Download PDF
Fortschr Neurol Psychiatr 2003; 71(5): 243-248
DOI: 10.1055/s-2003-39050
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Plazebokontrollierte Antidepressiva-Studien

Überlegungen zur Frage der ethischen BeurteilungPlacebo-Controlled Antidepressant Drug TrialsConsidering the Ethical ImplicationsE.  A.  Deisenhammer1 , H.  Hinterhuber1
  • 1Klinische Abteilung für Allgemeine Psychiatrie, Universität Innsbruck (Leiter: Univ.-Prof. Dr. Hartmann Hinterhuber)
Further Information

Publication History

Publication Date:
12 May 2003 (online)

    Permissions and Reprints

Zusammenfassung

Als Voraussetzung für die Zulassung neuer Antidepressiva wird von den Arzneimittelbehörden nach wie vor der Nachweis einer signifikant besseren Wirkung im Vergleich zu Plazebo in kontrollierten Studien gefordert. Demgegenüber stehen - nicht zuletzt aus den Reihen der Ärzteschaft - ethische Bedenken hinsichtlich eines möglichen zusätzlichen Risikos, welchem die Kontrollgruppe durch das damit verbundene Unterbleiben einer Behandlung mit Antidepressiva ausgesetzt sei. Der vorliegende Artikel gibt einen Überblick über häufig vorgebrachte Argumente pro und kontra Plazebokontrollen in Antidepressiva-Studien, behandelt die Problematik der verschiedenen Wirkfaktoren von Antidepressiva und Plazebo in der Behandlung der Depression und diskutiert abschließend einige Vorschläge zur Planung plazebokontrollierter Studien, welche deren Aussagekraft verbessern können und dabei das Risiko für den Patienten so gering wie möglich halten. Eine weltweite Lösung des Problems ist grundsätzlich anzustreben. Das aus der Deklaration von Helsinki vereinzelt herausgelesene Verbot einer Verwendung von Plazebo in Antidepressiva-Studien sollte so lange ausgesetzt werden, bis Antidepressiva mit einer klareren Überlegenheit gegenüber Plazebo zur Verfügung stehen.

Abstract

For the approval of a new antidepressant for clinical use drug authorities still demand the proof of a significantly superior efficacy of the compound over placebo shown in controlled comparison studies. On the other side serious ethical concerns have been raised upon the use of placebos in clinical trials with depressed patients in that this would implicitly mean a withholding of an efficacious treatment from patients in the control groups of such trials. This article summarises frequently quoted arguments for and against placebo use in antidepressant clinical trials focussing on the specific issues involved in the therapeutic effect of antidepressants and placebos in depressed patients and discusses measures that might contribute to study designs that may better evaluate the true efficacy of a new drug while keeping the risk for the individual patient at the lowest possible level. A worldwide solution of the problem is clearly called for. A ban of placebos in antidepressant trials as it might be derived from the Declaration of Helsinki should be postponed until antidepressants with a more convincing superiority over placebo have been developed.

