Placebo Responses in Genetically Determined Intellectual Disability: A Meta-Analysis
Open accessAbstract
BACKGROUND: Genetically determined Intellectual Disability (ID) is an intractable condition that involves severe impairment of mental abilities such as learning, reasoning and predicting the future. As of today, little is known about the placebo response in patients with ID. OBJECTIVE: To determine if placebo response exists in patients with genetically determined ID. DATA SOURCES AND STUDY SELECTION: We searched Medline/PubMed, EMBASE, CENTRAL and PsycINFO to find all placebo-controlled double-blind randomized clinical trials (RCTs) in patients with genetically determined ID, published up to April 2013, focusing on core ID symptoms. DATA EXTRACTION AND SYNTHESIS: Two investigators extracted outcome data independently. MAIN OUTCOMES AND MEASURES: Bias-corrected standardized mean difference (Hedge's g) was computed for each outcome measure, using the Comprehensive Meta-Analysis software. A priori defined patient sub-groups were analyzed using a mixed-effect model. The relationship between pre-defined continuous variable moderators (age, IQ, year of publication and trial duration) and effect size was analyzed using meta-regression. RESULTS: Twenty-two placebo-controlled double-blind RCTs met the inclusion criteria (n = 721, mean age = 17.1 years, 62% men, mean trial duration = 35 weeks). There was a significant overall placebo response from pre- to post-treatment in patients with ID (g = 0.468, p = 0.002), both for "subjective outcomes" (a third-person's evaluation of the patient) (g = 0.563, p = 0.022) and "objective outcomes" (direct evaluation of the patient's abilities) (g = 0.434, p = 0.036). Individuals with higher IQ had higher response to placebo (p = 0.02) and no placebo response was observed in ID patients with comorbid dementia. A significant effect of age (p = 0.02) was found, indicating higher placebo responses in treatment of younger patients. CONCLUSIONS AND RELEVANCE: Results suggest that patients with genetically determined ID improve in the placebo arm of RCTs. Several mechanisms may contribute to placebo effects in ID, including expectancy, implicit learning and "placebo-by-proxy" induced by clinicians/family members. As the condition is refractory, there is little risk that improvements are explained by spontaneous remission. While new avenues for treatment of genetically determined ID are emerging, our results demonstrate how contextual factors can affect clinical outcomes and emphasize the importance of being vigilant on the role of placebos when testing novel treatments in ID.
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This placebo response is similar to the placebo response in adult patients without intellectual disability.
“This is similar to the placebo response in adult patients without intellectual disability108.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [108]
A meta-analysis of all placebo-controlled, double-blinded randomized controlled trials in patients with a genetic diagnosis of intellectual disability showed a placebo response with an effect size of 0.5, which is moderate.
“A meta-analysis including all placebo-controlled, double-blinded RCTs conducted in patients with a genetic diagnosis of intellectual disability showed a placebo response with an effect size of 0.5 (moderate).”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [108]
Some studies employ a dilution method or do not follow manufacturer-recommended extraction of plasma samples before oxytocin assay, which may result in physiologically implausible levels of oxytocin, rendering conclusions about differences between groups, or associations with clinical measures, unverifiable.
“For example, some studies employ a dilution method 24 or do not follow manufacturer-recommended extraction of plasma samples 25 before oxytocin assay.This may result in physiologically implausible levels of oxytocin, rendering conclusions about differences between groups, or associations with clinical measures, unverifiable.”
From Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder (2017) · cites this paper as [25]
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- Authors
- Curie, A., Yang, K., Kirsch, I., Gollub, R. L., des Portes, V., Kaptchuk, T. J., & Jensen, K. B.
- Affiliations
- Lyon 1 Université (FR)
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Curie, Aurore
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-07-30
- Volume
- 10
- Issue
- 7
- Pages
- e0133316
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4520690
- OpenAlex
- W1725011155
- Cited by
- 43
- References
- 85
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 10 · 2016: 2
- FWCI
- 0.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Svenska Sällskapet för Medicinsk Forskning
- National Institutes of Health
- National Center for Complementary and Integrative Health (K24AT004095, R01AT005280)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- placebo response, dementia comorbidity, expectancy, implicit learning, refractory disease
- MeSH terms
- Double-Blind Method, Female, Humans, Male, Mental Processes, Intellectual Disability, Placebo Effect, Randomized Controlled Trials as Topic
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