EDITORIAL Peter A. LeWitt, MD, MMedSc Scott Kim, MD, PhD Correspondence to Prof. LeWitt: plewitt1@hfhs.org Neurology ® 2015;84:766–767 See page 794 The pharmacodynamics of placebo Expectation effects of price as a proxy for efficacy For shoppers of luxury goods, satisfaction with a pur- chase might be proportionate to its expense. Suppose, however, that a patient’s perception of medication benefit is similarly governed by its cost: does that make sense? Espay et al., 1 reporting in the current issue of Neurology ® , would have us think so. Their research takes the study of placebo effect to a new dimension of inquiry by investigating treatment cost as a determinant of antiparkinsonian control. In this small but well-designed study, the authors conclude that price does matter as to how patients with Par- kinson disease (PD) perceive benefit. This may be bad news for health care providers committed to cost control, especially if such a mindset assumes better results should arise from more expensive drugs. This blinded, randomized crossover study of pla- cebo effect tested changes in objective ratings of par- kinsonian motor function. The authors compared outcomes from levodopa with 2 sequential placebo (saline) injections. The latter were described to study participants as containing the same dopaminergic agonist but differing in manufacturing cost ($100 per dose vs $1,500). Participants received no further comment as to why treatment expense was men- tioned. Secondary study endpoints included 2 quan- tified motor tasks, a self-rating for global impression of change, and an fMRI brain activation analysis involving a feedback-based visual-motor associative learning task. The authors reported that, when the “expensive” treatment was administered first, the mean improvement on the Unified Parkinson’s Dis- ease Rating Scale motor score for the “expensive drug” was 10% greater than with the “cheap” pla- cebo. Both placebo treatments showed improvement over baseline scores, although not as much as enacted by levodopa. The results in this randomized crossover study were confounded with “treatment-by-period” effect, in that results from the same treatment given in the second period differed from first-period results. The fMRI-monitored associative learning task also provided intriguing findings that differentiated outcomes from the “$100” vs “$1,500” injections. Task performance after levodopa treatment led to deactivation for several left-sided brain regions. In contrast, activation occurring in different brain re- gions followed the placebo treatments. Given as ini- tial treatment, the cheap but not the expensive placebo resulted in more regional brain activation. As with the motor ratings, the treatment order con- founded the interpretation of the second-given treat- ment results. Taken together, the results indicate that sympto- matic actions of placebo on several measurements were modified by price perception, with “expensive therapy” leading to greater improvement. The impli- cations of fMRI results are more difficult to interpret, especially in a small number of persons undergoing limited testing; however, the placebo “price” also dif- ferentiated treatment results. The authors acknowl- edge several study limitations, and the differential effects conferred by treatment order also challenge their interpretations. A responder analysis might have helped to elucidate whether results were driven by subgroups. Characterizing opinions of subjects regarding drug price would also have been informa- tive. It would also be of interest to learn whether participants receiving a “drug” priced at $100/dose would actually regard this as a “cheap” medication. Placebo can be the physician’s friend when it en- hances therapeutic efficacy. The effects of placebo also can confound clinical trial outcomes or lead to endorsement of worthless treatments. For patients with PD, placebo effect is often robust and enduring. A meta-analysis of symptomatic actions from placebo and sham interventions in a number of clinical trials 2 suggested mean improvements averaging 16% (a greater magnitude of effect than reported by Espay et al. 1 ). The findings of the current study build on other insights into placebo effect and PD, including evidence that regional release of dopamine in the stri- atum may be increased in response to expectation of reward or clinical improvement. 3 From the Department of Neurology (P.A.L.), Parkinson’s Disease and Movement Disorders Center, Henry Ford West Bloomfield Hospital; Department of Neurology (P.A.L.), Wayne State University School of Medicine, Detroit, MI; and Department of Bioethics (S.K.), National Institutes of Health, Bethesda, MD. The views expressed are those of the authors and do not represent the views or policies of the NIH, Department of Health and Human Services, or the United States Government. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 766 © 2015 American Academy of Neurology ª 2015 American Academy of Neurology. 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