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Placebo pp 273–290Cite as

Lessons to be Learned from Placebo Arms in Psychopharmacology Trials

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 225))

Abstract

Large placebo effects are typically reported in clinical drug trials and evidence suggests placebo effects have increased over time. The diminishing drug–placebo difference calls into question the effectiveness of pharmacological treatments and provides a challenge to prove the effectiveness of new medications. This chapter discusses explanations for the increasing placebo effect. It highlights the contribution of spontaneous remission to the improvement in placebo groups, but focuses particularly on the role of patient and clinician expectations. Certain characteristics of the trial design can influence the formation of patient expectations and, subsequently, true placebo responses. Side effects in clinical trials may also contribute inadvertently to placebo responses. Side effects after starting medication can inform participants about their allocation to an active treatment group. Thus, they may enhance expectations of improvement and contribute to nonspecific effects in clinical trials. It is argued that specific and nonspecific effects interact in drug groups of clinical trials. This interaction influences drug–placebo differences in clinical trials (i.e., trial sensitivity). Future research should aim to identify which patients will respond best to drugs and those who may be better treated with placebos.

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References

  • Alphs L, Benedetti F, Fleischhacker WW, Kane JM (2012) Placebo-related effects in clinical trials in schizophrenia: what is driving this phenomenon and what can be done to minimize it? Int J Neuropsychopharmacol 15:1003–1014

    Article  PubMed  PubMed Central  Google Scholar 

  • Amanzio M, Corazzini LL, Vase L, Benedetti F (2009) A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 146:261–269

    Article  PubMed  CAS  Google Scholar 

  • Arrindell WA (2001) Changes in waiting-list patients over time: data on some commonly-used measures. Beware! Behav Res Ther 39:1227–1247

    Article  PubMed  CAS  Google Scholar 

  • Aulas JJ, Rosner I (2003) Efficacy of a non blind placebo prescription. Encéphale 29:68–71

    PubMed  Google Scholar 

  • Barsky AJ, Saintfort R, Rogers MP, Borus JF (2002) Nonspecific medication side effects and the nocebo phenomenon. JAMA 287:622–627

    Article  PubMed  Google Scholar 

  • Blease C (2010) Deception as treatment: the case of depression. J Med Ethics 37:13

    Article  PubMed  Google Scholar 

  • Bridge JA, Birmaher B, Iyengar S, Barbe RP, Brent DA (2009) Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder. Am J Psychiatry 166:42–49

    Article  PubMed  Google Scholar 

  • Chen Y-F, Wang S-J, Khin NA, Hung HMJ, Laughren TP (2010) Trial design issues and treatment effect modeling in multi-regional schizophrenia trials. Pharm Stat 9:217–229

    Article  PubMed  Google Scholar 

  • Doering BK, Rief W (2013) Nocebos in daily clinical practice: the potential side effects of the treatment context and the patient–doctor interaction on pain in clinical populations. In: Colloca L, Flaten MA, Meissner K (eds) Placebo and pain. Academic, San Diego, pp 257–266

    Chapter  Google Scholar 

  • Enck P, Bingel U, Schedlowski M, Rief W (2013) The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov 12:191–204

    Article  PubMed  CAS  Google Scholar 

  • Fava M, Evins AE, Dorer DJ, Schoenfeld DA (2003) The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother Psychosom 72:115–127

    Article  PubMed  Google Scholar 

  • Fountoulakis K, Veroniki A, Siamouli M, Moller H-J (2013) No role for initial severity on the efficacy of antidepressants: results of a multi-meta-analysis. Ann Gen Psychiatry 12:26

    Article  PubMed  PubMed Central  Google Scholar 

  • Gueorguieva R, Mallinckrodt C, Krystal JH (2011) Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressant and placebo responses. Arch Gen Psychiatry 68:1227–1237

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hill AB (1990) Suspended judgment. Memories of the British streptomycin trial in tuberculosis. The first randomized clinical trial. Control Clin Trials 11:77–79

    Article  PubMed  CAS  Google Scholar 

  • Horder J, Matthews P, Waldmann R (2010) Placebo, Prozac and PLoS: significant lessons for psychopharmacology. J Psychopharmacol 25:1277–1288

    Article  PubMed  Google Scholar 

  • Hrobjartsson A, Gotzsche PC (2004) Placebo interventions for all clinical conditions. Cochrane Database Syst Rev:Cd003974

    Google Scholar 

  • Hunter AM, Cook IA, Leuchter AF (2010) Impact of antidepressant treatment history on clinical outcomes in placebo and medication treatment of major depression. J Clin Psychopharmacol 30:748–751

