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Special Article

Methodological Issues in Clinical Trials of Antidepressant Medications: Perspectives from Psychotherapy Outcome Research

Gaudiano B.A.a · Herbert J.D.b

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aDepartment of Psychiatry and Human Behavior, Brown University School of Medicine and Butler Hospital, Providence, R.I., and bDepartment of Psychology, Drexel University, Philadelphia, Pa., USA

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Psychother Psychosom 2005;74:17–25

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Article / Publication Details

First-Page Preview
Abstract of Special Article

Published online: December 23, 2004
Issue release date: December 2004

Number of Print Pages: 9
Number of Figures: 0
Number of Tables: 1

ISSN: 0033-3190 (Print)
eISSN: 1423-0348 (Online)

For additional information: https://www.karger.com/PPS

Abstract

Despite their widespread use, the specific efficacy of antidepressant medications has been a source of debate in recent years. Examination of the literature reveals that a significant proportion of the benefit produced in antidepressant trials is duplicated in pill placebo conditions. Furthermore, early trials utilizing active placebos, or medications that mimic the common side effects of antidepressants, showed even smaller differences as compared with active medications. We examine issues surrounding the use of placebo control conditions in antidepressant trials, including the pros and cons of active placebos. We conclude that similar challenges are faced by psychotherapy outcome researchers who have focused more on the separation of specific from nonspecific treatment factors and on the effects of researcher allegiance and patient expectancy on outcome. Within this context, recommendations for improving future antidepressant research are discussed.

