title: Determining Whether a Definitive Causal Relationship Exists Between Aripiprazole and Tardive Dyskinesia and/or Dystonia in Patients With Major Depressive Disorder, Part 2: Preclinical and Early Phase Human Proof of Concept Studies.
abstract: 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 treated with antipsychotics. The first column in this series began with the case of a 76-year-old man with major depressive disorder who developed orofacial dyskinesias while being treated with aripiprazole as an antidepressant augmentation strategy. It was alleged that a higher than intended dose of aripiprazole (ie, 20 mg/d for 2 wk followed by 10 mg/d for 4 wk instead of the intended dose of 2 mg/d) was the cause of the dyskinetic movements in this man, and the authors were asked to review the case and give their opinion. The principal basis for this theory of causation was the class warning about TD in the package insert for aripiprazole. The rationale for concluding aripiprazole caused TD in the 76-year-old man led to this series of columns about aripiprazole, its potential--if any--to cause TD, and the presence of a class warning about TD in its package insert. The central point is to illustrate why class warnings exist and their implications for practice. The first column in this series focused on the historical background, incidence, prevalence, risk factors, and clinical presentations of tardive and spontaneous dyskinesias and concluded with a discussion of diagnostic considerations explaining why clinicians should avoid making a diagnosis of TD until a thorough differential diagnosis has been considered. This second column in the series reviews the pharmacology of aripiprazole and the preclinical and phase I translational human studies that suggest aripiprazole should have a low to nonexistent risk of causing TD compared with other antipsychotics. The third column in the series will review the systematic clinical trial data and "real-world" data on TD and the use of aripiprazole as adjunctive treatment with antidepressants for major depressive disorder to see whether these data support the conclusion of a low to nonexistent relationship between aripiprazole treatment and the development of TD. The fourth and final column in the series will consider the type of study that would need to be performed to avoid a specific class warning, focusing on the TD class warning as an example and discussing why such studies are rarely done.
authors.affiliation: MACALUSO and PRESKORN: Department of Psychiatry, University of Kansas School of Medicine-Wichita, Wichita, KS FLYNN: Robert J. Dole VA Medical Center, Wichita, KS.
authors.forename: Matthew
authors.initials: M
authors.lastname: Macaluso
authors.forename: Alexandra
authors.initials: A
authors.lastname: Flynn
authors.forename: Sheldon
authors.initials: S
authors.lastname: Preskorn
mesh_terms: D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000266:history / Q000494:pharmacology*; D000068180:Aripiprazole / Q000009:adverse effects / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D003024:Clozapine / Q000266:history; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D049673:History, 20th Century; D006801:Humans; D008297:Male; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003024:Clozapine