European Group for the Study of Resistant Depression (GSRD)--where have we gone so far: review of clinical and genetic findings.

The primary objective of this review is to give an overview of the main findings of the European multicenter project "Patterns of Treatment Resistance and Switching Strategies in Affective Disorder", performed by the Group for the Study of Resistant Depression (GSRD). The aim was to study methodological issues, operational criteria, clinical characteristics, and genetic variables associated with treatment resistant depression (TRD), that is failure to reach response after at least two consecutive adequate antidepressant trials. The primary findings of clinical variables associated with treatment resistance include comorbid anxiety disorders as well as non-response to the first antidepressant received lifetime. Although there is a plethora of hints in textbooks that switching the mechanism of action should be obtained in case of nonresponse to one medication, the results of the GSRD challenge this notion by demonstrating in retrospective and prospective evaluations that staying on the same antidepressant mechanism of action for a longer time is more beneficial than switching, however, when switching is an option there is no benefit to switch across class. The GSRD candidate gene studies found that metabolism status according to cytochrome P450 gene polymorphisms may not be helpful to predict response and remission rates to antidepressants. Significant associations with MDD and antidepressant treatment response were found for COMT SNPs. Investigating the impact of COMT on suicidal behaviour, we found a significant association with suicide risk in MDD patients not responding to antidepressant treatment, but not in responders. Further significant associations with treatment response phenotypes were found with BDNF, 5HTR2A and CREB1. Additional investigated candidate genes were DTNBP1, 5HT1A, PTGS2, GRIK4 and GNB3.