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Placebo Effects and Clinical Trials of Neuropsychiatric Drugs  

Kim, Sung-Wan (Department of Psychiatry, Chonnam National University Medical School)
Jang, Ji-Eun (Department of Psychiatry, Chonnam National University Medical School)
Yoon, Jin-Sang (Department of Psychiatry, Chonnam National University Medical School)
Publication Information
Korean Journal of Biological Psychiatry / v.19, no.4, 2012 , pp. 164-171 More about this Journal
Abstract
The placebo effect, a response observed during the placebo arm of a clinical trial, is produced by the psychobiological action of the placebo as well as by other potential contributors to symptom amelioration such as spontaneous improvement, regression to the mean, biases, concurrent treatments, and study design. From a psychological viewpoint, there are many mechanisms that contribute to placebo effects, including expectations, conditioning, learning, and anxiety reduction. Placebo responses are also mediated by opioid and non-opioid mechanisms including dopamine, serotonin, cholecystokinin, and immune mediators. During recent years, a trend towards increased placebo effects in clinical trials of neuropsychiatric drugs has been noted. Indeed, the placebo effects observed in clinical trials constitute an increasing problem and interfere with signal-detection analyses of potential treatments. Several potential factors including protocol/study design and conduct related factors may account for the placebo effect observed in clinical trials. This paper reviews key issues related to this problem and aims to identify potential solutions.
Keywords
Placebo; Clinical trial; Neuropsychiatric drugs; Antipsychotics;
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1 Price DD, Finniss DG, Benedetti F. A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol 2008;59:565-590.   DOI   ScienceOn
2 Benedetti F, Amanzio M. The placebo response: how words and rituals change the patient's brain. Patient Educ Couns 2011;84:413-419.   DOI   ScienceOn
3 Alphs L, Benedetti F, Fleischhacker WW, Kane JM. Placebo-related effects in clinical trials in schizophrenia: what is driving this phenomenon and what can be done to minimize it? Int J Neuropsychopharmacol 2012;15:1003-1014.   DOI   ScienceOn
4 Kemp AS, Schooler NR, Kalali AH, Alphs L, Anand R, Awad G, et al. What is causing the reduced drug-placebo difference in recent schizophrenia clinical trials and what can be done about it? Schizophr Bull 2010;36:504-509.   DOI   ScienceOn
5 Benedetti F. Placebo effects: understanding the mechanisms in health and disease. New York: Oxford University Press;2009. p.38-46.
6 Benedetti F. Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu Rev Pharmacol Toxicol 2008;48:33-60.   DOI   ScienceOn
7 Kirsch I. Response expectancy as a determinant of experience and behavior. American Psychologist 1985;40:1189-1202.   DOI
8 Price DD, Fields HL. The Contribution of Desire and Expectation to Placebo Analgesia: Implications for New Research Strategies. In: Harrington A, editor. The Placebo Effect: An Interdisciplinary Exploration. Cambridge, MA: Harvard UP;1997. p.117-137.
9 Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, Nicholls SS. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain 1999;83:147-156.   DOI   ScienceOn
10 Evans FJ. The Placebo Response in Pain Reduction. In: Bonica JJ, editor. Advances in Neurology. New York: Raven Press;1974. p.289- 296.
11 Benedetti F, Amanzio M, Maggi G. Potentiation of placebo analgesia by proglumide. Lancet 1995;346:1231.   DOI   ScienceOn
12 Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain 2001;90:205-215.   DOI   ScienceOn
13 Price DD, Barrell JJ. Mechanisms of analgesia produced by hypnosis and placebo suggestions. Prog Brain Res 2000;122:255-271.
14 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.   DOI   ScienceOn
15 Price DD, Barrell JE, Barrell JJ. A quantitative-experiential analysis of human emotions. Motiv Emot 1985;9:19-38.   DOI   ScienceOn
16 Price DD, Riley J, Barrell JJ. Are lived choices based on emotional processes? Cogn Emot 2001;15:365-379.   DOI
17 Geers AL, Helfer SG, Weiland PE, Kosbab K. Expectations and placebo response: a laboratory investigation into the role of somatic focus. J Behav Med 2006;29:171-178.   DOI   ScienceOn
18 Brody HB, Brody D. Placebo and health--II. Three perspectives on the placebo response: expectancy, conditioning, and meaning. Adv Mind Body Med 2000;16:216-232.
