Journal Mobile Options
Table of Contents
Vol. 72, No. 3, 2003
Issue release date: May–June 2003
Psychother Psychosom 2003;72:115–127
(DOI:10.1159/000069738)

The Problem of the Placebo Response in Clinical Trials for Psychiatric Disorders: Culprits, Possible Remedies, and a Novel Study Design Approach

Fava M. · Evins A.E. · Dorer D.J. · Schoenfeld D.A.
aDepartment of Psychiatry and bBiostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, Mass., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

The placebo response is a major issue in clinical trials for psychiatric disorders. Possible contributing factors to this problem include diagnostic misclassification, issues concerning inclusion/exclusion criteria, outcome measures’ lack of sensitivity to change, measurement errors, poor quality of data entry and verification, waxing and waning of the natural course of illness, regression toward the mean phenomenon, patient and clinician expectations about the trial, study design issues, non-specific therapeutic effects, and high attrition. Over the past few decades, researchers have attempted to reduce the placebo effect in a variety of ways. Unfortunately, approaches with very little or no benefit have included restricting enrollment to selected populations, rater training, requirement of same rater, and placebo lead-in phases. Some benefits, although often marginal, have been derived from standardizing diagnostic procedures, managing clinicians’ overestimation of change, simplification of study visits and assessments, minimizing non-specific, therapeutic effects, extending trial duration, reducing number of sites, increasing the sensitivity of outcome measures, and reducing the number of treatment arms. Thus far, there has been no attempt to develop new study designs aimed at reducing the placebo effect. We are proposing a novel study design, called ‘Sequential Parallel Comparison Design’, suitable for double-blind, placebo-controlled trials in psychiatric disorders. This design is aimed at reducing both the overall placebo response rate and the sample size required for such trials. Its usefulness in clinical research needs to be tested empirically. If this study design were to be found to meet its stated goals, this could markedly facilitate the process of clinical development of new compounds for the treatment of psychiatric disorders.