Literatur

  • 1 Rothman K J, Michels K B, Baum M. Declaration of Helsinki should be strengthened. For and Against.  BMJ. 2000;  321 442-445
    CrossrefPubMedGoogle Scholar
  • 2 Roberts L W, Lauriello J, Geppert C, Keith S J. Plazebos and paradoxes in psychiatric research: an ethics perspective.  Biol Psychiatry. 2001;  49 887-893
    CrossrefPubMedGoogle Scholar
  • 3 Anonymous . Fifty years of randomised controlled trials.  BMJ. 1998;  317 1166
    PubMedGoogle Scholar
  • 4 World Medical Association Declaration of Helsinki . Ethical principles for medical research involving human subjects.  JAMA. 2000;  284 3043-3045
    CrossrefPubMedGoogle Scholar
  • 5 Leber P D. Hazards of inference: the active control investigation.  Epilepsia. 1989;  30 (suppl 1) S57-S63
    PubMedGoogle Scholar
  • 6 Leber P. Is there an alternative to the randomized controlled trial?.  Psychopharmacol Bull. 1991;  27 3-8
    PubMedGoogle Scholar
  • 7 Bollini P, Pampallona S, Tibaldi G, Kupelnick B, Munizza C. Effectiveness of antidepressants.  Br J Psychiatry. 1999;  174 297-303
    CrossrefPubMedGoogle Scholar
  • 8 Quitkin F M. Placebos, drug effects, and study design: a clinician's guide.  Am J Psychiatry. 1999;  156 829-836
    PubMedGoogle Scholar
  • 9 Gumnick J F, Nemeroff C B. Problems with currently available antidepressants.  J Clin Psychiatry. 2000;  61 (suppl 10) 5-15
    Google Scholar
  • 10 Khan A, Leventhal R M, Khan S R, Brown W A. Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database.  J Clin Psychopharmacol. 2002;  22 40-45
    CrossrefPubMedGoogle Scholar
  • 11 Elkin I, Shea M T, Watkins J T, Imber S D, Sotsky S M, Collins J F, Glass D R, Pilkonis P A, Leber W R, Docherty J P. et al . National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments.  Arch Gen Psychiatry. 1989;  46 971-982
    CrossrefPubMedGoogle Scholar
  • 12 Wilcox C S, Cohn J B, Linden R D, Heiser J F, Lucas P B, Morgan D L, DeFrancisco D. Predictors of placebo response: a retrospective analysis.  Psychopharmacol Bull. 1992;  28 157-162
    PubMedGoogle Scholar
  • 13 Ribeiro S C, Tandon R, Grunhaus L, Greden J F. The DST as a predictor of outcome in depression: a meta-analysis.  Am J Psychiatry. 1993;  150 1618-1629
    PubMedGoogle Scholar
  • 14 Trivedi M H, Rush H. Does a placebo run-in or a placebo treatment cell affect the efficacy of antidepressant medications?.  Neuropsychopharmacol. 1994;  11 33-43
    PubMedGoogle Scholar
  • 15 Kramer M. Placebo run-in for antidepressant trials.  Neuropsychopharmacol. 1996;  15 105
    PubMedGoogle Scholar
  • 16 Bardy A H. Bias in reporting clinical trials.  Br J Clin Pharmacol. 1998;  46 147-150
    CrossrefPubMedGoogle Scholar
  • 17 Olson C M, Rennie D, Cook D, Dickersin K, Flanagin A, Hogan J W, Zhu Q, Reiling J, Pace B. Publication bias in editorial decision making.  JAMA. 2002;  287 2825-2828
    CrossrefPubMedGoogle Scholar
  • 18 van Mil F. Submission bias.  Pharm World Sci. 2001;  23 iii
    PubMedGoogle Scholar
  • 19 Zimbroff D L. Placebo response in antidepressant trials.  Br J Psychiatry. 2001;  178 573-574
    CrossrefPubMedGoogle Scholar
  • 20 Bark N. Placebo response in depression.  Br J Psychiatry. 2001;  179 79
    CrossrefPubMedGoogle Scholar
  • 21 Zimbroff D L. Patient and Rater Education of Expectations in Clinical Trials (PREECT).  J Clin Psychopharmacol. 2001;  21 251-252
    CrossrefPubMedGoogle Scholar
  • 22 Benson H, Epstein M D. The placebo effect. A neglected asset in the care of patients.  JAMA. 1975;  232 1225-1227
    CrossrefPubMedGoogle Scholar
  • 23 Kirsch I, Sapirstein G. Listening to prozac but hearing placebo: a meta-analysis of antidepressant medication. Prevention & Treatment I, Article 0002a (1998) zitiert in: 24. 
    Google Scholar
  • 24 Andrews G. Placebo response in depression: bane of research, boon to therapy.  Br J Psychiatry. 2001;  178 192-194
    CrossrefPubMedGoogle Scholar
  • 25 Brown W A. Placebo as a treatment for depression.  Neuropsychopharmacol. 1994;  10 265-269
    PubMedGoogle Scholar
  • 26 Emilien G, Maloteaux J M, Seghers A, Charles G. Use of a placebo in clinical trials.  Eur Psychiatry. 1998;  13 254-263
    CrossrefPubMedGoogle Scholar
  • 27 De la Fuente Fernandez R, Ruth T J, Sossi V, Schulzer M, Calne D B, Stoessl A J. Expectation and dopamine release: mechanism of the placebo effect in parkinson's disease.  Science. 2001;  293 1164-1166
    CrossrefPubMedGoogle Scholar
