Alterations in leukocyte transcription factor activities are associated with major depressive disorder and antidepressant treatment

Rationale : Previous work in our and other laboratories has demonstrated dysregulated immune function and cellular oxidative stress responses in subjects with Major Depressive Disorder (MDD). In the current study, we determined whether there were differences in the transcriptional regulation of these pathways in leukocytes from subjects with MDD, and healthy controls. Methods : We used genome-wide transcriptional profiling (Affymetrix U133 Plus 2 oligonucleotide arrays) and promoter-based bioinformatic strategies (TELiS) to assess transcription factor (TF) activity in leukocytes from 15 unmedicated MDD patients versus 19 age-, gender-, and ethnicity-matched healthy controls, prior to initiation of antidepressant therapy, and after 8 weeks of sertraline treatment. Results : Bioinformatic analysis of 39,000 differentially expressed genes indicated increased transcriptional activity of cAMP Response Element-Binding (CREB) factor, Interferon Response Factors, and the oxidative stress-responsive Nuclear Factor (erythroid-derived 2)-like 2 (NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not CREB or interferon response factor activities. Several other transcriptionally regulated pathways previously associated with depression, including the glucocorticoid receptor (GR), nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), and early growth response proteins 1-4 (EGR1-4) pathways, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized in previous research. Quantitative RT-PCR analysis confirmed the expression profiling data. Conclusions : These results are consistent with the hypothesis that oxidative stress and innate antiviral responses may be involved in MDD by activating immune cell transcriptional pathways, and that successful antidepressant therapy may result in reduced oxidative stress responses at the level of gene transcription.