Reclassifying dropouts from antipsychotic trials due to study-reported adverse events: a systematic review and...

In antipsychotic trials for acute schizophrenia, dropout reasons are typically classified into inefficacy, adverse events (AEs), and other reasons. AEs can include not only somatic, but also psychiatric AEs, which may reflect inefficacy. However, studies seldom report them separately. We examined detailed reasons for dropouts attributed to AEs and assessed the impact of reclassification. We searched Vivli for randomized controlled trials with individual-participant-data on adults with acute schizophrenia (up to April 9, 2025). When dropout was attributed to an AE, we cross-checked reports and recategorized the corresponding dropouts into somatic, psychiatric, and other AEs using MedDRA(v28.1). We performed random-effects meta-analyses to compare antipsychotics and placebo for i) the study-reported dropouts due to AEs, and for ii) dropouts reclassified as due to somatic AEs. Seventeen trials (6823 participants; 70% male; mean age 40.9 years; mean Positive and Negative Syndrome Score 93.1) were included. Studies reported that 1369 dropouts due to inefficacy, 445 dropouts due to AEs, and 1173 dropouts due to other reasons. We reclassified the study-reported dropouts due to AEs as due to psychiatric (n = 223), somatic (n = 207), and other AEs (n = 15). We did not find evidence of difference between antipsychotics and placebo with respect to study-defined dropouts due to AEs (OR, 0.93 [95% CI; 0.72, 1.12]). However, we found evidence that dropouts reclassified as somatic AEs were more frequent with antipsychotics (OR, 1.54 [95% CI; 1.04, 2.27]). We conclude that combining somatic with psychiatric AEs may mask the true impact of antipsychotics on tolerability. Future trials should report these categories separately.