Comparative bioethics in bipolar and epilepsy research.
BACKGROUND
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.


METHODS
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.
Kaufman
Kenneth R
KR
UMDNJ-Robert Wood Johnson Medical School, 125 Paterson Street, Suite #2200, New Brunswick, NJ 08901, USA. kaufmakr@umdnj.edu
D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D018692:Antimanic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D004992:Ethics, Medical; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000331:legislation & jurisprudence*; D012307:Risk Factors; D013405:Suicide / Q000523:psychology; D000092864:Suicide Prevention
D000927:Anticonvulsants; D018692:Antimanic Agents