A: We were surprised by these findings. No one has looked at brain function in patients taking placebo, because it is thought to be "no treatment." We expected that placebo would have no effect on brain activity, whether or not the patients improved. In retrospect, the finding that when patients improve their brain function changes, regardless of the treatment used, should not have been so surprising. The condition of the patient can be improved through many different types of interventions and, whenever this happens, the brain may reflect this improved condition.

What is most surprising about our results is that the changes in brain function that were seen during medication-related improvement were the opposite of the changes that were seen during placebo-related improvement. To our knowledge, this is the first time that treatments that appear to yield the same clinical result are associated with distinct, different changes in brain function.

A: Both the medication responders and the placebo responders in this study had changes in brain function in the prefrontal brain region. This area is implicated in the regulation of mood, as well as motivation and self-observation. The findings of opposite changes in brain function in this area in the two groups suggest that there are several different pathways to improvement, involving perhaps this and other brain areas. It is possible that placebo responders were able to activate different mechanisms that enabled them to report feeling better.

A: Not at all. This study shows that some subjects treated with placebo improve, a fact that already was known. In this study, only 38% of those patients treated with placebo improved, as opposed to more than half of the medication treated subjects. One fact not reported in the paper is what happened at the end of the study, when subjects were told what they really had received. Most of the placebo treated subjects had a deterioration of their mood, and ended up receiving medication. This is consistent with the traditional view of the placebo response, that it does not yield enduring benefit.

The most important point to make is that patients with depression must seek out effective treatment, and not give up hope. Studies such as this one are identifying new ways to help patients get better, even those who may have suffered with the illness for years.

A: We plan to examine what aspects of treatment are important to engender the "placebo response." These patients got better not just because of a pill, but because they were participating in a study that offered them human contact and hope, among other things. Exactly what factors are critical must be determined. In addition, we plan to determine how long the placebo response can last, and how to potentially extend the benefits of the placebo response. Placebo commonly does not cure patients of their illnesses. Many of these patients who "responded" to placebo did not remain well, but quickly relapsed.