TY - JOUR
T1 - Placebo response and practice effects in schizophrenia cognition trials
AU - Keefe, Richard S.E.
AU - Davis, Vicki G.
AU - Harvey, Philip D.
AU - Atkins, Alexandra S.
AU - Haig, George M.
AU - Hagino, Owen
AU - Marder, Stephen
AU - Hilt, Dana C.
AU - Umbricht, Daniel
N1 - Funding Information:
Dr Keefe reported receiving investigator-initiated research funding support from the Department of Veterans Affairs, the National Institute of Mental Health, and the Singapore National Medical Research Council; receiving honoraria and serving as a consultant, speaker, or advisory board member for Abbvie, Acadia, Akebia, Akili, Alkermes, Astellas, Asubio, Avanir, AviNeuro/ChemRar, Axovant, Biogen, Boehringer Ingelehim, Cerecor, CoMentis, FORUM, Global Medical Education, GW Pharmaceuticals, Intracellular Therapeutics, Janssen, Lundbeck, MedScape, Merck, Minerva Neurosciences Inc, Mitsubishi, the Moscow Research Institute of Psychiatry, Neuralstem, Neuronix, Novartis, the New York State Office of Mental Health, Otsuka, Pfizer, Reviva, Roche, Sanofi, Sunovion, Takeda, Targacept, the University of Moscow, the University of Texas Southwest Medical Center, and WebMD; receiving royalties from the Brief Assessment of Cognition in Schizophrenia (BACS) testing battery and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery (BACS Symbol Coding); and being a shareholder in NeuroCog Trials and Sengenix. Dr Harvey reported serving as a consultant to AbbVie, Allergan, Boehringer Ingelheim, Forum Pharma, Genentech, Lundbeck Pharma, Otsuka Digital Health, Roche Pharma, Sanofi, Sunovion, and Takeda Pharma; receiving royalties for the BACS; and receiving research grants from Lundbeck and the Stanley Medical Research Foundation. We acknowledge data contributions from Eli Lilly, Abbvie, Sanofi, the National Institute of Mental Health Treatment Units for Research on Neurocognition in Schizophrenia, FORUM Pharmaceuticals, and F. Hoffmann–La Roche Ltd.
Publisher Copyright:
© 2017 American Medical Association. All rights reserved.
PY - 2017/8
Y1 - 2017/8
N2 - IMPORTANCE: Patients’ previous experience with performance-based cognitive tests in clinical trials for cognitive impairment associated with schizophrenia can create practice-related improvements. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects. OBJECTIVES: To conduct a systematic evaluation of the magnitude of practice effects on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) in cognitive impairment associated with schizophrenia and to examine which demographic, clinical, and cognitive characteristics were associated with improvement in placebo conditions. DESIGN, SETTING, AND PARTICIPANTS: A blinded review was conducted of data from 813 patients with schizophrenia who were treated with placebo in 12 randomized placebo-controlled clinical trials conducted mostly in outpatient clinics in North America, Europe, Asia, and Latin America from February 22, 2007, to March 1, 2014. A total of 779 patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients. INTERVENTIONS: Placebo compared with various experimental drug treatments. MAIN OUTCOMES AND MEASURES: Composite score on the MCCB. RESULTS: Of the 813 patients in the study (260 women and 553 men; mean [SD] age, 41.2 [11.5] years), the mean MCCB composite score at baseline was 22.8 points below the normative mean, and the mean (SEM) total change in the MCCB during receipt of placebo was 1.8 (0.2) T-score points (95% CI, 1.40-2.18), equivalent to a change of 0.18 SD. Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Baseline factors associated with greater improvements in the MCCB during receipt of placebo included more depression/anxiety (F1,438 = 5.41; P = .02), more motivation (F1,272 = 4.63; P = .03), and less improvement from screening to baseline (F1,421 = 59.32; P < .001). CONCLUSIONS AND RELEVANCE: Placebo effects were minimal and associated with the number of postbaseline assessments and several patient characteristics. Given that the patients performed 2.28 SDs below normative standards on average at baseline, a mean placebo-associated improvement of less than 0.2 SD provides evidence that ceiling effects do not occur in these trials. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo.
AB - IMPORTANCE: Patients’ previous experience with performance-based cognitive tests in clinical trials for cognitive impairment associated with schizophrenia can create practice-related improvements. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects. OBJECTIVES: To conduct a systematic evaluation of the magnitude of practice effects on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) in cognitive impairment associated with schizophrenia and to examine which demographic, clinical, and cognitive characteristics were associated with improvement in placebo conditions. DESIGN, SETTING, AND PARTICIPANTS: A blinded review was conducted of data from 813 patients with schizophrenia who were treated with placebo in 12 randomized placebo-controlled clinical trials conducted mostly in outpatient clinics in North America, Europe, Asia, and Latin America from February 22, 2007, to March 1, 2014. A total of 779 patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients. INTERVENTIONS: Placebo compared with various experimental drug treatments. MAIN OUTCOMES AND MEASURES: Composite score on the MCCB. RESULTS: Of the 813 patients in the study (260 women and 553 men; mean [SD] age, 41.2 [11.5] years), the mean MCCB composite score at baseline was 22.8 points below the normative mean, and the mean (SEM) total change in the MCCB during receipt of placebo was 1.8 (0.2) T-score points (95% CI, 1.40-2.18), equivalent to a change of 0.18 SD. Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Baseline factors associated with greater improvements in the MCCB during receipt of placebo included more depression/anxiety (F1,438 = 5.41; P = .02), more motivation (F1,272 = 4.63; P = .03), and less improvement from screening to baseline (F1,421 = 59.32; P < .001). CONCLUSIONS AND RELEVANCE: Placebo effects were minimal and associated with the number of postbaseline assessments and several patient characteristics. Given that the patients performed 2.28 SDs below normative standards on average at baseline, a mean placebo-associated improvement of less than 0.2 SD provides evidence that ceiling effects do not occur in these trials. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo.
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U2 - 10.1001/jamapsychiatry.2017.1574
DO - 10.1001/jamapsychiatry.2017.1574
M3 - Article
C2 - 28636694
AN - SCOPUS:85027481712
VL - 74
SP - 807
EP - 814
JO - JAMA Psychiatry
JF - JAMA Psychiatry
SN - 2168-622X
IS - 8
ER -