19 McGlashan TH, Evans FJ, Orne MT. The nature of hypnotic analgesia and placebo response to experimental pain. Psychosom Med 1969;31:227-246.   DOI
20 Vase L, Robinson ME, Verne GN, Price DD. Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms. Pain 2005;115:338-347.   DOI   ScienceOn
21 Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, Ingvar M. Placebo in emotional processing--induced expectations of anxiety relief activate a generalized modulatory network. Neuron 2005;46:957-969.   DOI   ScienceOn
22 Gliedman LH, Gantt WH, Teitelbaum HA. Some implications of conditional reflex studies for placebo research. Am J Psychiatry 1957;113:1103-1107.   DOI
23 Siegel S. Explanatory Mechanisms for Placebo Effects: Pavlovian Conditioning. In: Guess HA, Kleinman A, Kusek JW, Engel LW, editors. The Science of the Placebo: Toward an Interdisciplinary Research Agenda. London: BMJ Books;2002. p.133-157.
24 Herrnstein RJ. Placebo effect in the rat. Science 1962;138:677-678.   DOI
25 Wickramasekera I. A conditioned response model of the placebo effect predictions from the model. Biofeedback Self Regul 1980;5:5-18.   DOI   ScienceOn
26 Siegel S. Drug-Anticipatory Responses in Animals. In: White L, Tursky B, Schwartz GE, editors. Placebo: Theory, Research and Mechanisms. New York: Guilford;1985. p.288-305.
27 Voudouris NJ, Peck CL, Coleman G. Conditioned placebo responses. J Pers Soc Psychol 1985;48:47-53.   DOI
28 Voudouris NJ, Peck CL, Coleman G. Conditioned response models of placebo phenomena: further support. Pain 1989;38:109-116.   DOI   ScienceOn
29 Voudouris NJ, Peck CL, Coleman G. The role of conditioning and verbal expectancy in the placebo response. Pain 1990;43:121-128.   DOI   ScienceOn
30 Sunshine A, Laska E, Meisner M, Morgan S. Analgesic studies of indomethacin as analyzed by computer techniques. Clin Pharmacol Ther 1964;5:699-707.   DOI
31 Batterman RC. Persistence of responsiveness with placebo therapy following an effective drug trial. J New Drugs 1966;6:137-141.
32 Batterman RC, Lower WR. Placebo responsiveness--influence of previous therapy. Curr Ther Res Clin Exp 1968;10:136-143.
33 Laska E, Sunshine A. Anticipation of analgesia. A placebo effect. Headache 1973;13:1-11.   DOI   ScienceOn
34 Ader R. The Role of Conditioning in Pharmacotherapy. In: Harrington A, editor. The Placebo Effect: an Interdisciplinary Exploration. Cambridge, MA: Harvard Univ Press;1997. p.138-165.
35 Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 1999;19:484-494.
36 Ader R. Conditioned Immunopharmacological Effects in Animals: Implications for a Conditioning Model of Pharmacotherapy. In: White L, Tursky B, Schwartz GE, editors. Placebo: Theory, Research, and Mechanisms. New York: Guilford;1985. p.306-323.
37 Wickramasekera I. A conditioned response model of the placebo effect: predictions from the model. In: White L, Tursky B, Schwartz GE, editors, Placebo: theory, research, and mechanisms. New York: Guilford; 1985. p.255-287.
38 Benedetti F, Amanzio M, Baldi S, Casadio C, Cavallo A, Mancuso M, et al. The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression. Pain 1998;75:313-319.   DOI   ScienceOn
39 Benedetti F, Pollo A, Lopiano L, Lanotte M, Vighetti S, Rainero I. Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J Neurosci 2003;23:4315-4323.
