Breaking free from the inflammatory trap of depression: Regulating the interplay between immune activation and plasticity to foster mental health

Immune alterations have been widely implicated in the onset, progression, and treatment of major depressive disorder. However, our comprehension of the intricate link between immune function and psychopathology remains fragmented and limited. Here we propose that the interplay between immune function and neural plasticity is key in the transition from psychopathology to mental wellbeing. In particular, any deviation toward an extreme immune activation or suppression leads to a dysregulation in the molecular machinery underlying neural plasticity. Therefore, pro–inflammatory conditions in depressed patients are associated with impaired plasticity, limiting the potential to recover. Patient's confinement within their pathological state is here referred to as an inflammatory trap of depression. The normalization of immune activation reinstates plasticity, thereby restoring the capacity to attain mental wellbeing. Since growing evidence is showing that reinstating plasticity does not lead to an improvement per se but increases the likelihood of recovery, combining the normalization of immune activity with environmental conditions promoting wellbeing is critical to achieve a beneficial outcome. This theoretical framework allows to reconcile key conceptual discrepancies in immunopsychiatry such as the egg and chicken and the nor sufficient nor necessary issues. Overall, we propose that tuning the immune system to promote neural plasticity is a promising approach to refine and develop innovative therapeutic strategies for depression, leading to personalized and highly effective treatments.