The role of neuroactive steroids in psychiatric and neurological disorders: Neurobiology and therapeutic perspectives.

Neuroactive steroids, encompassing both peripherally derived hormones and neurosteroids synthesized de novo within the central nervous system, have emerged as pivotal modulators of brain physiology and pathology. This rapidly evolving field is transforming our understanding of how steroid signaling influences neural function, paving the way for novel biomarkers and targeted therapeutic strategies. Acting on specific neuronal receptors, these compounds finely regulate excitability, synaptic integration, and network dynamics, thereby linking endocrine and neural mechanisms in the maintenance of brain homeostasis. Over the past three decades, these mediators have been shown to exert broad influences on neurotransmitter systems, the hypothalamic-pituitary-adrenal (HPA) axis, and neuroinflammatory pathways. Mounting evidence implicates both neurosteroids and peripheral neuroactive steroids in the pathophysiology of numerous psychiatric and neurological disorders, including depression, bipolar disorder, anxiety disorders, PTSD, schizophrenia, autism spectrum disorder, substance use disorders, epilepsy, Alzheimer's disease, Parkinson's disease, tic disorders, and multiple sclerosis. This review synthesizes current evidence on how neurosteroids (and, more broadly, neuroactive steroids) contribute to the endogenous regulation of neural excitability, affective reactivity, and immune signaling, and explores how their dysregulation may represent a shared mechanism of vulnerability across diverse brain disorders. Finally, we highlight emerging therapeutic opportunities, underscored by recent advances such as zuranolone and ganaxolone, and discuss future challenges in optimizing delivery, enhancing receptor specificity, and refining clinical trial design to establish neurosteroid-based interventions as a versatile platform for treating and preventing complex neuropsychiatric disease.