Neurosteroids in Schizophrenia: Pathogenic and Therapeutic Implications

Abstract

Neurosteroids are a group of important endogenous molecules affecting many neural functions in the brain. Increasing evidence suggests a possible role of these neurosteroids in the pathology and symptomatology of schizophrenia (SZ) and other mental disorders. The aim of this review is to summarize the current knowledge about the neural functions of neurosteroids in the brain, and to evaluate the role of the key neurosteroids as candidate modulators in the etiology and therapeutics of SZ. The present paper provides a brief introduction of neurosteroid metabolism and distribution, followed by a discussion of the mechanisms underlying neurosteroid actions in the brain. The content regarding the modulation of the GABAA receptor is elaborated, given the considerable knowledge of its interactions with other neurotransmitter and neuroprotective systems, as well as its ameliorating effects on stress that may play a role in the SZ pathophysiology. In addition, several preclinical and clinical studies suggested a therapeutic benefit of neurosteroids in SZ patients, even though the presence of altered neurosteroid pathways in the circulating blood and/or brain remains debatable. Following treatment of antipsychotic drugs in SZ, therapeutic benefits have also been linked to the regulation of neurosteroid signaling. Specifically, the neurosteroids such as pregnenolone and dehydroepiandrosterone affect a broad spectrum of behavioral functions through their unique molecular characteristics and may represent innovative therapeutic targets for SZ. Future investigations in larger cohorts with long-term follow-ups will be required to ascertain the neuropsychopharmacological role of this yet unexploited class of neurosteroid agents.

Neurobehavioural complications of sleep deprivation: Shedding light on the emerging role of neuroactive steroids

“…As highlighted above, our findings suggest that neurosteroids may contribute to the link between SD and gating disorders. In line with this idea, we and others have pointed to the involvement of these molecules in the pathophysiology of schizophrenia, Tourette's syndrome and PTSD . Future studies will be needed to fully evaluate the integration of neurosteroids with other pathogenic factors in these disorders.…”

How promising is neuroactive steroid drug discovery?

“…NAS may be implicated in the regulation of dopamine system directly or through GABA modulation, as indicated by several reports in the rat model [9].…”

“…Certain NASs present significant affinity for Sigma-1 receptors in binding affinity studies. By interacting with Sigma-1 receptors, they may affect other systems such as the glutamatergic and the cholinergic ones [9].…”

Potentialités thérapeutiques des neurostéroïdes en psychiatrie

“…Au cours des années 1990, plusieurs essais cliniques ont montré que la DHEA permettait de réduire les symptômes dépressifs chez des patients souffrant de dépression majeure, en particulier des patients âgés (Wolkowitz et al, 1997(Wolkowitz et al, , 1999. La DHEA a également été administrée chez des patients atteints de schizophrénie dans de nombreuses études, qui ont conclu à des efficacités contrastées pour réduire les symptômes négatifs (Ritsner, 2010 ;Cai et al, 2018). La PREG a fait, elle aussi, l'objet de plusieurs études cliniques chez des patients schizophrènes (Ritsner, 2010).…”