© 2005 S. Karger AG, Basel


References

  1. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS: The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095–3105.
  2. Antonuccio DO, Danton WG, DeNelsky GY, Greenberg RP, Gordon JS: Raising questions about antidepressants. Psychother Psychosom 1999;68:3–14.
  3. Department of Health: Prescription Cost Analysis 1997. London, HMSO, 1998.
  4. Gaudiano BA, Herbert JD: The antidepressant-placebo debate in the media: Balanced coverage or placebo hype? Sci Rev Ment Health Pract 2003;2:74–77.
  5. Leber P: The use of placebo control groups in the assessment of psychiatric drugs: An historical context. Biol Psychiatry 2000;47:699–706.
  6. Lohr JM, DeMaio C, McGlynn FD: Specific and nonspecific treatment factors in the experimental analysis of behavioral treatment efficacy. Behav Modif 2003;27:322–368.
  7. White L, Tursky B, Schwartz GE: Placebo: Theory, Research, and Mechanisms. New York, Guilford, 1985.
  8. Greenberg RP, Bornstein RF, Greenberg MD, Fisher S: A meta-analysis of antidepressant outcome under ‘blinder’ conditions. J Consult Clin Psychol 1992;60:664–669.
  9. Quitkin FM, Rabkin JG, Gerald J, Davis JM, Klein DF: Validity of clinical trials of antidepressants. Am J Psychiatry 2000;157:327–337.
  10. Kirsch I, Sapirstein G: Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication. Prevention & Treatment 1998;1:Article 0002a. Retrieved from: http:// journals.apa.org/prevention/volume1/pre0010002a.html.
  11. Klein DF: Listening to meta-analysis but hearing bias. Prevention & Treatment 1998;1:Article 0006c. Retrieved from: http://journals.apa.org/prevention/volume1/pre0010006c.html.
  12. Klein DF: Reply to Kirsch’s rejoinder regarding antidepressant meta-analysis. Prevention & Treatment 1998;1:Article 0008r. Retrieved from: http://journals.apa.org/prevention/volume1/pre0010008r.html.
  13. Kirsch I: Reducing noise and hearing placebo more clearly. Prevention & Treatment 1998;1:Article 0007r. Retrieved from: http://journals.apa.org/prevention/volume1/pre0010009r.html.
  14. Kirsch I: On the importance of reading carefully: A response to Klein. Prevention & Treatment 1998;1:Article 0009r. Retrieved from: http://journals.apa.org/prevention/volume1/pre0010009r.html.
  15. Kirsch I, Moore TJ, Scoboria A, Nicholls SS: The emperor’s new drugs: An analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment 2002;5:Article 23. Retrieved from: http://journals.apa.org/prevention/volume5/pre0050023a.
  16. Rosenthal R: The ‘file drawer problem’ and tolerance for null results. Psychol Bull 1979;86:638–641.
    External Resources
  17. Thase ME: Small effects are not trivial from a public health perspective. Psychiatric Times 2003;19(9). Retrieved from: http://www.psychiatrictimes.com/p020909.html.
  18. Smith D, Dempster C, Glanville J, Freemantle N, Anderson I: Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: A meta-analysis. Br J Psychiatry 2002;180:396–404.
  19. 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.
  20. Walsh BT, Seidman SN, Sysko R, Gould M: Placebo response in studies of major depression: Variable, substantial, and growing. JAMA 2002;287:1840–1847.
  21. Greenberg RP, Fisher S: Examining antidepressant effectiveness: Findings, ambiguities, and some vexing puzzles; in Fisher S (ed): The Limits of Biological Treatment for Psychological Distress: Comparisons with Psychotherapy and Placebo. Hillsdale, Erlbaum, 1989, pp 1–37.
  22. Double DB: Unblinding in trials of the withdrawal of anticholinergic agents in patients maintained on neuroleptics. J Nerv Ment Dis 1995;183:599–602.
  23. Bystritsky A, Waikar SV: Inert placebo versus active medication: Patient blindability in clinical pharmacological trials. J Nerv Ment Dis 1994;182:485–487.
  24. White K, Kando J, Park T, Waternaux C, Brown WA: Side effects and the ‘blindability’ of clinical drug trials. Am J Psychiatry 1992;149:1730–1731.
  25. Piasecki MP, Antonuccio DO, Steinagel GM, Kohlenberg BS, Kafadar K: Penetrating the blind in a study of an SSRI. J Behav Ther Exp Psychiatry 2002;33:67–71.
  26. Sharpe L, Ryan B, Allard S, Sensky T: Testing for the integrity of blinding in clinical trials: How valid are forced choice paradigms? Psychother Psychosom 2003;72:128–131.
  27. Basoglu M, Marks I, Livanou M, Swinson R: Double-blindness procedures, rater blindness, and ratings of outcome: Observations from a controlled trial. Arch Gen Psychiatry 1997;54:744–748.
  28. Thomson R: Side effects and placebo amplification. Br J Psychiatry 1982;140:64–68.
  29. Moncrieff J, Wessley S, Hardy R: Meta-analysis of trials comparing antidepressants with active placebos. Br J Psychiatry 1998;172:227–231.
  30. Moncrieff J, Wessely S, Hardy R: Active placebos versus antidepressants for depression (Cochrane Review). The Cochrane Library 2002, issue 1. Oxford, Update Software.
  31. Quitkin FM: Placebos, drug effects, and study design: A clinician’s guide. Am J Psychiatry 1999;156:829–836.
  32. Cooney JM: Active placebos in antidepressant trials. Br J Psychiatry 1998;172:541–542.
  33. Salamone JD: A critique of recent studies on placebo effects of antidepressants: Importance of research on active placebos. Psychopharmacology 2000;152:1–6.
  34. Klein DF: Flawed meta-analyses comparing psychotherapy with pharmacology. Am J Psychiatry 2000;157:1204–1211.
  35. Otto MW, Nierenberg AA: Assay sensitivity, failed clinical trials, and the conduct of science. Psychother Psychosom 2002;71:241–243.
  36. Moncrieff J: Are antidepressants overrated? A review of methodological problems in antidepressant trials. J Nerv Ment Dis 2001;198:288–295.
    External Resources
  37. Tedlow J, Fava M, Uebelacker J, Nierenberg AA, Alpert JE, Rosenbaum J: Outcome definitions and predictors in depression. Psychother Psychosom 1998;67:266–270.
  38. Sensky T: The utility of systematic reviews: The case of psychological debriefing after trauma. Psychother Psychom 2003;72:171–175.