  • 28 Leuchter A F, Cook I A, Witte E A, Morgan M, Abrams M. Changes in brain function of depressed subjects during treatment with placebo.  Am J Psychiatry. 2002;  159 122-129
    CrossrefPubMedGoogle Scholar
  • 29 Mayberg H S, Silva J A, Brannan S K, Tekell J L, Mahurin R K, McGinnis S, Jerabek P A. The functional neuroanatomy of the placebo effect.  Am J Psychiatry. 2002;  159 728-737
    Google Scholar
  • 30 Moncrieff J. Are antidepressants overrated? A review of methodological problems in antidepressant trials.  J Nerv Ment Dis. 2001;  189 288-295
    CrossrefPubMedGoogle Scholar
  • 31 Crismon M L, Trivedi M, Pigott T A, Rush A J, Hirschfeld R M, Kahn D A, DeBattista C, Nelson J C, Nierenberg A A, Sackeim H A, Thase M E. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder.  J Clin Psychiatry. 1999;  60 142-156
    PubMedGoogle Scholar
  • 32 Härter M, Bermejo I, Aschenbrenner A, Berger M. Analyse und Bewertung aktueller Leitlinien zur Diagnostik und Behandlung depressiver Störungen.  Fortschr Neurol Psychiatr. 2001;  69 390-401
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Kasper S, Zapotoczky H G, Stuppäck C, König P, Wuschitz A. Diagnostik und Therapie der Depression.  Neuropsychiatrie. 1997;  11 59-67
    PubMedGoogle Scholar
  • 34 Khan A, Warner H A, Brown W A. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials.  Arch Gen Psychiatry. 2000;  57 311-317
    CrossrefPubMedGoogle Scholar
  • 35 Khan A, Khan S R, Leventhal R M, Brown W A. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: a replication analysis of the Food and Drug Administration Database.  Int J Neuropsychopharmacol. 2001;  4 113-118
    PubMedGoogle Scholar
  • 36 Storosum J G, Van Zwieten B J, Van den Brink W, Gersons B PR, Broekmans A W. Suicide risk in placebo-controlled studies of major depression.  Am J Psychiatry. 2001;  158 1271-1275
    CrossrefPubMedGoogle Scholar
  • 37 Laughren T P. The scientific and ethical basis for placebo-controlled trials in depression and schizophrenia: an FDA perspective.  Eur Psychiatry. 2001;  16 418-423
    CrossrefPubMedGoogle Scholar
  • 38 Appelbaum P S, Grisso T, Frank E, O'Donnell S, Kupfer D J. Competence of depressed patients for consent to research.  Am J Psychiatry. 1999;  156 1380-1384
    PubMedGoogle Scholar
  • 39 Murphy F C, Rubinsztein J S, Michael A, Rogers R D, Robbins T W, Paykel E S, Sahakian B J. Decision-making cognition in mania and depression.  Psychol Med. 2001;  31 679-693
    CrossrefPubMedGoogle Scholar
  • 40 Hummer M, Holzmeister R, Kemmler G, Eder U, Hofer A, Kurzthaler I, Oehl M, Weiss E, Fleischhacker W W. Placebo-controlled clinical trials: patients' attitudes.  J Clin Psychiatry (in press).
    PubMedGoogle Scholar
  • 41 Leon A C. Placebo protects subjects from nonresponse. A paradox of power.  Arch Gen Psychiatry. 2000;  57 329-330
    PubMedGoogle Scholar
  • 42 Fritze J, Möller H J. Design of clinical trials of antidepressants. Should a placebo control arm be included?.  CNS Drugs. 2001;  15 755-764
    PubMedGoogle Scholar
  • 43 Rothman K J, Michels K B. The continuing unethical use of placebo controls.  NEJM. 1994;  331 394-398
    CrossrefPubMedGoogle Scholar
  • 44 Barbui C, Violante A, Garattini S. Does placebo help establish equivalence in trials of new antidepressants?.  Eur Psychiatry. 2000;  15 268-273
    CrossrefPubMedGoogle Scholar
  • 45 Solomon D A, Keller M B, Leon A C, Mueller T I, Lavori P W, Shea M T, Coryell W, Warshaw M, Turvey C, Maser J D, Endicott J. Multiple recurrences of major depressive disorder.  Am J Psychiatry. 2000;  157 229-233
    CrossrefPubMedGoogle Scholar
  • 46 Fava G A. Potential sensitising effects of antidepressant drugs on depression.  CNS Drugs. 1999;  12 247-256
    PubMedGoogle Scholar
  • 47 Enserink M. Are placebo-controlled drug trials ethical?.  Science. 2000;  288 416
    PubMedGoogle Scholar
  • 48 Khan A, Brown W A. The placebo enigma in antidepressant clinical trials.  J Clin Psychopharmacol. 2001;  21 123-125
    CrossrefPubMedGoogle Scholar
  • 49 Charney D S, Nemeroff C B, Lewis L, Laden S K, Gorman J M, Laska E M. et al . National Depressive and Manic-Depressive Association Consensus Statement on the use of placebo in clinical trials of mood disorders.  Arch Gen Psychiatry. 2002;  59 262-270
    PubMedGoogle Scholar

Dr. E. A. Deisenhammer

Universitätsklinik für Psychiatrie

Anichstraße 35

6020 Innsbruck

Österreich

Email: eberhard.deisenhammer@uibk.ac.at

      >