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Schatzberg AF, Kraemer HC: Use of placebo control groups in evaluating efficacy of treatment of unipolar major depression. Biol Psychiatry 2000;47:736–744.
  2. Demitrack MA, Faries D, Herrera JM, DeBrota D, Potter WZ: The problem of measurement error in multisite clinical trials. Psychopharmacol Bull 1998;34:19–24.
  3. Robinson DS, Rickels K: Concern about clinical drug trials. J Clin Psychopharmacol 2000;20:593–596.
  4. Otto MW, Nierenberg AA: Assay sensitivity, failed clinical trials and the conduct of science. Psychother Psychosom 2002;71:241–243.
  5. Hooper M, Amsterdam JD: Do clinical trials reflect drug potential? A review of FDA evaluation of new antidepressants. 39th Annual NCDEU Meeting, Boca Raton, June 11–14, 1998.
  6. NDA 18-936, FDA 1988.
  7. Walsh BT, Seidman SN, Sysko R, Gould M: Placebo response in studies of major depression: Variable, substantial and growing. JAMA 2002;287:1840–1847.
  8. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR, Smith SS, Muramoto ML, Daughton DM, Doan K, Fiore MC, Baker TB: A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340:685–691.
  9. Fiore MC, Smith SS, Jorenby DE, Baker TB: The effectiveness of the nicotine patch for smoking cessation. A meta-analysis. JAMA 1994;271:1940–1947.
  10. Niaura R, Spring B, Borrelli B, Hedeker D, Goldstein MG, Keuthen N, DePue J, Kristeller J, Ockene J, Prochazka A, Chiles JA, Abrams DB: Multicenter trial of fluoxetine as an adjunct to behavioral smoking cessation treatment. J Consult Clin Psychol 2002;70:887–896.
  11. Quitkin FM, Stewart JW, McGrath PJ, Taylor BP, Tisminetzky MS, Petkova E, Chen Y, Ma G, Klein DF: Are there differences between women’s and men’s antidepressant responses? Am J Psychiatry 2002;159:1848–1854.
  12. Peselow ED, Sanfilipo MP, Difiglia C, Fieve RR: Melancholic/endogenous depression and response to somatic treatment and placebo. Am J Psychiatry 1992;149:1324–1334.
  13. Fava M, Rosenbaum JF: How to write a study protocol: A primer for the clinician; in Fava M, Rosenbaum JF (eds): Research Designs and Methods in Psychiatry, Amsterdam, Elsevier Science, 1992, pp 297–305.
  14. Fava M, Uebelacker LA, Alpert JE, Nierenberg AA, Pava J, Rosenbaum JF: Major depressive subtypes and treatment response. Biol Psychiatry 1997;42:568–576.
  15. Kellner R: The development of sensitive scales for research in therapeutics; in Fava M, Rosenbaum JF (eds): Research Designs and Methods in Psychiatry. Amsterdam, Elsevier Science, 1992, pp 213–222.
  16. Gibbons RD, Clark DC, Kupfer DJ: Exactly what does the Hamilton Depression Rating Scale measure? J Psychiatr Res 1993;27:259–273.
  17. Faries D, Herrera J, Rayamajhi J, DeBrota D, Demitrack M, Potter WZ: The responsiveness of the Hamilton Depression Rating Scale. J Psychiatr Res 2000;34:3–10.
  18. Bech P, Allerup P, Gram LF, Reisby N, Rosenberg R, Jacobsen O, Nagy A: The Hamilton Depression Scale. Evaluation of objectivity using logistic models. Acta Psychiatr Scand 1981;63:290–299.
  19. O’Sullivan RL, Fava M, Agustin C, Baer L, Rosenbaum JF: Sensitivity of the six-item Hamilton Depression Rating Scale. Acta Psychiatr Scand 1997;95:379–384.
  20. Simpson GM, Lee HJ, Cuculic Z, Kellner R: Two dosages of imipramine in hospitalized endogenous and neurotic depressives. Arch Gen Psychiatry 1976;33:1093–1102.
  21. Chmura-Kraemer H, Pruyn JP, Gibbons RD, Greenhouse JB, Grochocinski VJ, Waternaux C, Kupfer DJ: Methodology in psychiatric research. Arch Gen Psychiatry 1987;44:1100–1106.
  22. Hrobjartsson A, Gotzsche PC: Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001;344:1594–1602.
  23. Laird N: Estimating rates of change in clinical studies; in Fava M, Rosenbaum JF (eds): Research Designs and Methods in Psychiatry. Amsterdam, Elsevier Science, 1992, pp 185–193.
  24. Campbell DT, Kenny DA, Reichardt, CS: A Primer on Regression Artifacts. Guilford, New York, 1999.
  25. Shelton RC, Keller MB, Gelenberg A, Dunner DL, Hirschfeld R, Thase ME, Russell J, Lydiard RB, Crits-Cristoph P, Gallop R, Todd L, Hellerstein D, Goodnick P, Keitner G, Stahl SM, Halbreich U: Effectiveness of St. John’s wort in major depression: A randomized controlled trial. JAMA 2001;285:1978–1986.
  26. Chassan JB: Intensive design: Statistics and the single case; in Fava M, Rosenbaum JF (eds): Research Designs and Methods in Psychiatry. Amsterdam, Elsevier Science, 1992, pp 173–183.
  27. Uhlenhuth EH, Turner DA, Purchaske G, Gift T, Chassan JB: Intensive design in evaluating anxiolytic agents. Psychopharmacology 1977;52:79–85.
  28. Fava M: Traditional and alternative research designs and methods in clinical pediatric psychopharmacology. J Am Acad Child Adolesc Psychiatry 1996;35:1292–1303.
  29. Myers ED, Calvert EJ: Information, compliance and side-effects: A study of patients on antidepressant medication.Br J Clin Pharmacol 1984;17:21–25.
  30. Hypericum Depression Trial Study Group: Effect of Hypericum perforatum (St. John’s wort) in major depressive disorder: A randomized controlled trial. JAMA 2002;287:1807–1814.
  31. Kobak KA, Greist JH, Jefferson JW, Mundt JC, Katzelnick DJ: Computerized assessment of depression and anxiety over the telephone using interactive voice response. MD Comput 1999;16:64–68.
  32. Rush AJ, Carmody T, Reimitz, PE: The Inventory of Depressive Symptomatology (IDS): Clinician (IDS-C) and Self-Report (IDS-SR) ratings of depressive symptoms. Int J Methods Psychiatr Res 2000;9:49–59.
  33. DeBrota DJ, Gelwicks SC, Potter WZ: Same rater versus different raters in depression clinical trials. 42nd Annual NCDEU Meeting, Boca Raton, June 10–13 2002.
  34. Trivedi MH, Rush AJ: Does a placebo run-in or a placebo treatment cell affect the efficacy of antidepressant medications? Neuropsychopharmacology 1994;11:33–43.
  35. Faries DE, Heiligenstein JH, Tollefson GD, Potter WZ: The double-blind variable placebo lead-in period: Results from two antidepressant clinical trials. J Clin Psychopharmacol 2001;21:561–568.
  36. Quitkin FM, Rabkin JG, Ross D, Stewart JW: Identification of true drug response to antidepressants: Use pattern analysis. Arch Gen Psychiatry 1984;41:782–786.
  37. Quitkin FM: Methodology of measuring the efficacy of antidepressants. Psychopharmacology (Berl) 1992;106(suppl):S87–S89.
  38. Rao CR: Linear Statistical Inference and Its Applications. New York, Wiley, 1973, pp 1–441.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50