Determining Whether a Definitive Causal Relationship Exists Between Aripiprazole and Tardive Dyskinesia and/or Dystonia in Patients With Major Depressive Disorder, Part 4: Case Report Data
Authors: MACALUSO MATTHEW , FLYNN ALEXANDRA , PRESKORN SHELDON 
Published: April 2016

This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients who develop abnormal movements during treatment with antipsychotics. The first column in the series presented a patient who developed abnormal movements while being treated with aripiprazole as an augmentation strategy for major depressive disorder and reviewed data concerning the historical background, incidence, prevalence, and risk factors for tardive and spontaneous dyskinesias, the clinical presentations of which closely resemble each other. The second column in the series reviewed the unique mechanism of action of aripiprazole and reviewed preclinical studies and an early-phase human translational study that suggest a low, if not absent, risk of TD with aripiprazole. The third column in this series reviewed the registration trial data for aripiprazole across all of its indications and found a raw incidence of TD ranging from 0.004 (4 out of 987) in long-term studies of the drug as an augmentation strategy for major depressive disorder to 0.0016 (19 out of 11,897) based on all short-term (ie, weeks to <6 mo) and long-term (6 mo to 1 y) studies combined. This fourth column in the series reviews the “real-world” data on aripiprazole and assesses whether these data also support the conclusion that aripiprazole has a low to absent risk of causing TD. The “real-world” data consist of case reports from the medical literature and the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We found 37 cases in the medical literature reporting what was termed TD in association with aripiprazole treatment as well as 27 case reports suggesting improvement in preexisting TD with aripiprazole treatment. On the basis of the case reports from the medical literature, the potential or raw incidence of TD during “real-world” treatment with aripiprazole was 0.0000062 (37 out of the 6 million individuals who had been treated with aripiprazole in the United States as of 2013 according to a report from Otsuka). A query of the FAERS yielded 312 cases of TD in which aripiprazole was the primary suspect. On the basis of the FAERS data and again assuming 6 million individuals exposed to aripiprazole, this yields a raw incidence of 0.000052 (312 out of 6 million) for TD in patients treated with aripiprazole. However, these estimates have limitations because they are based on anecdotal reports and pharmacovigilance data and, thus, the events themselves were not confirmed or verified in a systematic way. Further, the figure of 6 million people exposed to aripiprazole was based on data reported to the authors by the drug’s manufacturer and only applies to exposure in the United States. The final column in this 5-part series will discuss the types of prohibitively expensive and logistically difficult studies that would be needed to determine whether a definitive causal relationship between aripiprazole and TD exists.