Transcriptomics in Interferon-α-Treated Patients Identifies Inflammation-, Neuroplasticity- and Oxidative Stress-Related Signatures as Predictors and Correlates of Depression

Owing to the unique opportunity to assess individuals before and after they develop depression within a short timeframe, interferon-alpha (IFN-a) treatment for chronic hepatitis C virus (HCV) infection is an ideal model to identify molecular mechanisms relevant to major depression, especially in the context of enhanced inflammation. Fifty-eight patients were assessed prospectively, at baseline and monthly over 24 weeks of IFN-alpha treatment. New-onset cases of depression were determined using the Mini International Neuropsychiatric Interview (MINI). Whole-blood transcriptomic analyses were conducted to investigate the following: (I) baseline gene expression differences associated with future development of IFN-alpha-induced depression, before IFN-alpha, and (2) longitudinal gene expression changes from baseline to weeks 4 or 24 of IFN-alpha treatment, separately in those who did and did not develop depression. Transcriptomics data were analyzed using Partek Genomics Suite (I.4-fold, FDR adjusted p <= 0.05) and Ingenuity Pathway Analysis Software. Twenty patients (34%) developed 1FN-alpha-induced depression. At baseline, 73 genes were differentially expressed in patients who later developed depression compared with those who did not. After 4 weeks of IFN-a treatment, 592 genes were modulated in the whole sample, representing primarily IFN-alpha-responsive genes. Substantially more genes were modulated only in patients who developed depression (n = 506, compared with n = 70 in patients who did not), with enrichment in inflammation-, neuroplasticity- and oxidative stress-related pathways. A similar picture was observed at week 24. Our data indicate that patients who develop IFN-alpha-induced depression have an increased biological sensitivity to IFN-alpha, as shown by larger gene expression changes, and specific signatures both as predictors and as correlates.