With regard to objective 1 we have found that the immune defects in MDD and BD differ.
1. MDD is characterized by premature senescence of the T helper and monocyte/macrophage compartment leading to mild low grade inflammation, which under circumstances of childhood trauma and obesity will lead to more signs of inflammation (clear monocyte inflammatory activation, higher serum levels of pro-inflammatory cytokines).
2. BD is characterized by a defect in the generation of T effector memory cells and a reduced level of IL-7 (a T cell differentiation factor). T central memory cells, including Th17 cells are increased. During depressive or manic episodes stronger signs of low grade inflammation are evident (monocyte activation, increase in inflammatory cytokines)
With regard to objective 2 we have developed simplified and reliable blood tests. APD (commercial partner, Belgium) has developed a set of reliable and sensitive ELISAs for IL-7, IL-6, hsCRP, BDNF and sCD25, while PRONTO (Israel) has developed a finger prick assay to test for the immune blood cell defects using limited gene expression profiles.
With regard to objective 3 two double blind placebo-controlled trials using low dose IL-2 have been carried out. Outcomes of both trial are a break through showing a novel way for treating depression. A significant increase in T regs was found after 5 days low dose IL-2 treatment , while depression scores improved reaching significance versus placebo at the end of the trials (day 60). Positive significant correlations were found between the improvement of the depression scores and the increase of T regs. Low dose IL-2 treatment hardly had side-effects. Patients with low signs of T cell activity, low numbers of naïve CD4+ and CD8+ T cells, and high signs of low grade inflammation had the highest chance of a favorable response to low dose IL-2.
In another small open label trial 5 depressed immune-deficient patients were treated with thymus hormone (Thymalfasin). Treatment with Thymalfasin was safe, did correct signs of T cell senescence and improved depression scores (particularly anxiety scores) in a similar fashion as treatment as usual with regular antidepressants.
For objective 4 we treated depressed patients with physical training schemes (spinning). Controls were treated as usual (TAU). We wanted to find an immune senescence parameter which predicts favorable outcome of spinning (it is known that physical activity combats immune senescence). Data indeed show that a premature senescence of T helper cells (as measured by a high percentage of T helper memory cells, in particular T helper central memory cells) is a predictor of better outcome of add-on spinning therapy iand preselection of patients via this immune senescence characteristic improved complete remitter percentages after half a year from 10% (TAU group) to 50% (spinning group plus TAU group).
By combining available evidence from the literature (disability weights, relapse rate, and empirical costs of depression) and available data (the remission and immune signature rates from the spinning cohort), we built an economic model of the health benefits of immune signature based approaches versus current practice. Findings (though preliminary) indicate that immune signature stratified add-on spinning therapy renders both a substantial decrease in the disability from depression and a substantial cost reduction in five years compared to the current practice.
