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

Summary & key facts

This paper reviews about 20 years of animal and human studies about two brain-made chemicals, allopregnanolone (often called Allo) and pregnanolone (PA). The authors say that some people with post-traumatic stress disorder (PTSD) make less of these chemicals. These chemicals normally help the brain’s “brake” system that calms activity. Low production is linked to worse, longer-lasting PTSD and to poor response to treatment. The paper suggests measuring these chemicals in people could help doctors match treatments to who needs them, but the idea still needs more testing in humans.

Key facts:

• Allopregnanolone and pregnanolone are neuroactive steroids, which means they are chemicals made by the brain and glands that can change how brain cells calm each other down.
• These neurosteroids help a brain receptor that acts like a brake on brain activity. When levels of these chemicals are low, the balance between calming and exciting signals in the brain can be disturbed.
• Across studies in people and in rodents over the past 20 years, researchers found that a subgroup of people with PTSD show deficient production of these neurosteroids.
• Lower production of these neurosteroids has been linked to higher PTSD risk, more severe symptoms, longer-lasting illness, and worse response to current treatments in the people studied.
• Stress, some drugs, and social isolation can change how much of these neurosteroids the body and brain make. That means life events and medicines might affect the chemical balance that matters for PTSD.
• The authors propose using careful lab measurements of these neurosteroids to find individual patterns of dysfunction. That could lead to more targeted, personalized treatments, but this is still a research idea and not yet a proven clinical

Abstract

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 GABAA 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.

Topics

Anesthesia and Neurotoxicity Research Stress Responses and Cortisol Tryptophan and brain disorders

Categories

Behavioral Neuroscience Life Sciences Neuroscience

Tags

GABAA receptor Internal medicine Medicine Neuroactive steroid Neuroscience Pathophysiology Psychology Receptor

Conditions & symptoms

PTSD Substance abuse disorder Anxiety or worry Feeling disconnected from others Poor sleep