N

C O

LU

Pearls in Clinical Neuroscience

Placebo: The Best Pill of All

By Dan J. Stein, MD, PhD, and Helen Mayberg, MD
CASE STUDY Charles is a 40-year-old who has suffered from anxiety in social situations since childhood. He has a light complexion and blushes easily. In situations where he was the center of attention his blushing contributed to his sense of humiliation. He learned from a newspaper advertisement that he might suffer from social anxiety disorder (SAD) and that he was eligible to participate in research on a new medication for SAD. Charles made an appointment at the anxiety disorder clinic of a prestigious teaching hospital. He was delighted to learn that there was indeed a name for his symptoms and treatments were available. The medication under study was a new formulation of an existing selective serotonin reuptake inhibitor (SSRI) that had already been shown effective and safe for SAD with minor adverse events, such as initial nausea. He signed his written informed consent and entered the trial. Charles experienced a slight sense of nausea in the first week. He gradually began to feel more confident in social situations. By the end of the 12 week trial he reported a significant change in his life; he was no longer avoiding talking in small groups and his work function therefore improved. He chose to switch to the already marketed SSRI formulation and continued to do well. Months later his physician learned that Charles was on placebo during the trial. COGNITIVE-AFFECTIVE NEUROSCIENCE OF PLACEBO RESPONSE Several key questions about response to placebo continue to be debated. There has been some controversy about whether it is ethical to test medications in placebo-controlled trials for serious illnesses when effective and safe medications are available.1,2 There is debate about whether the placebo response represents a meaningful change that is greater than the effect of no treatment or whether it represents merely regression to the mean due to effects such as symptom fluctuation.3,4 If placebo effects are more than regression to the mean, there are questions about the nature of the relevant psychological processes and their underlying neurobiology. For example, the question of whether the placebo response reflects primarily expectancy or conditioning processes has been debated.5,6 The present consensus of regulators, investigators, and advocacy groups is that placebo-controlled trials remain crucial because other designs (such as non-inferiority trials) provide insufficient evidence that a new molecule is effective.1,2,7 Surprisingly, there is relatively little evidence that placebo response is greater than the effect of no treatment, although in the case of pain and phobia, there does appear to be clear benefit.3 Similarly, differences between antidepressants and active placebos in depression trials are small.8 Nevertheless, there is a growing literature investigating the psychobiology of the placebo response, allowing the preliminary formulation of a cognitive-affective neuroscience of this phenomenon.9-13
Neurocircuitry/Neurochemistry

N EW

Early research14,15 indicated that placebo analgesia was reversed by the mu-opioid antagonist naloxone. Recent work has suggested that placebo analgesia is associated with decreased activity in pain-sensitive brain regions (eg, thalamus, insula) (Figure 1), 10 but with increased activity in orbitofrontal and prefrontal areas (Figure 2). 13 Taken together, these data suggest that pain includes both sensory components as well as cognitive evaluation, and that the opioid system is able to mediate altered experience of pain during placebo analgesia. In Parkinsons disease, placebo-induced release of endogenous dopamine in the striatum was as high as with active medication.16,17 Ventral striatal dopamine release occurred in all patients, consistent with basic work showing such release during reward anticipation.18 Dorsal striatal dopamine release was higher in placebo responders, consistent with the role of this region in motor performance. Furthermore, placebo response in panic disorder led to decreased activity in neurons in the subthalamic nucleus.19 Such work strengthens the hypothesis that placebo response involves an expectancy effect.5

Dr. Stein is professor and chair at the University of Cape Town in South Africa and visiting professor at the University of Florida in Gainesville. Dr. Mayberg is professor of Psychiatry and Neurology at Emory University in Atlanta, Georgia. Disclosure: Dr. Stein has received grant support/honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, and Wyeth. Dr. Mayberg is a consultant for Advanced Neuromodulation Systems, Cyberonics, GlaxoSmithKline, and Novartis. Funding/Support: This paper was supported by grants from the Medical Research Council of South Africa to Dr. Stein, and from the National Institute of Mental Health (grant # MH-49553) and a physician-initiated grant from Eli Lilly to Dr. Mayberg. Author's note: The current case is based on an amalgam of the authors' experiences.
Volume 10 Number 6 MBL Communications Inc.

