Y Intensive Course in Transcranial Magnetic Stimulation, 10/26/18 P PLACEBO EFFECTS O C & TRANSCRANIAL T O MAGNETIC N STIMULATION O D E S A MATTHEW BURKE, MD FRCPC E SIDNEY R. BAER, JR. FOUNDATION FELLOW BERENSON-ALLEN CENTER FOR NONINVASIVE BRAIN STIMULATION L DIVISION OF COGNITIVE NEUROLOGY P BETH ISRAEL DEACONESS MEDICAL CENTER HARVARD MEDICAL SCHOOL, BOSTON MA
Y P DISCLOSURES O C None T O N O D E S A E L P
Y P CONTEXT O C T O N O D E S A E L P Dr. Alvaro Pascual-Leone Dr. Ted Kaptchuk Director of the Berenson-Allen Center for Director of the Harvard University Program in Noninvasive Brain Stimulation Placebo Studies
Y P THE TIME IS NOW… O C T O N O D E S A E L P
Y P OUTLINE O C 1. Neurobiology of Placebo Effects 1. T O ▪ Definitions ▪ Mechanisms of action N Evidence and theories ▪ O 2. 2. “Differential” Placebo Effects D ▪ Historical context E ▪ Meta-analytic approaches S ▪ Prospective approaches A 3. TMS and Placebo Effects 3. E ▪ Sham devices L ▪ Quantifying magnitude P ▪ Implications on clinical trial results
Y P 1 NEUROBIOLOGY OF PLACEBO EFFECTS O C T O N O D E S A E L P
Y P PLACEBO EFFECTS O C T O N O D E S A E L P
Y P NEUROIMAGING STUDIES O C T O N O D E S A E L P
Y P META-ANALYSES AND MODELS O C T O N O D E S A E L P Zubieta & Stohler 2009 Wager and Atlas 2015
Y P BIOLOGICAL MECHANISMS O C T Opioid, dopamine, cannabinoid, serotonergic, O neuroendocrine, and neuro-immunological pathways (+ others) have all been implicated in placebo effects N O D E S A E L P
Y P NEUROPHARMACOLOGICAL STUDIES O C T O N O D E S A E L P
Y P THEORIES OF PLACEBO EFFECTS O C T Two major theories to explain placebo effects: O N O D E LEARNING/ EXPECTATION EXPECTATION S CONDITIONING A E L P
Y P EXPECTATION O C T O N O D E S “Placebo effects generally correspond to people’s A knowledge or beliefs about the kind of drug they believe they are receiving, and for that reason, a E causal relation between expectancy and placebo L reaction has generally been assumed…” P
Y P OPEN-HIDDEN PARADIGMS O C T O N O D E S A E L P Enck et al. 2013
Y P THEORIES OF PLACEBO EFFECTS O C T Two major theories to explain placebo effects: O N O D E LEARNING/ LEARNING/ EXPECTATION S CONDITIONING CONDITIONING A E L P
Y P CONDITIONING O C T O N O D E S A E L P
Y P CONDITIONING PARADIGMS O C T O N O D E S A E L P
Y P THEORIES OF PLACEBO EFFECTS O C T Two major theories to explain placebo effects: O N O D E LEARNING/ EXPECTATION S CONDITIONING A E L P “Rather than being viewed as an alternative to expectancy, classical conditioning can be understood as one method by which expectancies are formed”
Y P FROM NUISANCE TO TREATMENT O C T O N O D E S A E L P
Y P HETEROGENEITY IN RESPONSES? O C T O N O D E S A E L P
Y P RESPONDERS AND NON-RESPONDERS O C T O N O D E S A E L P
Y P ALL DISEASES? O C T O N O D E S A E L P
Y P PLACEBO EFFECTS? O C T O N O D E S A E L P
Y P 2 “DIFFERENTIAL” PLACEBO EFFECTS O C T O N O D E S A E L P The concept that different types of placebos may yield different magnitudes of placebo effects
Y P EARLY CONCEPTIONS… O C T O N O D E S A E L P
Y P SHAM-CONTROLLED SURGICAL TRIALS O C T O N O D E S A E L P
Y P SHAM-CONTROLLED SURGICAL TRIALS O C T O N O D E S A E L P
Y P RECENT ATTENTION… O C T O N O D E S A E L P
Y P META-ANALYTIC APPROACHES O C T O N O D “Meta -regression analyses showed that larger E effects of placebo interventions were associated with physical placebo S interventions” (e.g. sham devices) A E L P Not head-to-head comparisons
Y P DIRECT APPROACHES O C T O N O D E S A E L P
Y P 3 TMS AND PLACEBO EFFECTS O C T O N O D E S A E L P
Y EXEMPLIFICATION OF AN ELABORATE P O THERAPEUTIC TECHNOLOGY C T O N O D E S A E L P Brainsi ght TMS
Y P SHAM TMS O C T ▪ Achieve blinding but avoid meaningful O stimulation to the brain N ▪ Goal: Mimic TMS’s visual and auditory (+/- tactile) experience but shield the O brain from the magnetic fields D ▪ Many different sham device techniques E S A E L P *Include a measure assessing success of blinding!
Y P QUANTIFYING PLACEBO EFFECTS O C T O N O 61 studies, large effect size of D 0.8 (Hedge’s g) Meta-regression E ▪ Placebo response magnitude was S positively associated with the year A of publication (increasing sham TMS responses over time). E ▪ Studies that included patients with L treatment-resistant depression had P lower placebo responses
Y P VARIABILITY IN PLACEBO RESPONSES O C T O N O D E “41.0% of the veterans in the active S treatment group achieved remission of A depressive symptoms ”* E L P *No difference from sham group (37%)
Y P PLACEBO MODULATION OF AMYGDALA O C T O N O D E S A E L P
Y P AN EXTREME EXAMPLE… O C T O N O D E “Contrary to our primary S hypothesis, the number of headache days decreased A significantly more in the sham E group than in the group treated with active rTMS-DLPFC at L eight weeks. Average decrease in headache days was >50% in P the sham group, indicating a powerful placebo response.”
Y P EVIDENCE FOR “DIFFERENTIAL EFFECT”? O C T O N O D Compared inert pill group from escitalopram E medication trials to the sham TMS group of TMS S trials A Reported no significant difference…BUT E Methodological limitations L ▪ Heterogenous patient populations – “refractory” P ▪ Blinding – double vs single ▪ Dated (only included trials 2002-2008)
Y P FURTHER RESEARCH? O C No studies comparing sham TMS to “no treatment” control T ▪ Needed to delineate placebo effects from “other” effects O (including activation of coming to hospital for treatment) N O D E S A E L P
Y P IMPLICATIONS O C Unfavorable impact on statistical power for sham controlled T treatment trials O ▪ RCT investigating a treatment with a large embedded placebo effect N will generally need more subjects to prove efficacy than a treatment with a smaller placebo effect (Kaptchuk et al. 2000) O D E S A E L P Active Placebo
Y P ONGOING ISSUES… O C T O N O D E S A E L P
Y ISSUES REQUIRING CRITICAL P O REFLECTION… C T How should we O measure efficacy? N New approaches? O D E S A E How do we leverage enhanced placebo L effects? P
Y P QUESTIONS O C T O N O D E S A E L P mburke11@bidmc.harvard.edu
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