Clinical lessons from GENDEP for the treatment of depression

Abstract

In GENDEP, a European multicentre pharmacogenomic study http://gendep.iop.kcl.ac.uk/results.php, subjects with major depression were treated with escitalopram (ESC) or nortriptyline (NOR), in a part-randomised potential crossover design, and prospectively rated for response and ADRs with measures including the MADRS, HDRS, BDI, UKU, and ASEC (a self-report measure developed for GENDEP, Uher et al, in press). Factor analysis and Item Response Theory applied to the three measures of depression employed in the study generated three symptom dimensions. Mixed linear regression models showed no difference between ESC and NOR on the three original scales, but symptom dimensions revealed drug-specific advantages: observed mood and cognitive symptoms improved more with ESC than with NOR; neurovegetative symptoms improved more with NOR than with ESC. CYP2C19 genotypic category significantly predicted steady-state (week 8) ESC concentration. Analysis of baseline weight as a predictor revealed that lower BMI predicted better response to NOR. There was good agreement between the UKU and the ASEC, and urinary symptoms, dry mouth, blurred vision, and orthostatic hypotension predicted discontinuation of either drug.