40 Stewart-Williams S, Podd J. The placebo effect: dissolving the expectancy versus conditioning debate. Psychol Bull 2004;130:324-340.   DOI
41 Montgomery GH, Kirsch I. Classical conditioning and the placebo effect. Pain 1997;72:107-113.   DOI
42 Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet 2010;375:686-695.   DOI   ScienceOn
43 Colloca L, Benedetti F. How prior experience shapes placebo analgesia. Pain 2006;124:126-133.   DOI
44 Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet 1978;2:654-657.
45 Colloca L, Benedetti F. Placebo analgesia induced by social observational learning. Pain 2009;144:28-34.   DOI   ScienceOn
46 Finniss DG, Benedetti F. Mechanisms of the placebo response and their impact on clinical trials and clinical practice. Pain 2005;114:3-6.   DOI
47 Colloca L, Benedetti F. Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci 2005;6:545-552.   DOI
48 Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia-- imaging a shared neuronal network. Science 2002;295:1737-1740.   DOI
49 Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 2008;65:220-231.   DOI   ScienceOn
50 Grevert P, Albert LH, Goldstein A. Partial antagonism of placebo analgesia by naloxone. Pain 1983;16:129-143.   DOI   ScienceOn
51 Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet 1978;2:654-657.
52 Levine JD, Gordon NC. Influence of the method of drug administration on analgesic response. Nature 1984-1985;312:755-756.   DOI   ScienceOn
53 Benedetti F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 1996;64:535-543.   DOI   ScienceOn
54 Benedetti F, Amanzio M. The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Prog Neurobiol 1997;52:109-125.   DOI   ScienceOn
55 Pollo A, Vighetti S, Rainero I, Benedetti F. Placebo analgesia and the heart. Pain 2003;102:125-133.   DOI
56 Fields HL, Price DD. Toward a neurobiology of placebo analgesia-analgesia. In: Harrington A, editor. The placebo effect: an interdisciplinary exploration. Cambridge, MA: Harvard Univ Press;1997. p.93-116.
57 Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, et al. Placebo effects mediated by endogenous opioid activity on muopioid receptors. J Neurosci 2005;25:7754-7762.   DOI   ScienceOn
58 Benedetti F, Amanzio M, Baldi S, Casadio C, Maggi G. Inducing placebo respiratory depressant responses in humans via opioid receptors. Eur J Neurosci 1999;11:625-631.   DOI   ScienceOn
59 de la Fuente-Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ. Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 2001;293:1164-1166.   DOI
60 de la Fuente-Fernandez R, Stoessl AJ. The placebo effect in Parkinson's disease. Trends Neurosci 2002;25:302-306.   DOI   ScienceOn
61 Benedetti F, Colloca L, Torre E, Lanotte M, Melcarne A, Pesare M, et al. Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 2004;7:587-588.   DOI   ScienceOn
62 Benedetti F, Lanotte M, Colloca L, Ducati A, Zibetti M, Lopiano L. Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response. J Physiol 2009;587:3869-3883.   DOI   ScienceOn
63 Schultz W. Behavioral theories and the neurophysiology of reward. Annu Rev Psychol 2006;57:87-115.   DOI   ScienceOn
64 Horvitz JC. Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience 2000;96:651-656.   DOI   ScienceOn
65 Marks DM, J T, Pae CU. Innovations in clinical research design and conduct in psychiatry: shifting to pragmatic approaches. Psychiatry Investig 2009;6:1-6.   DOI   ScienceOn
66 Hurko O, Ryan JL. Translational research in central nervous system drug discovery. NeuroRx 2005;2:671-682.   DOI   ScienceOn
67 Liu KS, Snavely DB, Ball WA, Lines CR, Reines SA, Potter WZ. Is bigger better for depression trials? J Psychiatr Res 2008;42:622-630.   DOI   ScienceOn
68 Kane JM, Correll CU, Goff DC, Kirkpatrick B, Marder SR, Vester-Blokland E, et al. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiatry 2009;70:1348-1357.   DOI   ScienceOn
69 Woods SW, Gueorguieva RV, Baker CB, Makuch RW. Control group bias in randomized atypical antipsychotic medication trials for schizophrenia. Arch Gen Psychiatry 2005;62:961-970.   DOI   ScienceOn
70 Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2007;68:843-853.   DOI   ScienceOn