psychotropic Drugs in Body Fluids. In H. Engelhardt (Ed) Practice of High Performance Liquid Chromatography. Heidelberg; Springer Verlag 1986: 394-407
    Google Scholar
  • 21 Laux G. Cost-benefit analysis of newer versus older antidepressants.  Pharmacopsychiat. 2001;  34 1-5
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Leucht S, Steimer W, Kreuz S, Abraham D, Orsulak P J, Kissling W. Doxepin serum concentrations: is there really a therapeutic range?.  J Clin Psychopharmacol. 2001;  21 432-439
    CrossrefPubMedGoogle Scholar
  • 23 Levine R R. The role of serum concentrations in the use of tricyclic antidepressant drugs.  Prog Neuropsychopharmacol. 1979;  3 211-222
    PubMedGoogle Scholar
  • 24 Lingjærde O, Ahlfors U G, Bech p, Dencker S J, Elgen K. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients.  Acta Psychiatr Scand. 1987;  Suppl 334 1-100
    PubMedGoogle Scholar
  • 25 Mitchell P B. Therapeutic drug monitoring of psychotropic medication.  Br J Clin Pharmacol. 2000;  49 303-312
    CrossrefPubMedGoogle Scholar
  • 26 Oshima A, Higuchi T, Fujiwara Y, Iida M, Iwanami A, Kanba S, Motohashi N, Uchitomi Y, Yamada K, Yamawaki S. Questionnaire survey on the prescribing practice of Japanese psychiatrists for mood disorders.  Psychiatry Clin Neurosci. 1999;  53 Suppl S67-72
    CrossrefPubMedGoogle Scholar
  • 27 Perry P J, Pfohl B M, Holstad S G. The relationship between antidepressant response and tricyclic antidepressant serum concentrations. A retrospective analysis of the literature using logistic regression analysis.  Clin Pharmacokinet. 1987;  13 381-392
    CrossrefPubMedGoogle Scholar
  • 28 Preskorn S H. Tricyclic antidepressants: the whys and hows of therapeutic drug monitoring.  J Clin Psychiatry. 1989;  50 Suppl 34-42
    PubMedGoogle Scholar
  • 29 Preskorn S H, Burke M J, Fast G A. Therapeutic drug monitoring. Principles and practice.  Psychiatr Clin North Am. 1993;  16 611-645
    PubMedGoogle Scholar
  • 30 Preskorn S H, Dorey R C, Jerkovich G S. Therapeutic drug monitoring of tricyclic antidepressants.  Clin Chem. 1988;  34 822-828
    PubMedGoogle Scholar
  • 31 Preskorn S H, Fast G A. Therapeutic drug monitoring for antidepressants: efficacy, safety, and cost effectiveness.  J Clin Psychiatry. 1991;  52 Suppl 23-33
    PubMedGoogle Scholar
  • 32 Preskorn S H, Fast G A. Tricyclic antidepressant-induced seizures and serum drug concentration.  J Clin Psychiatry. 1992;  53 160-162
    PubMedGoogle Scholar
  • 33 Preskorn S H, Jerkovich G S. Central nervous system toxicity of tricyclic antidepressants, phenomenology, course, risk factors, and role of therapeutic drug monitoring.  J Clin Psychopharmacology. 1990;  10 88-95
    PubMedGoogle Scholar
  • 34 Rao M L, Deister A, Laux G, Staberock U, Höflich G, Möller H J. Low serum levels of tricyclic antidepressants in amitriptyline- and doxepin-treated inpatients with depressive syndromes are associated with nonresponse.  Pharmacopsychiat. 1996;  29 97-102
    PubMedGoogle Scholar
  • 35 Risch S C, Kalin N H, Janowsky D S, Huey L Y. Indications and guidelines for serum tricyclic antidepressant concentration monitoring.  J Clin Psychopharmacol. 1981;  1 59-63
    PubMedGoogle Scholar
  • 36 Rodriguez de la Torre B, Dreher J, Malevany I, Bagli M, Kolbinger M, Omran H, Luderitz B, Rao M L. Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients.  Ther Drug Monit. 2001;  23 435-440
    CrossrefPubMedGoogle Scholar
  • 37 Sclar D A, Robinson L M, Skaer T L, Galin R S. Trends in the prescribing of antidepressant pharmacotherapy: office-based visits, 1990 - 1995.  Clin Ther. 1998;  20 871-884
    CrossrefPubMedGoogle Scholar
  • 38 Simmons S A, Perry P J, Rickert E D, Browne J L. Cost-benefit analysis of prospective pharmacokinetic dosing of nortriptyline in depressed inpatients.  J Affect Disord. 1985;  8 47-53
    PubMedGoogle Scholar
  • 39 Tonkin A L, Bochner F. Therapeutic drug monitoring and patient outcome.  Clin Pharmacokinetics. 1994;  27 169-174
    PubMedGoogle Scholar
  • 40 Ulrich S, Northoff G, Wurthmann C, Partscht G, Pester U, Herscu H, Meyer F P. Serum levels of amitriptyline and therapeutic effect in non-delusional moderately to severely depressed in-patients: a therapeutic window relationship.  Pharmacopsychiatry. 2001;  34 33-40
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Vuille F, Amey M, Baumann p. Use of serum level monitoring of antidepressants in clinical practice.  Pharmacopsychiat.. 1991;  24 190-195
    PubMedGoogle Scholar
  • 42 Walker E A, Katon W J, Russo J, Von Korff M, Lin E, Simon G, Bush T, Ludman E, Unutzer J. Predictors of outcome in a primary care depression trial.  J Gen Intern Med. 2000;  15 859-867
    CrossrefPubMedGoogle Scholar
  • 43 Zullino D, Baumann p. Lithium augmentation in depressive patients not responding to selective serotonin reuptake inhibitors.  Pharmacopsychiat. 2001;  34 119-127
    Article in Thieme ConnectPubMedGoogle Scholar

Dr. med. Dipl.-Psych. Matthias J. Müller

Department of Psychiatry, University of Mainz

Untere Zahlbacher Straße 8

55131 Mainz

Germany

Phone: +49 (6131) 17-7363

Fax: +49 (6131) 17-6690

Email: mjm@mail.psychiatrie.klinik.uni-mainz.de