Background In the development of new antidepressant treatments, the failed study has unfortunately become a prevalent problem. The number of failed studies could probably be reduced significantly by applying more informative outcome measures. Previous studies have indicated that the 6-item melancholia subscale (HAM-D₆) of the 17-item Hamilton Depression Rating Scale (HAM-D₁₇) may be more informative than other scales, due to its superior psychometric properties. In the present study we investigated whether the HAM-D₆ had higher informativeness than the HAM-D₁₇ based on data from a randomized placebo-controlled trial (RCT) testing the effect of erythropoietin (EPO) as augmentation therapy in patients with treatment-resistant depression. 

Methods We assessed the scalability (Mokken analysis of unidimensionality), responsiveness (item responsiveness analysis) and ability to show drug-placebo separation (estimation of sample size needed to detect statistically significant difference between EPO and placebo) of the HAM-D₆ and the HAM-D₁₇. 

Results The HAM-D₆ demonstrated higher scalability, higher responsiveness, and better drug-placebo separation compared to the HAM-D₁₇. As a consequence, only 39 participants per group would be required to detect a statistically significant difference between EPO and placebo when using the HAM-D₆ as outcome measure, whereas the required group size for HAM-D₁₇ would be 146 participants. Limitations The EPO RCT was not originally designed to investigate the research questions addressed in this study. 

Conclusions Both for ethical and financial reasons it is of interest to minimize the number of participants in clinical trials. Therefore, we suggest employing the HAM-D₆ as outcome measure in clinical trials of depression.