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Neurosteroids as Novel Antidepressants and Anxiolytics: GABA-A Receptors and Beyond

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Neurosteroids as Novel Antidepressants and Anxiolytics: GABA-A Receptors and Beyond

Charles F Zorumski et al. Neurobiol Stress.

Abstract

The recent FDA approval of the neurosteroid, brexanolone (allopregnanolone), as a treatment for women with postpartum depression, and successful trials of a related neuroactive steroid, SGE-217, for men and women with major depressive disorder offer the hope of a new era in treating mood and anxiety disorders based on the potential of neurosteroids as modulators of brain function. This review considers potential mechanisms contributing to antidepressant and anxiolytic effects of allopregnanolone and other GABAergic neurosteroids focusing on their actions as positive allosteric modulators of GABAA receptors. We also consider their roles as endogenous "stress" modulators and possible additional mechanisms contributing to their therapeutic effects. We argue that further understanding of the molecular, cellular, network and psychiatric effects of neurosteroids offers the hope of further advances in the treatment of mood and anxiety disorders.

Keywords: Allopregnanolone; Brexanolone; SGE-217; Steroid enantiomers; Tonic inhibition.

Conflict of interest statement

CZ and SP are members of the Scientific Advisory Board of Sage Therapeutics and CZ, SP and DC have stock in Sage Therapeutics. Sage Therapeutics was not involved in writing or review of this manuscript.

Figures

Fig. 1
Fig. 1
Typical pharmacological effects of NAS PAMs on GABAA receptor function at the whole-cell level. NAS at a modest, fixed concentration usually shift the GABA EC50 value to the left and increase the maximum GABA response, i.e., increase agonist efficacy. Because GABA is a lower efficacy agonist on δ-containing receptors than on γ2-containing receptors, NAS may have a somewhat larger effect on δ containing receptors.
Fig. 2
Fig. 2
The figure shows structures of AlloP and several other NAS discussed in the text.
Fig. 3
Fig. 3
Possible endogenous and exogenous NAS roles in depression-like syndromes. A, B. Endogenous NAS levels change as a result of stress and postpartum hormonal changes. In stress (panel A), acute stressors increase NAS levels, but more chronic stress may lead to a state of NAS deficiency, contributing to symptoms. B. In pregnancy, NAS levels rise, and GABA receptor expression decreases, yielding stable inhibition. Following the sudden loss of NAS at parturition (dotted red line), recovery of GABA receptor expression lags, creating a hyperexcitable state that may persist and participate in symptomology of postpartum depression. C, D. Two intracellular pathways through which NAS may have underappreciated beneficial effects: by activating autophagy (panel C) and by inhibiting neuroinflammation (panel D). See text for details and citations. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

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