Neuroactive steroids and the pathophysiology of PTSD: Biomarkers for treatment targeting

Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder that arises after acute or chronic exposure to threatened death, serious injury, or sexual violence. The pathophysiology of PTSD is complex and involves dysregulation of multiple interacting brain regions and neurobiological systems including the sympathetic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, and the immune system. Deficient biosynthesis of neurosteroids that positively modulate GABA_A receptor function, including allopregnanolone (Allo) and its equipotent stereoisomer pregnanolone (PA), also affects a subpopulation of individuals with PTSD and is associated with increased PTSD risk, severity, chronicity and treatment resistance. The synthesis of these neuroactive steroids by the brain, adrenal glands, and gonads may be influenced by stress, drugs, social isolation and other factors with impact on the balance of inhibitory versus excitatory (I/E) neurotransmission in brain. These neuroactive steroids are thus considered a potential target for new PTSD therapeutics. In this review, we first present studies in humans and rodents performed over the past 20 years that have shaped our current understanding of the role of Allo and PA in the pathophysiology of PTSD. We will also discuss the means by which rigorous measurement of neurosteroids can be used to identify individually-variable dysfunctional patterns of neurosteroidogenesis that could be targeted to prevent or treat PTSD. This broadened precision medicine approach to diagnosis of neuroendocrinopathies associated with PTSD may aid in reducing PTSD risk and facilitating the effective prescribing of PTSD therapeutics. We hope that such an approach will also forestall development of individually variable but common psychiatric, substance abuse, and medical PTSD-comorbidities.