Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression

BMC Medicine

Michael Bauer¹  Hans-Jürgen Möller⁴  Sophia Frangou³  Michael Riedel²  Andrea Pfennig¹  Michael Obermeier⁴  Sandra Dittmann⁴  Michael Berger⁴  Florian Seemüller⁴  Emanuel Severus⁴ 

[1] Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany;Vinzenz von Paul Hospital, Schwenninger Str. 55, 78628 Rottweil, Germany;Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK;Department of Psychiatry and Psychotherapy, LMU Munich, Nussbaumstr. 7, 80336 Munich, Germany

关键词: psychopharmacology;    randomized controlled trials;    clinical trials;    major depression;   

Others  :  1126066
DOI  :  10.1186/1741-7015-10-67

 received in 2012-01-04, accepted in 2012-07-02,  发布年份 2012

【 摘 要 】

Background

Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection.

Discussion

To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population.

Summary

We propose a list of measures to be taken to improve the external validity of double-blind, placebo-controlled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself.

【 授权许可】

   
2012 Severus et al; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Kennedy SH, Lam RW, Parikh SV, Patten SB, Ravindran AV: Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. Introduction. J Affect Disord 2009, 117(Suppl 1):S1-S2.
• [2]Patten SB, Kennedy SH, Lam RW, O'Donovan C, Filteau MJ, Parikh SV, Ravindran AV, Canadian Network for Mood and Anxiety Treatments (CANMAT): Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. I. Classification, burden and principles of management. J Affect Disord 2009, 117(Suppl 1):S5-14.
• [3]Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jonsson B, Olesen J, Allgulander C, Alonso J, Faravelli C, Fratiglioni L, Jennum P, Lieb R, Maercker A, van Os J, Preisig M, Salvador-Carulla L, Simon R, Steinhausen HC: The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011, 21:655-679.
• [4]Moller HJ, Bitter I, Bobes J, Fountoulakis K, Hoschl C, Kasper S: Position statement of the European Psychiatric Association (EPA) on the value of antidepressants in the treatment of unipolar depression. Eur Psychiatry 2012, 27:114-128.
• [5]Lam RW, Kennedy SH, Grigoriadis S, McIntyre RS, Milev R, Ramasubbu R, Parikh SV, Patten SB, Ravindran AV, Canadian Network for Mood and Anxiety Treatments (CANMAT): Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord 2009, 117(Suppl 1):S26-S43.
• [6]Moller HJ: Are placebo-controlled studies required in order to prove efficacy of antidepressants? World J Biol Psychiatry 2005, 6:130-131.
• [7]Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS: Evidence based medicine: what it is and what it isn't. BMJ 1996, 312:71-72.
• [8]Hegerl U, Allgaier AK, Henkel V, Mergl R: Can effects of antidepressants in patients with mild depression be considered as clinically significant? J Affect Disord 2012, 138:183-191.
• [9]Sinyor M, Levitt AJ, Cheung AH, Schaffer A, Kiss A, Dowlati Y, Lanctot KL: Does inclusion of a placebo arm influence response to active antidepressant treatment in randomized controlled trials? Results from pooled and meta-analyses. J Clin Psychiatry 2010, 71:270-279.
• [10]Rutherford BR, Sneed JR, Roose SP: Does study design influence outcome? The effects of placebo control and treatment duration in antidepressant trials. Psychother Psychosom 2009, 78:172-181.
• [11]Papakostas GI, Fava M: Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol 2009, 19:34-40.
• [12]Odgaard-Jensen J, Vist GE, Timmer A, Kunz R, Akl EA, Schunemann H, Briel M, Nordmann AJ, Pregno S, Oxman AD: Randomisation to protect against selection bias in healthcare trials. Cochrane Database Syst Rev 2011., (4) MR000012
• [13]Parker G: Antidepressants on trial: how valid is the evidence? Br J Psychiatry 2009, 194:1-3.
• [14]Seemuller F, Moller HJ, Obermeier M, Adli M, Bauer M, Kronmuller K, Holsboer F, Brieger P, Laux G, Bender W, Heuser I, Zeiler J, Gaebel W, Schennach-Wolff R, Henkel V, Riedel M: Do efficacy and effectiveness samples differ in antidepressant treatment outcome? an analysis of eligibility criteria in randomized controlled trials. J Clin Psychiatry 2010, 71:1425-1433.
