We appreciate the thoughtful attention that our article has received from Drs Baldessarini and Viguera and from Dr Volavka. They provide information that is important for investigators to consider when determining the optimal compromise among the scientific requirements of protocol design, clinical considerations, financial considerations, and general burden to patient subjects. Among their several suggestions is consideration of an alternative approach that substitutes low-dose drug treatment for placebo. This has become a rather common practice in Europe, but we believe it is associated with 2 substantial problems. To be effective in the scientific design, the low dose must be inferior treatment to the standard dose. To the extent that this is true, the same ethical issues that must be addressed regarding placebo are relevant. When the intent of the low dose is to provide a no-treatment control, it fails to alter either the safety or ethical considerations related to placebo-controlled studies. We are also concerned that to the extent the low dose is therapeutically effective, it undermines the scientific design and requires an ever-greater number of subjects to provide statistical power. We believe these issues merit much discussion and appreciate the informed commentary of these colleagues.