Unraveling the complex interplay of immunometabolic systems that contribute to the neuroprogression of psychiatric disorders

In this review article we present an integrative overview of parameters and mechanisms underlying psychiatric and neuropsychiatric disorders that involve the immune and autonomic nervous systems along with neurotransmission and specific endocrine mechanisms. At the center of these highly complex and interactive mechanisms is stress and stress perception by the afflicted individual. Stress reactivity is governed by genetic and epigenetic factors that have yet to be fully clarified. Stress is defined as a state of threatened homeostasis following exposure to extrinsic or intrinsic adverse forces. The major pathways activated by stressors are the HPA axis and the autonomic nervous system. Loss of dynamic variability in the autonomic nervous system, during which one branch dominates over the other for extended periods of time and across multiple environmental demands, is associated with illness and eventually chronic disease. This state of dysregulation can be achieved by excessive sympathetic activation, too little parasympathetic activation, or some combination of both. Autonomic dysregulation leads to immune system dysregulation which in turn interferes with the metabolism of tryptophan leading to the formation of toxic and diabetogenic metabolites. We introduce the concept of neuroprogression as a suitable conceptual framework that allows integration of the complex component mechanisms that contribute to recurrence and chronicity of mental disorders if left untreated or undertreated. The complex interactions among the autonomic, endocrine, immune and metabolic systems and associated cascades provide unique opportunities for development of novel therapeutic agents.