    Article  PubMed  Google Scholar 

  • Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, Singer JP, Kowalczykowski M, Miller FG, Kirsch I, Lembo AJ (2010) Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS ONE 5:e15591

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kelley JM, Kaptchuk TJ, Cusin C, Lipkin S, Fava M (2012) Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychother Psychosom 81:312–314

    Article  PubMed  Google Scholar 

  • Kemp AS, Schooler NR, Kalali AH, Alphs L, Anand R, Awad G, Davidson M, Dube S, Ereshefsky L, Gharabawi G, Leon AC, Lepine JP, Potkin SG, Vermeulen A (2010) What is causing the reduced drug-placebo difference in recent schizophrenia clinical trials and what can be done about it? Schizophr Bull 36:504–509

    Article  PubMed  PubMed Central  Google Scholar 

  • Khin NA, Chen YF, Yang Y, Yang P, Laughren TP (2011) Exploratory analyses of efficacy data from major depressive disorder trials submitted to the US Food and Drug Administration in support of new drug applications. J Clin Psychiatry 72:464–472

    Article  PubMed  Google Scholar 

  • Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT (2008) Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 5:e45

    Article  PubMed  PubMed Central  Google Scholar 

  • Krogsboll LT, Hrobjartsson A, Gotzsche PC (2009) Spontaneous improvement in randomised clinical trials: meta-analysis of three-armed trials comparing no treatment, placebo and active intervention. BMC Med Res Methodol 9:1

    Article  PubMed  PubMed Central  Google Scholar 

  • Laughren TP (2001) The scientific and ethical basis for placebo-controlled trials in depression and schizophrenia: an FDA perspective. Eur Psychiatry 16:418–423

    Article  PubMed  CAS  Google Scholar 

  • Leucht S, Arbter D, Engel RR, Kissling W, Davis JM (2009) How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 14:429–447

    Article  PubMed  CAS  Google Scholar 

  • Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, Davis JM (2012) Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 379:2063–2071

    Article  PubMed  CAS  Google Scholar 

  • Margraf J, Ehlers A, Roth WT, Clark DB, Sheikh J, Agras WS, Taylor CB (1991) How “blind” are double-blind studies? J Consult Clin Psychol 59:184–187

    Article  PubMed  CAS  Google Scholar 

  • Miller FG, Colloca L (2009) The legitimacy of placebo treatments in clinical practice: evidence and ethics. Am J Bioeth 9:39–47

    Article  PubMed  Google Scholar 

  • Mitsikostas DD, Chalarakis NG, Mantonakis LI, Delicha E-M, Sfikakis PP (2012) Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for clinical practice. Eur J Neurol 19:672–680

    Article  PubMed  CAS  Google Scholar 

  • Moncrieff J, Wessely S, Hardy R (2004) Active placebos versus antidepressants for depression. Cochrane Database Syst Rev:CD003012

    Google Scholar 

  • Mora MS, Nestoriuc Y, Rief W (2011) Lessons learned from placebo groups in antidepressant trials. Philos Trans R Soc Lond B Biol Sci 366:1879–1888

    Article  PubMed  PubMed Central  Google Scholar 

  • Papakostas GI, Fava M (2009) Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol 19:34–40

    Article  PubMed  CAS  Google Scholar 

  • Park LC, Covi L (1965) Nonblind placebo trial: an exploration of neurotic patients’ responses to placebo when its inert content is disclosed. Arch Gen Psychiatry 12:36–45

    PubMed  CAS  Google Scholar 

  • Pope A, Adams C, Paton C, Weaver T, Barnes TR (2010) Assessment of adverse effects in clinical studies of antipsychotic medication: survey of methods used. Br J Psychiatry 197:67–72

    Article  PubMed  Google Scholar 

  • Potkin S, Agid O, Siu C, Watsky E, Vanderburg D, Remington G (2011) Placebo response trajectories in short-term and long-term antipsychotic trials in schizophrenia. Schizophr Res 132:108–113

    Article  PubMed  Google Scholar 

  • Price DD, Finniss DG, Benedetti F (2008) A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol 59:565–590

    Article  PubMed  Google Scholar 

  • Rhebergen D, Beekman ATF, Rd G, Nolen WA, Spijker J, Hoogendijk WJ, Penninx BWJH (2009) The three-year naturalistic course of major depressive disorder, dysthymic disorder and double depression. J Affect Disord 115:450–459

    Article  PubMed  Google Scholar 

  • Rhebergen D, Batelaan NM, de Graaf R, Nolen WA, Spijker J, Beekman ATF, Penninx BWJH (2011) The 7-year course of depression and anxiety in the general population. Acta Psychiat Scand 123:297–306

    Article  PubMed  CAS  Google Scholar 

  • Rief W, Glombiewski JA (2012) The hidden effects of blinded, placebo-controlled randomized trials: an experimental investigation. Pain 153:2473–2477

