Fewer study participants needed to demonstrate superior antidepressant efficacy when using the Hamilton melancholia subscale (HAM-D6) as outcome measure

Østergaard SD, Bech P, Miskowiak KW

 J Affect Disord. 2016 Jan 15;190:842-5

Abstract

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.

The effect of recombinant erythropoietin on plasma brain derived neurotrophic factor levels in patients with affective disorders: a randomised controlled study

Vinberg M, Miskowiak K, Hoejman P, Pedersen M, Kessing LV

PLoS One. 2015 May 26;10(5):e0127629

Abstract
The study aims to investigate the effect of repeated infusions of recombinant erythropoietin (EPO) on plasma brain derived neurotrophic factor (BDNF) levels in patients with affective disorders. In total, 83 patients were recruited: 40 currently depressed patients with treatment-resistant depression (TRD) (Hamilton Depression Rating Scale-17 items (HDRS-17) score >17) (study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS) ≤ 14) (study 2). In both studies, patients were randomised to receive eight weekly EPO (Eprex; 40,000 IU) or saline (0.9% NaCl) infusions in a double-blind, placebo-controlled, parallel–group design. Plasma BDNF levels were measured at baseline and at weeks 5, 9 and at follow up, week 14. In contrast with our hypothesis, EPO down regulated plasma BDNF levels in patients with TRD (mean reduction at week 9 (95% CI): EPO 10.94 ng/l (4.51-21.41 ng/l); mean increase at week 9: Saline 0.52 ng/l, p=0.04 (-5.88-4.48 ng/l) p=0.04, partial ŋ2=0.12). No significant effects were found on BDNF levels in partially remitted patients with BD (p=0.35). The present effects of EPO on BDNF levels in patients with TRD point to a role of neurotrophic factors in the potential effects of EPO seen in TRD and BD. The neurobiological mechanisms underlying these effects and the interaction between EPO and peripheral levels on BDNF need to be further elucidated in human studies including a broad range of biomarkers.

TRIAL REGISTRATION:
ClinicalTrials.gov: NCT00916552.