We are responding to the letter from Bernard Carroll and Robert Rubin regarding our paper ‘Clinical and Biological Effects of Mifepristone Treatment for Psychotic Depression’, which was published in your journal in March 2006 (Flores et al, 2006). Although Rubin and Carroll make some interesting points, they have overlooked the larger picture. Our study was an NIH-funded, exploratory study begun in 1999 to examine whether there was a signal that would support further investigation into the mechanism and efficacy of mifepristone as a treatment for major depressive disorder with psychotic features (PMD). A medication trial of only 30 patients is obviously not a definitive study on any treatment. Below we respond to their specific points. (1) Carroll and Rubin state that we ‘used an uncorrected chi-square to test to obtain this result, even though the frequency is less than 5 in one of the cells of the 2 2 distributiony .’ It is true that the p-value computed is an approximation, as is the p-value using the Yates’ correction, as is the p-value that Carroll and Rubin report using the Fisher’s Exact test, based on the assumption that all four marginals are kept constant in resampling. The issue here is not the exact p-value but the indication that the treatment effect may have an effect size of clinical significance for future studies. Incidentally, a Yates correction should be used when an expected cell size is less than 5 and is not based on the actual cell size found. The expected cell sizes in this study were not less than 5 given the high placebo response rates observed in a recent PMD in-patient, add-on trial (DeBattista et al, 2003). Moreover, in a previous criticism of the Belanoff case series (Rubin and Carroll, 2004), they themselves applied an uncorrected w to even smaller cell sizes. The inconsistency is striking. Rubin and Carroll further state, ‘However, similar to our concerns about earlier trials of mifepristone for this disorder (Rubin and Carroll, 2004), we have reservations about the authors’ interpretations of their data.’ Again, their interpretation concerns appear to be linked with statistical significance, for which this pilot study is not powered. We did, however, observe an effect size of 0.7 for psychotic symptoms at 1 week over placebo, which is a moderate effect. We believe this is particularly striking when one considers it was above and beyond the background effects of stable treatment and hospitalization. In the Belanoff et al (2002) study, the effect size for psychotic symptoms for the 600 mg/day dose at the end of 1 week was 0.9. These are dramatic when one considers that antidepressants and atypical antipsychotics have effect sizes of 0.2–0.3 after 6–8 weeks of treatment (eg Faries et al, 2000). Further, large effect sizes have been observed in all of the other small studies published to date on mifepristone in psychotic depression (Belanoff et al, 2001a, 2002). (2) Carroll and Rubin criticize the study for utilizing multiple outcome measures (the BPRS total, the BPRSpositive symptom scale, and the Hamilton Depression Rating Scale). Our hypothesis, first stated in 1985, was that glucocorticoid overactivity played a role in PMD in the pathogenesis of psychotic symptoms and not in depressive symptoms: ‘This hypothesis is not intended primarily to account for why patients become depressed but rather why some depressed patients become psychotic’ (Schatzberg et al, 1985). Depression scores were never intended to be the primary outcome for this research. The authors note we did not observe an antidepressant effect at 1 week but that was exactly what was to be expected from our hypothesis. In our report, we found little effect on depressive symptoms, Cohen’s d1⁄4 0.20, although the Simpson (Simpson et al, 2005) report found marked antidepressant effects at 4 and 8 weeks post 6 days of mifepristone monotherapy. Further studies are needed to determine the effect sizes on both depressive and psychotic symptoms. Online publication: 21 June 2006 at http://www.acnp.org/citations/ Npp062106060380/default.pdf Received 7 June 2006; accepted 9 June 2006 *Correspondence: Dr AF Schatzberg, Department of Psychiatry and Behavoral Sciences, Stanford University School of Medicine, 401 Quarry Road, Administration, 3rd Floor, Stanford, CA 94305-5717, USA, Tel: + 1 650 723 6811, Fax: + 1 650 498 5294, E-mail: afschatz@leland.stanford.edu Neuropsychopharmacology (2006) 31, 2795–2797 & 2006 Nature Publishing Group All rights reserved 0893-133X/06 $30.00