Identification of candidate genes that mediate depressive side effects of pegylated IFN-α2a in patients with chronic hepatitis C

Aims and background: Combination therapy with pegylated interferon IFN-α plus ribavirin has been shown to be the most effective treatment for chronic hepatitis C (HCV). One of the most common side effects is IFN-induced severe depression, which can impair quality of life, reduce treatment adherence and even lead to suicide. Therefore, defining relevant risk factors for IFN-α induced depression is essential for designing preventative treatment strategies. This study assessed the primary transcriptional response to IFN-α2a plus ribavirin in HCV patients to identify possible candidate genes that mediate the depressive side effects of IFN-α.

Patients and methods: A total of 26 Caucasian patients with histologically proven chronic hepatitis C were treated with standard combination therapy consisting of pegylated IFN-α2a (Pegasys, 180µg once weekly) for 12 months (HCV genotype 1, n=25) or 6 months (HCV genotype 2/3, n=1/7) in combination with ribavirin (800–1200mg daily). RNA was isolated (PAXgene, PreAnalytiX) from peripheral blood which was collected 12h before and 12h after the first injection of IFN-α. The transcriptional profile was analysed using human genomic microarrays (Affymetrix HG U133A) and quantitative real-time RT-PCR. Array data were normalized (RMA Express software) and fold changes were calculated from before and after IFN injection. Fold change values were subjected to significance analysis (SAM software) and class prediction analysis (PAM software) to identify genes which are differentially regulated in patients with or without IFN-induced depression. The patients were investigated using the Mini-DIPS, a semi-structured interview, which facilitates relevant diagnostic criteria according to the four axis of the DSM-IV. Furthermore, depression scores were evaluated with psychometric instruments, Beck's Depression Inventory and Hospital Anxiety and Depression Scale. During the 12 months interferon therapy psychiatric interviews were conducted every three months.

Results: 14/26 patients in this cohort suffered from IFN-induced depression. Using class prediction analysis, the development of an IFN-induced depression could be predicted by 24 genes with 95% accuracy. 10 genes were significantly higher expressed in patients with IFN-induced depression compared to patients without depression. 6 of these genes were identified as typical interferon response genes. Interestingly, the remaining 4 genes were previously described as being associated with recurrent major depression. These results could be verified by quantitative RT-PCR. There were no significant differences in basal gene expression before IFN injection between both groups.

Conclusions: These data suggest a direct role of IFN response genes in generating depression as side effect of antiviral therapy which is predictable in the initial phase of therapy. The functional analysis of the differentially regulated genes that were identified in this study could lead to the discovery of novel drug targets to improve the efficacy of and adherence to HCV therapy. Finally, we are currently investigating whether the genes identified in this study play a role in IFN unrelated major depression.