    Article  PubMed  Google Scholar 

  • Rief W, Avorn J, Barsky AJ (2006) Medication-attributed adverse effects in placebo groups. Arch Intern Med 166:155–160

    Article  PubMed  Google Scholar 

  • Rief W, Nestoriuc Y, von Lilienfeld-Toal A, Hofmann SG, Barsky AJ, Avorn J (2009a) Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials: a systematic review and meta-analysis. Drug Saf 32:1041–1056

    Article  PubMed  CAS  Google Scholar 

  • Rief W, Nestoriuc Y, Weiss S, Welzel E, Barsky AJ, Hofmann SG (2009b) Meta-analysis of the placebo response in antidepressant trials. J Affect Disord 118:1–8

    Article  PubMed  CAS  Google Scholar 

  • Rief W, Barsky AJ, Glombiewski JA, Nestoriuc Y, Glaesmer H, Braehler E (2011a) Assessing general side effects in clinical trials: reference data from the general population. Pharmacoepidem Drug Saf 20:405–415

    Article  Google Scholar 

  • Rief W, Bingel U, Schedlowski M, Enck P (2011b) Mechanisms involved in placebo and noceco responses and implications for drug trials. Clin Pharmacol Ther 90:722–726

    Article  PubMed  CAS  Google Scholar 

  • Rutherford BR, Mori S, Sneed JR, Pimontel MA, Roose SP (2012a) Contribution of spontaneous improvement to placebo response in depression: a meta-analytic review. J Psychiatr Res 46:697–702

    Article  PubMed  PubMed Central  Google Scholar 

  • Rutherford BR, Sneed JR, Roose SP (2012b) Does differential drop-out explain the influence of study design on antidepressant response? A meta-analysis. J Affect Disord 140:57–65

    Article  PubMed  PubMed Central  Google Scholar 

  • Rutherford BR, Marcus SM, Wang P, Sneed JR, Pelton G, Devanand D, Duan N, Roose SP (2013) A randomized, prospective pilot study of patient expectancy and antidepressant outcome. Psychol Med 43:975–982

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sandler AD, Bodfish JW (2005) Open-label use of placebos in the treatment of ADHD: a pilot study. Child Care Hlth Dev 34:104–110

    Article  Google Scholar 

  • Sandler AD, Glesne CE, Bodfish JW (2010) Conditioned placebo dose reduction: a new treatment in attention-deficit hyperactivity disorder? J Dev Behav Pediatr 31:369–375

    Article  PubMed  PubMed Central  Google Scholar 

  • Shelton RC, Keller MB, Gelenberg A, Dunner DL, Hirschfeld R, Thase ME, Russell J, Lydiard RB, Crits-Christoph P, Gallop R, Todd L, Hellerstein D, Goodnick P, Keitner G, Stahl SM, Halbreich U (2001) Effectiveness of St. John’s worth in major depression: a randomized controlled trial. JAMA 285:1978–1986

    Article  PubMed  CAS  Google Scholar 

  • Sinyor M, Levitt AJ, Cheung AH, Schaffer A, Kiss A, Dowlati Y, Lanctot KL (2010) 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 71:270–279

    Article  PubMed  CAS  Google Scholar 

  • Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (2008) Selective publication of antidepressant trials and its influence on apparent efficacy. New Engl J Med 358:252–260

    Article  PubMed  CAS  Google Scholar 

  • Walsh BT, Seidman SN, Sysko R, Gould M (2002) Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287:1840–1847

    Article  PubMed  Google Scholar 

  • Wells R, Kaptchuk TJ (2012) To tell the truth, the whole truth, may do patients harm: the problem of the nocebo effect for informed consent. Am J Bioeth 12:22–29

    Article  PubMed  PubMed Central  Google Scholar 

  • Wells KB, Burnam MA, Rogers W, Hays R, Camp P (1992) The course of depression in adult outpatients. Results from the medical outcomes study. Arch Gen Psychiatry 49:788–794

    Article  PubMed  CAS  Google Scholar 

  • Woods SW, Gueorguieva RV, Baker CB, Makuch RW (2005) Control group bias in randomized atypical antipsychotic medication trials for schizophrenia. Arch Gen Psychiatry 62:961–970

    Article  PubMed  Google Scholar 

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Correspondence to Bettina K. Doering .

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Doering, B.K., Rief, W., Petrie, K.J. (2014). Lessons to be Learned from Placebo Arms in Psychopharmacology Trials. In: Benedetti, F., Enck, P., Frisaldi, E., Schedlowski, M. (eds) Placebo. Handbook of Experimental Pharmacology, vol 225. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44519-8_15

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