title: Placebo Responses in Genetically Determined Intellectual Disability: A Meta-Analysis.
abstract: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  Two investigators extracted outcome data independently.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Martinos Center for Biomedical Imaging, Boston, Massachusetts, United States of America; L2C2, Institut des Sciences Cognitives, CNRS UMR5304, Bron, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital Femmes Mères Enfants, Hospices Civils de Lyon, Bron, France; Université Claude Bernard Lyon1, Lyon, France; EPICIME-CIC1407/INSERM, Bron, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Curie
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Martinos Center for Biomedical Imaging, Boston, Massachusetts, United States of America.
authors.forename: Kathy
authors.initials: K
authors.lastname: Yang
authors.affiliation: Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, United States of America; School of Psychology, Plymouth University, Plymouth, United Kingdom.
authors.forename: Irving
authors.initials: I
authors.lastname: Kirsch
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Martinos Center for Biomedical Imaging, Boston, Massachusetts, United States of America.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Gollub
authors.affiliation: L2C2, Institut des Sciences Cognitives, CNRS UMR5304, Bron, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital Femmes Mères Enfants, Hospices Civils de Lyon, Bron, France; Université Claude Bernard Lyon1, Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.affiliation: Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ted J
authors.initials: TJ
authors.lastname: Kaptchuk
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Martinos Center for Biomedical Imaging, Boston, Massachusetts, United States of America; Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, United States of America; Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors.forename: Karin B
authors.initials: KB
authors.lastname: Jensen
mesh_terms: D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000188:drug therapy* / Q000235:genetics* / Q000523:psychology; D008297:Male; D008606:Mental Processes / Q000187:drug effects; D015990:Placebo Effect; D016032:Randomized Controlled Trials as Topic