  39. Khan A, Warner HA, Brown WA: Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: An analysis of the Food and Drug Administration database. Arch Gen Psychiatry 2000;57:311–317.
  40. Healy D: Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors. Psychother Psychosom 2003;72:71–79.
  41. Schatzberg AF, Cole JO: Benzodiazepines in depressive disorders. Arch Gen Psychiatry 1978;35:1359–1365.
  42. Klein DF, Thase ME, Endicott J, Adler L, Glick I, Kalali A, Leventer S, Mattes J, Ross P, Bystritsky A: Improving clinical trials: American Society of Clinical Psychopharmacology recommendations. Arch Gen Psychiatry 2002;59:272–278.
  43. Fava M, Evins AE, Dorer DJ, Shoenfeld DA: The problem of the placebo response in clinical trials for psychiatric disorders: Culprits, possible remedies, and a novel study design approach. Psychother Psychosom 2003;72:115–127.
  44. TenHave TR, Coyne J, Salzer M, Katz I: Research to improve the quality of care for depression: Alternatives to the simple randomized clinical trial. Gen Hosp Psychiatry 2003;25:115–123.
  45. Luborsky L, Diguer L, Seligman DA, Rosenthal R, Krause ED, Johnson S, Halperin G, Bishop M, Berman JS, Schweizer E: The researcher’s own therapy allegiances: A ‘wild card’ in comparisons of treatment efficacy. Clin Psychol Sci Pract 1999;6:95–106.
    External Resources
  46. Herbert JD: The science and practice of empirically supported treatments. Behav Modif 2003;27:412–430.
  47. Benedetti F, Maggi G, Lopiano L: Open versus hidden medical treatments: The patient’s knowledge about a therapy affects the therapy outcome. Prevention & Treatment 2003;6:Article 1. Retrieved from: http://journals.apa.org/prevention/volume6/pre0060001a.html.
  48. Miller JL, Delgado PL, Salomon RM, Berman R, Krystal JH, Heninger GR, Charney DS: Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry 1996;53:117–128.
  49. Young LT, Bakish D, Beaulieu S: The neurobiology of treatment response to antidepressants and mood stabilizing medications. J Psychiatry Neurosci 2002;27:260–265.
  50. Kazdin AE: Research Design in Clinical Psychology, ed 3. Boston, Allyn & Bacon, 1998.
  51. Borkovec TD, Newman MG, Pincus AL, Lytle R: A component analysis of cognitive-behavioral therapy for generalized anxiety disorder and the role of interpersonal problems. J Consult Clin Psychol 2002;70:288–298.
  52. Fava GA: Conflict in interest in psychopharmacology: Can Dr. Jekyll still control Mr. Hyde? Psychother Psychosom 2004;73:1–4.
  53. Kjaergard LL, Als-Nielsen B : Association between competing interests and authors’ conclusions: Epidemiological study of randomized clinical trials published in the BMJ. BMJ 2002;325:249.
  54. Kirsch I, Lynn SJ: Automaticity in clinical psychology. Am Psychol 1999;54:504–515.
  55. Holt CS, Heimberg RG: The Reaction to Treatment Questionnaire: Measuring treatment credibility and outcome expectancies. Behav Ther 1990;13:213–214.
  56. Antonuccio DO, Burns DD, Danton WG: Antidepressants: A triumph of marketing over science? Prevention & Treatment 2002;5:Article 25. Retrieved from: http://journals.apa.org/prevention/volume5/pre0050025c.html.
    External Resources
  57. Even C, Siobud-Dorocant E, Dardennes RM: Critical approach to antidepressant trials: Blindness protection is necessary, feasible, and measurable. Br J Psychiatry 2000;177:47–51.
  58. Petkova E, Quitkin FM, McGrath PJ, Stewart JW, Klein DF: A method to quantify rater bias in antidepressant trials. Neuropsychopharmacology 2000;22:559–565.
  59. Katz RJ, Deveaugh-Geiss J: The issue of side effects and the ‘blindability’ of clinical drug trials. Am J Psychiatry 1994;150:1759–1760.
  60. Ross DC, Quitkin FM, Klein DF: A typological model for estimation of drug and placebo effects in depression. J Clin Psychopharmacol 2002;22:414–418.
  61. Stassen HH, Delini-Stula A, Angst J: Time course of improvement under antidepressant treatment: A survival-analytical approach. Eur Neuropsychopharmacol 1993;3:127–135.
  62. Herbert JD, Rheingold AA, Gaudiano BA, Harwell VD: Standard versus extended cognitive behavior therapy for social anxiety disorder: A randomized-controlled trial. Behav Cogn Psychother 2004;32:131–147.
    External Resources
  63. Haynes SN, O’Brien WH: Principles and Practice of Behavioral Assessment. New York, Kluwer/Plenum Press, 2000.
  64. Herbert JD, Rheingold AA, Brandsma LL: Assessment of social anxiety and social phobia; in Hofmann SG, DiBartolo PM (eds): From Social Anxiety to Social Phobia: Multiple Perspectives. New York, Guilford, 2001, pp 20–45.
  65. Jacobson NS, Truax P: Clinical significance: A statistical approach to defining meaningful change in psychotherapy research. J Consult Clin Psychol 1991;59:12–19.
  66. Möller HJ: Methodological aspects in the assessment of severity of depression by the Hamilton Depression Scale. Eur Arch Psychiatry Clin Neurosci 2001;251(Suppl 2):II13–II20.
    External Resources
  67. Beck AT, Rush AJ, Shaw BF, Emery G: Cognitive Therapy of Depression. New York, Guilford, 1979.
  68. Jacobson NS, Dobson KS, Truax PA, Addis ME, Koerner K, Gollan JK, Gortner E, Prince SE: A component analysis of cognitive-behavioral treatment for depression. J Consult Clin Psychol 1996;64:295–304.
  69. Kendall PC, Holmbeck G, Verduin T: Methodology, design, and evaluation in psychotherapy research; in Lamberg MJ (ed): Bergin and Garbield’s Handbook of Psychotherapy and Behavior Change, ed 5. New York, Wiley, 2004, p 43.
  70. Moher D, Schulz KF, Altman DG: The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomized trials. Ann Intern Med 2001;134:657–662.

Article / Publication Details

First-Page Preview
Abstract of Special Article

Published online: December 23, 2004
Issue release date: December 2004

Number of Print Pages: 9
Number of Figures: 0
Number of Tables: 1

ISSN: 0033-3190 (Print)
eISSN: 1423-0348 (Online)

For additional information: https://www.karger.com/PPS


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