440

CNS Spectrums June 2005

Pearls in Clinical Neuroscience

In depression, fluoxetine and placebo response were associated with decreased activity in limbicparalimbic areas and increased activity in dorsal-cortical regions (Figure 3).11 Unpublished analyses found greater ventral striatum activity in week 1 predicted fluoxetine and placebo response, but did not persist after response onset. Thus, facilitation of reciprocal cortical-limbic changes may be needed for response, and expectancy effects play an initial role, irrespective of modality. Fluoxetine response was, however, associated with additional subcortical and limbic changes.
Gene/Environment

tage.26,27 In less cognitively flexible animals, where conditioning is more important than expectancy, the literature on placebo responses is relatively sparse.28 CLINICAL IMPLICATIONS
DSM-IV-TR Diagnosis

At this point there is no evidence that placebo responses should be conceptualized as pathological. On the other hand, nocebo responses, in which adverse reactions take place in response to inert

A range of factors may contribute to the placebo response, including physician characteristics (eg, empathy), patient characteristics (eg, suggestibility), and study and illness characteristics.5,20-25 Many features of clinical trials, such as patient evaluation and attention, may be particularly likely to create expectancy effects, thus promoting a placebo response. If the placebo response is mediated by dopamine, then speculatively, variants in dopamine candidate genes may be associated with variability in placebo response.
Evolutionary Aspects

Is it possible to understand the placebo response within an evolutionary framework? Placebo responses are more linked to expectancies by cognition than by conditioning.6 Capacity to have expectancies in social situations in general reflects our evolved cognitive abilities, and capacity to have expectancies in therapeutic contexts in particular may carry an evolutionary advan-

FIGURE 2. Placebo analgesia is accompanied by

increased activity (yellow dots) in cortical regions, such as the orbitfrontal cortex13

Reprinted with permission from Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesiaimaging a shared neuronal network. Science. 2002;295(5560):1737-1740. Copyright 2002, AAAS. Stein DJ, Mayberg H. CNS Spectr. Vol 10, No 6. 2005.

FIGURE 1. Placebo analgesia is accompanied

by decreased activity in pain-sensitive brain regions (eg, INS, TH)10

FIGURE 3. Response to both placebo and fluox-

Reprinted with permission from Wager TD, Rilling JK, Smith EE, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science. 2004;303(5661):1162-1167. Copyright 2004, AAAS. INS=insula; TH=thalamus. Stein DJ, Mayberg H. CNS Spectr. Vol 10, No 6. 2005.

etine is accompanied by increased activity (red dots) in dorsal-cortical regions and decreased activity (yellow dots) in limbic-paralimbic areas11

Reprinted with permission from the American Journal of Psychiatry. Mayberg HS, Silva JA, Brannan SK, et al. The functional neuroanatomy of the placebo effect. Am J Psychiatry. 2002;159:728-737. Copyright 2002, American Psychiatric Association. Stein DJ, Mayberg H. CNS Spectr. Vol 10, No 6. 2005.

Volume 10 Number 6 MBL Communications Inc.

