OBJECTIVES: Current adverse event (AE) reporting in clinical trials is comprehensive; however, it is difficult to compare treatment tolerability across treatments or between studies. This study proposes a new assessment of the overall tolerability of an antipsychotic medication by applying a tolerability burden index (TBI) to pivotal trial data. METHODS: Most patients experience multiple AEs of varying duration and severity, the burden of which is not reflected in standard tabular AE reporting. The proposed TBI algorithm combines frequency, severity, and duration into a global burden score of treatment-emergent AEs (TEAEs) per patient. For each patient, each TEAE was adjusted by intensity, duration (adjusted to account for severity as well as days), and burden weight, and the average burden score was calculated. Finally, we computed the TBI score as the inverse of the overall burden experienced by each patient (ie, higher index score indicates less burden) to derive a score between 0 and 100. TBI score=100 × [(Maximum burden score – Average burden score)/(Maximum burden score – Minimum burden score)] The mean TBI score for each trial arm represents the average of TBI scores for all patients in that arm. We applied this approach to a randomized, double-blind placebo-controlled trial (~150 patients per arm) from a discontinued development program on the antipsychotic drug bifeprunox, with risperidone included as an active reference. RESULTS: Results demonstrated that TEAE rates varied widely among patients. As expected, the mean TBI, adjusted based on TEAE severity, severity-adjusted duration, and burden weight was higher for bifeprunox and risperidone compared with placebo and increased with dose. CONCLUSIONS: This approach will allow comparison of TEAE burden and tolerability between treatments. Further algorithm validation and elicitation of burden weight are ongoing. The approach presented here suggests that such scoring is possible, clinically relevant, and allows standardized comparison of tolerability profiles of antipsychotics.