Effects of expectation on placebo-induced dopamine release in Parkinson disease.
BACKGROUND
Expectations play a central role in the mechanism of the placebo effect. In Parkinson disease (PD), the placebo effect is associated with release of endogenous dopamine in both nigrostriatal and mesoaccumbens projections, yet the factors that control this dopamine release are undetermined.


OBJECTIVE
To determine how the strength of expectation of clinical improvement influences the degree of striatal dopamine release in response to placebo in patients with moderate PD.


METHODS
Randomized, repeated-measures study with perceived expectation as the independent between-subjects variable.


METHODS
University of British Columbia Hospital, Vancouver, British Columbia, Canada. Patients Thirty-five patients with mild to moderate PD undergoing levodopa treatment. Intervention Verbal manipulation was used to modulate the expectations of patients, who were told that they had a particular probability (25%, 50%, 75%, or 100%) of receiving active medication when they in fact received placebo.


METHODS
The dopaminergic response to placebo was measured using [11C]raclopride positron emission tomography. The clinical response was also measured (Unified Parkinson Disease Rating Scale) and subjective responses were ascertained using patient self-report.


RESULTS
Significant dopamine release occurred when the declared probability of receiving active medication was 75%, but not at other probabilities. Placebo-induced dopamine release in all regions of the striatum was also highly correlated with the dopaminergic response to open administration of active medication. Whereas response to prior medication was the major determinant of placebo-induced dopamine release in the motor striatum, expectation of clinical improvement was additionally required to drive dopamine release in the ventral striatum.


CONCLUSIONS
The strength of belief of improvement can directly modulate dopamine release in patients with PD. Our findings demonstrate the importance of uncertainty and/or salience over and above a patient's prior treatment response in regulating the placebo effect and have important implications for the interpretation and design of clinical trials.
Lidstone
Sarah C
SC
Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Schulzer
Michael
M
Dinelle
Katherine
K
Mak
Edwin
E
Sossi
Vesna
V
Ruth
Thomas J
TJ
de la Fuente-Fernández
Raul
R
Phillips
Anthony G
AG
Stoessl
A Jon
AJ
D000368:Aged; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001294:Attitude to Health; D001479:Basal Ganglia / Q000000981:diagnostic imaging; D001955:British Columbia; D002986:Clinical Trials as Topic / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D015990:Placebo Effect; D010919:Placebos; D049268:Positron-Emission Tomography; D020891:Raclopride; D012107:Research Design; D012201:Reward
D000978:Antiparkinson Agents; D010919:Placebos; D020891:Raclopride; D007980:Levodopa; D004298:Dopamine