• [15]Wisniewski SR, Rush AJ, Nierenberg AA, Gaynes BN, Warden D, Luther JF, McGrath PJ, Lavori PW, Thase ME, Fava M, Trivedi MH: Can phase III trial results of antidepressant medications be generalized to clinical practice? A STAR*D report. Am J Psychiatry 2009, 166:599-607.
• [16]Jones R, Jones RO, McCowan C, Montgomery AA, Fahey T: The external validity of published randomized controlled trials in primary care. BMC Fam Pract 2009, 10:5. BioMed Central Full Text
• [17]Gross CP, Mallory R, Heiat A, Krumholz HM: Reporting the recruitment process in clinical trials: who are these patients and how did they get there? Ann Intern Med 2002, 137:10-16.
• [18]Largent EA, Joffe S, Miller FG: Can research and care be ethically integrated? Hastings Cent Rep 2011, 41:37-46.
• [19]Loh A, Simon D, Wills CE, Kriston L, Niebling W, Harter M: The effects of a shared decision-making intervention in primary care of depression: a cluster-randomized controlled trial. Patient Educ Couns 2007, 67:324-332.
• [20]Drake RE, Cimpean D, Torrey WC: Shared decision making in mental health: prospects for personalized medicine. Dialogues Clin Neurosci 2009, 11:455-463.
• [21]Brody H, Colloca L, Miller FG: The placebo phenomenon: implications for the ethics of shared decision-making. J Gen Intern Med 2012, 27:739-742.
• [22]Colloca L, Miller FG: Role of expectations in health. Curr Opin Psychiatry 2011, 24:149-155.
• [23]Hegerl U, Mergl R: The clinical significance of antidepressant treatment effects cannot be derived from placebo-verum response differences. J Psychopharmacol 2010, 24:445-448.
• [24]Moller HJ, Maier W: Evidence-based medicine in psychopharmacotherapy: possibilities, problems and limitations. Eur Arch Psychiatry Clin Neurosci 2010, 260:25-39.
• [25]Hrobjartsson A, Kaptchuk TJ, Miller FG: Placebo effect studies are susceptible to response bias and to other types of biases. J Clin Epidemiol 2011, 64:1223-1229.
• [26]Colloca L, Lopiano L, Lanotte M, Benedetti F: Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol 2004, 3:679-684.
• [27]Brody H, Miller FG: Lessons from recent research about the placebo effect--from art to science. JAMA 2011, 306:2612-2613.
• [28]Posternak MA, Zimmerman M: Therapeutic effect of follow-up assessments on antidepressant and placebo response rates in antidepressant efficacy trials: meta-analysis. Br J Psychiatry 2007, 190:287-292.
• [29]Miller FG, Colloca L: The placebo phenomenon and medical ethics: rethinking the relationship between informed consent and risk-benefit assessment. Theor Med Bioeth 2011, 32:229-243.
• [30]Krell HV, Leuchter AF, Morgan M, Cook IA, Abrams M: Subject expectations of treatment effectiveness and outcome of treatment with an experimental antidepressant. J Clin Psychiatry 2004, 65:1174-1179.
• [31]Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C: Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009, 373:746-758.
• [32]Cipriani A, Furukawa TA, Geddes JR, Malvini L, Signoretti A, McGuire H, Churchill R, Nakagawa A, Barbui C, MANGA Study Group: Does randomized evidence support sertraline as first-line antidepressant for adults with acute major depression? A systematic review and meta-analysis. J Clin Psychiatry 2008, 69:1732-1742.
• [33]Severus E, Lipkovich I, Seemuller F, Obermeier M, Grunze H, Bernhard B, Dittmann S, Riedel M, Möller HJ: The potential role of Marginal Structural Models (MSMs) in testing the effectiveness of antidepressants in the treatment of patients with major depression in everyday clinical practice. World J Biol Psychiatry, in press.
• [34]Wechsler ME, Kelley JM, Boyd IO, Dutile S, Marigowda G, Kirsch I, Israel E, Kaptchuk TJ: Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med 2011, 365:119-126.
• [35]Moerman DE: Meaningful placebos--controlling the uncontrollable. N Engl J Med 2011, 365:171-172.