Objective:  To describe the contents of a Drug Approval Package and to describe the efficacy and safety of iloperidone for the treatment of schizophrenia.

Data sources:  Drug Approval Package from the US Food and Drug Administration available at

Data synthesis:  The Drug Approval Package contains several different sections that describe both the preclinical (animal) and the clinical (human) studies conducted that led to the approval of iloperidone, a second-generation antipsychotic medication. Most of this information has not been published in the peer-reviewed literature and much of it had not been previously publicly available. Iloperidone’s indication for the acute treatment of schizophrenia in adults is supported by two of the four principal registration studies completed by the manufacturer. The documents made available reveal that there was disagreement between the Food and Drug Administration (FDA) and the manufacturer as to which study was considered ‘positive’ for iloperidone. There was additional controversy surrounding the appropriateness of combining patients with schizophrenia and schizoaffective disorder in the same study. Questions were also raised by the FDA about the relative efficacy of iloperidone vs. other antipsychotics; the need for an initial titration period was offered as a possible explanation as to why risperidone appeared to have superior efficacy. Moreover, there was disagreement as to what constitutes an appropriate study to test the long-term efficacy of an antipsychotic. Additional information is made available regarding the safety and tolerability of iloperidone, with the FDA acknowledging an overall attractive profile that includes less akathisia and extrapyramidal symptoms than other agents in its class. Of potential clinical utility are the results from FDA analyses of patients where clinical variables shifted from the normal to abnormal range.

Conclusions:  Iloperidone is efficacious and reasonably tolerable. The information made publicly available in the Drug Approval Package from the US FDA allows a closer examination as to how the medication was approved and allows for outside clinicians and researchers to appraise the data more carefully. Safety signals generated by FDA analyses of outliers can provide the impetus for the conduct of additional studies and post hoc analyses of registration study data already collected.