Sickness behaviour and depression: An updated model of peripheral-central immunity interactions

Current research into mood disorders indicates that circulating immune mediators participating in the patho-physiology of chronic somatic disorders have potent influences on brain function. This paradigm has brought to the fore the use of anti-inflammatory therapies as adjunctive to standard antidepressant therapy to improve treatment efficacy, particularly in subjects that do not respond to standard medication. Such new practice re-quires biomarkers to tailor these new therapies to those most likely to benefit but also validated mechanisms of action describing the interaction between peripheral immunity and brain function to optimize target interven-tion. These mechanisms are generally studied in preclinical models that try to recapitulate the human disease, MDD, through peripherally induced sickness behaviour. In this proposal paper, after an appraisal of the data in rodent models and their adherence to the data in clinical cohorts, we put forward a modified model of periphery -brain interactions that goes beyond the currently established view of microglia cells as the drivers of depression. Instead, we suggest that, for most patients with mild levels of peripheral inflammation, brain barriers are the primary actors in the pathophysiology of the disease and in treatment resistance. We then highlight data gaps in this proposal and suggest novel lines of research.

Automated summary

Current research suggests that immune mediators related to chronic somatic disorders have significant effects on brain function in mood disorders. Anti-inflammatory therapies are being explored as adjunctive treatments to standard antidepressants to improve efficacy, especially in non-responsive patients. Biomarkers are needed to personalize these therapies for optimal outcomes, along with a better understanding of the interaction between peripheral immunity and brain function. This proposal presents a modified model of periphery-brain interactions, suggesting that brain barriers play a crucial role in the pathophysiology and treatment resistance of mood disorders, particularly in patients with mild peripheral inflammation.