Early Placebo Improvement May Be a Marker for Long-Term Placebo Response in Schizophrenia Trials

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Investigators examine patients who demonstrated improvement after placebo injections and aimed to determine criteria to predict subsequent response.

Early improvement after placebo injections may be predictive of longer-term placebo response in long-acting injectable antipsychotic trials for schizophrenia, according to study data published in the Journal of Clinical Psychiatry.

Investigators abstracted data from 4 double-blind randomized controlled trials through the Yale Open Data Access project. These 4 studies were conducted between October 2003 and March 2008, and each assessed the efficacy of long-acting injectable paliperidone palmitate compared with placebo injections. The present analysis included only patients with schizophrenia who received placebo injections during study participation (n=450). Multiple regression analyses were conducted to examine associations between demographic and clinical characteristics and placebo response. Specifically, the predictive power of improvement observed at week 1 for response at week 9 was assessed. Treatment response was defined as a 25% or greater reduction in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 9. Both per protocol and last-observation-carried forward analyses were conducted.

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Percentage reduction in PANSS total score at week 1 was significantly associated with placebo response at week 9 (odds ratio, 1.063; 95% confidence interval, 1.040-1.087; P <.001). Cutoffs of a 10% (accuracy, 0.724 for per protocol analysis) and 15% (accuracy, 0.714 for last-observation-carried forward analysis) reduction in PANSS total score at week 1 showed the highest predictive power for response at week 9. In addition, a lower PANSS G12 item score at baseline, denoting better judgment and insight, was associated with greater response at week 9 (odds ratio, 0.739; 95% confidence interval, 0.553-0.986; P =.040). As such, longer-term placebo response may be predicted by a 10% to 15% reduction in PANSS total score at week 1, as well as by lower PANSS G12 item score at baseline.

These data may be helpful in the design of future clinical trials of long-acting injectable antipsychotics in schizophrenia, allowing investigators to identify and exclude potential placebo responders early in the study course.


Kumagai F, Suzuki T, Fleischhacker WW, Yasui-Furukori N, Mimura M, Uchida H. Early placebo improvement is a marker for subsequent placebo response in long-acting injectable antipsychotic trials for schizophrenia: combined analysis of 4 RCTs. J Clin Psychiatry. 2019;80(1):18m12144.