441

CNS Spectrums June 2005

Pearls in Clinical Neuroscience

substances, are arguably not well conceptualized in current nosological systems.29 The current patient experienced nausea; if he were instead to have experienced a psychological adverse event, it is unclear what the appropriate psychiatric diagnosis would be.
Assessment/Evaluation
4. McDonald CJ, Mazzuca SA, McCabe GP Jr. How much of the placebo effect is really statistical regression? Stat Med. 1983;2:417-427. 5. Brody H. Three perspectives on the placebo response: Expectancy, conditioning, and meaning. Adv Mind Body Med. 2000;16:211-232. 6. Kirsch I. Conditioning, expectancy, and the placebo effect: comment on StewartWilliams and Podd. Psychol Bull. 2004;130:341-343. 7. Charney DS, Nemeroff CB, Lewis L, et al. National Depressive and ManicDepressive Association consensus statement on the use of placebo in clinical trials of mood disorders. Arch Gen Psychiatry. 2002;59:262-270. 8. Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants for depression. Cochrane Database Syst Rev. 2004;1:CD003012. 9. Benedetti F, Amanzio M. The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Prog Neurobiol. 1997;51:109-125. 10. Wager TD, Rilling JK, Smith EE, et al. Placebo-induced changes in fMRI in the anticipation and experience of pain. Science. 2004;303:1162-1167. 11. Mayberg HS, Silva JA, Brannan SK, et al. The functional neuroanatomy of the placebo effect. Am J Psychiatry. 2002;159:728-737. 12. Leuchter AF, Cook IA, Witte EA, et al. Changes in brain function of depressed patients during treatment with placebo. Am J Psychiatry. 2002;159:122-129. 13. Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesiaimaging a shared neuronal network. Science. 2002;295:1737-1740. 14. Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet. 1978;2:654-657. 15. Amanzio M, Pollo A, Maggi G, Benadetti F. Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain. 2001;90:205-215. 16. de la Fuente-Fernandez R, Phillips AG, Zamburlini MJ, et al. Dopamine release in human ventral striatum and expectation of reward. Behav Brain Res. 2002;136:359-363. 17. de la Fuente-Fernandez R, Ruth TJ, Sossi V, et al. Expectation and dopamine release: mechanism of the placebo effect in Parkinsons disease. Science. 2001;293:1164-1166. 18. Fiorillo CD, Tobler PN, Schultz W. Discrete coding of reward probability and uncertainty by dopamine neurons. Science. 2003;299:1898-1902. 19. Benedetti F, Colloca L, Torre E, et al. Placebo-responsive Parkinson patients showed decreased activity in single neurons of subthalamic nucleus. Nat Neurosci. 2004;7:587-588. 20. Shapiro AK, Shapiro E. The Powerful Placebo: From Ancient Priest to Modern Physician. Baltimore, MD: Johns Hopkins University Press; 2001. 21. Guess HA, Kleinman A, Kusek JW, Engel LW. The Science of the Placebo: Toward an Interdisciplinary Research Agenda. London: BMJ Books; 2002. 22. Brody H. Placebos and the Philosophy of Medicine: Clinical, Conceptual, and Ethical Issues. Chicago, IL: University of Chicago Press; 1980. 23. Harrington A. The Placebo Effect: An Interdisciplinary Collaboration. Cambridge, Mass: Harvard University Press; 1999. 24. White L, Tursky B, Schwartz GE. Placebo: Theory, Research, and Mechanisms. New York, NY: Guilford Press; 1985. 25. Moerman DE. Meaning, Medicine and the Placebo Effect. Cambridge, Mass: Cambridge University Press; 2002. 26. Bendesky A, Sonabend AM. On Schlepfuss path: the placebo response in human evolution. Med Hypotheses. 2005;64:414-416. 27. Evans D. Placebo: The Belief Effect. New York, NY: HarperCollins; 2003. 28. McMillan FD. The placebo effect in animals. J Am Vet Med Assoc. 1999;215:992-999. 29. Barksy AJ, Saintfort R, Rogers MP, Borus, JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287:622-627. 30. Posternak MA, Zimmerman M, Keitner GI, Miller IW. A reevaluation of the exclusion criteria used in antidepressant efficacy trials. Am J Psychiatry. 2002;159:191-200. 31. Quitkin FM, Raskin JG, Markowitz JM, et al. Use of pattern analysis to identify true drug response: a replication. Arch Gen Psychiatry. 1987;44:259-264. 32. Nierenberg AA, Quitkin FM, Kremer C, et al. Placebo-controlled continuation treatment with mirtazapine: acute pattern of response predicts relapse. Neuropsychopharmacology. 2004;29:1012-1018. 33. Zimbroff DL. Patient rater education of expectations in clinical trials (PREECT). J Clin Psychopharmacol. 2001;21:251-252. 34. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA. 2002;287:1840-1847. 35. Rickels K. Non-Specific Factors in Drug Therapy. Springfield, IL; Charles C. Thomas: 1968. 36. Di Blasi Z, Kaptchuk TJ, Weinman J, Kleijnen J. Informing participants of allocation to placebo at trial closure: postal survey. BMJ. 2002;325:1329. 37. Kirsch I, Weixel LJ. Double-blind versus deceptive administration of a placebo. Behav Neurosci. 1988;102:319-323. 38. Kent MA, Camfield CS, Camfield PR. Double-blind methylphenidate trials: practical, useful, and highly endorsed by families. Arch Pediatr Adolesc Med. 1999;153:1292-1296.

There is little evidence that a 1-week single-blind, placebo run-in prior to randomization successfully lowers placebo response rate.30 However, it is possible that a flexible pre-randomization baseline period may be useful in ensuring accurate assessment of baseline symptomatology. It has been argued that the placebo response in clinical trials is characterized by earlier onset and shorter persistence.31,32 Rigorous methods to reduce placebo response during trials deserve more attention.33
Pharmacotherapy/Psychotherapy

If placebo responses in clinical trials are due to patient evaluation and attention, then their high prevalence34 underscores the power of expectancy effects created by the therapeutic context and the meaningfulness of the doctor-patient relationship.5,20-25,35 On a facetious note, even if a pill for every psychic ill were found, it would be a mistake to make such a medication available over the counter, for this would reduce the potentially powerful effects of the doctor-patient relationship within which it can be prescribed. CONCLUSION Much remains to be understood about the phenomenology and psychobiology of the placebo response. Additional work is necessary, for example, to delineate the time course of placebo response,31,32 and to characterize the underlying neurobiology across different conditions. The questions of whether and how to communicate to research subjects that they were on placebo deserve more attention.36 If the placebo response is based on expectancy effects and the meaningfulness of the therapeutic context, rather than simply on effects such as regression to the mean, then a detailed understanding of its underlying cognitive-affective neuroscience can potentially be used to decrease placebo response in clinical trials,33,37 and to increase the efficacy of standard psychiatric and medical interventions.5,25,38 CNS REFERENCES
1. Leber P. The use of placebo control groups in the assessment of psychiatric drugs: an historical context. Biol Psychiatry. 2000;47:699-706. 2. Khan A, Khan S, Brown WA. Are placebo controls necessary to test new antidepressants and anxiolytics? Int J Neuropsychopharmacol. 2002;5:193-197. 3. Hrobjartsson A, Gotzsche PC. Is the placebo powerless? Update of a systematic review with new randomized trials comparing placebo with no treatment. J Intern Med. 2004;256:91-100.

Volume 10 Number 6 MBL Communications Inc.

442

CNS Spectrums June 2005