Citation

Kaufman KR. Seizure 2002; 11(1): 51-56.

Copyright

(Copyright © 2002, Elsevier Publishing)

DOI

10.1053/seiz.2001.0585

PMID

11888261

Abstract

RATIONALE: AEDs are increasingly evaluated for efficacy in bipolar disorders utilizing double-blind, placebo-controlled, randomized clinical trials (RCTs) as required by the FDA. However, the risk to patients is under-estimated in trial design. Bipolar depression has a significant risk for suicide; bipolar episodes can lead to kindling with increased long-term morbidity; rapid regression may occur during the placebo phase or during dose ranging trials with resultant active suicide status. The associated risks mandate that the ethics of FDA-required protocols are addressed.
METHOD: Comparative analysis and literature review of bipolar and epilepsy research designs.
RESULTS: In psychiatry, all INDs require RCTs for approval. In epilepsy, AEDs are initially approved as add-on agents only. Once AEDs have demonstrated add-on efficacy, cross-over studies comparing active AEDs, sub-optimal dosing paradigms, new-onset, and pre-surgical inpatient placebo trials are utilized to prove efficacy of the new AED in monotherapy. Ethical considerations to avoid seizures and to minimize risks to subjects have led to newer clinical trial designs.
CONCLUSIONS: The FDA initially requires add-on studies with new AEDs due to the risk of seizures during the placebo phase. The author argues that bipolar research warrants similar add-on studies to prove efficacy because the risk of suicide and increased long-term morbidity in the bipolar population is as significant as the risk of seizures in the epilepsy population. Although the number of patients needed to prove statistical efficacy would increase, the safety of such research would also markedly increase. The author further concludes that with the risk of suicide during bipolar research, ethical considerations require increased frequency of patient contact with a significant other co-signing the informed consent for research and serving as a contact for the coordinator.

Language: en

Keywords

Anticonvulsants; Antimanic Agents; Biomedical and Behavioral Research; Bipolar Disorder; Dose-Response Relationship, Drug; Epilepsy; Ethics, Medical; Humans; Randomized Controlled Trials as Topic; Risk Factors; Suicide; Suicide Prevention