Major depressive disorder (MDD) is a debilitating disease with a high prevalence (16.2% according to the most recent National Comorbidity Survey (1
)). In the year 2020, depressive disorders are estimated to be one of the top ranked disease burdens world wide (2
). Finding more effective interventions for depression must therefore have high priority for clinical and basic research efforts.
With pharmacological treatment options available today, only a minority of the patients disabled by depression experience full remission (4
). In addition, clinical and pharmacogenetic studies have shown strong individual variation in treatment outcome and side effects with antidepressants (7
Different methods are used to elucidate possible genetic determinants of susceptibility for depression as well as prediction of success when treating the disease. While whole-genome assays will shortly become available, up to now most studies have employed candidate-gene approaches based on known gene function in mood and depression.
Candidate genes regularly include members of the main neurotransmitter systems such as serotonin, dopamine and glutamate (11
). However, other pathways that have influence over several neuroendocrine systems have recently received considerable attention. One such pathway, the Hypothalamic-Pituitary-Adrenal axis (HPA-axis), plays a major role in stress hormone regulation (14
A study by Binder and collaborators (16
) has suggested that single-nucleotide polymorphisms (SNPs) in the FKBP5
-gene are associated with outcome of antidepressant treatment and recurrence in major depression. The FKBP5
-gene codes for a chaperone protein important for fine-tuning of the HPA-axis. In further analyses, it was shown that the TT-homozygote genotype of the marker rs1360780 was most strongly associated with better treatment response and more previous depressive episodes. No association of FKBP5
markers with disease status was observed.
While the Binder et al. study provided a very interesting new lead on involvement of FKBP5 in treatment response, the study had several limitations. The sample size was relatively modest for detecting risk loci of small effect, the study only included hospitalized patients and contained both psychotic and non-psychotic depression, and the sample was limited to individuals of White non-Hispanic ancestry.
The objective of the present study was to investigate correlation of the associated markers with treatment-response in an ethnically diverse sample of non-hospitalized, non-psychotic depressed patients using data generated within the STAR*D study, the largest treatment-response study carried out to date.
The genetic sub-study of STAR*D was carried out following a pre-agreed analysis plan employing a two-split design in order to correct for multiple testing. Findings of significant associations have been summarized in two reports (9
) that did not include the FKBP5
-gene among the reported associations. However, the split sample design we employed may have reduced power to detect a genuine association with FKBP5
In order to maximize power to detect such association, this report therefore did not employ a two-split design. Rather, data from all 1809 treated individuals with available genotypes were analyzed together herein. Correction for multiple testing was carried out using the Bonferroni method. Similarly to the Binder et al. study, we also tested whether FKBP5 markers might show association with the diagnosis of depression itself and the number of depressive episodes.