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.

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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.