Introduction: Neuroprogression has been defined as pathological reorganization of the central nervous system (CNS) along the course of severe psychiatric disorders. Ιn the context of post-traumatic stress disorder (PTSD), stress affects neural substrate reactivity and promotes brain rewiring resulting in symptoms expression and increased vulnerability to adversity. While PTSD has a lifetime prevalence of 8% in the general population, its neurochemical basis is yet to be discussed. This review examines the current evidence supporting the PTSD neuroprogression hypothesis focusing on neurochemical biomarkers and therapeutic targets.

Methods: Mechanistic and clinical studies focusing on molecules mediating neuroprogression in PTSD are summarized based on PubMed/MEDLINE search and relevant articles, which have been presented at international conferences. Original, peer-reviewed studies and systematic reviews in English were included.

Results: The biological underpinnings of neuroprogression in PTSD involve cross talk between the stress and immune systems. Elevated levels of circulating peripheral IL-6, IL-1β, TNFα, and interferon ϒ have been identified in previous studies. The landscape of neuroprogression in PTSD involves chronic sympathetic and renin-angiotensin-aldosterone system (RAAS) hyperarousal glutamatergic excitotoxicity, alterations in neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF), and underactivity of the parasympathetic, serotonergic, dopaminergic, and GABAergic system. Their involvement appears linked to the progression from PTSD to mental or physical conditions

Conclusions: The neuroprogression hypothesis is leading to the re-conceptualization of PTSD as a potentially progressive psychiatric disorder with a corollary of medical implications. In this frame identifying involved molecules that can serve as biomarkers or therapeutic targets is of high importance.