We agree that this is the only feasible design for a broad –spectrum agent. We disagree with Marder et al, however, in the interpretation of a finding of a difference in negative symptom between the two agent in a trail of this design. Marder et al acknowledge the problem of misinterpretation of a difference that is based on what might be called secondary as opposed to primary negative symptom, ie, related to poorly controlled positive symptom, extra pyramidal symptom, or depression caused by the standard agent. They feel that problem can be addressed by selection of an appropriate standard agent and dose for that agent. We are not confident that this problem can be addressed in this manner, and we have previously discussed this concern. In our view, without a placebo arm in such a trail, a finding of an advantage for the new “broad-spectrum” agent over the “standard” agent on negative symptom cannot be clearly interpreted with regard to an effect on primary negative symptom. One interpretation, of course, would be that the new agent improves negative symptoms, and the standard agent is having no effect. A second interpretation would be that the new agent in fact has little benefit on negative symptom but the standard agent is actually causing negative symptoms. A third possibility is that in fact both agent are causing negative symptom, but the newer agent has less of this negative effect. It’s not that we don’t feel that such a difference is a benefit but rather that such a difference without a placebo arm for reference cannot be clearly interpreted with regard on primary negative symptoms. Of course, if the new agent returns patients to an entirely normal state with no negative active symptom, there would be no problem in interpretation. Such an outcome seems unlikely.