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GABA-ergic Modulators: New Therapeutic Approaches to Premenstrual Dysphoric Disorder

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Abstract

Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal phase of the menstrual cycle. Although menstrual-related affective dysfunction is responsible for considerable functional impairment and reduction in quality of life worldwide, currently approved treatments for PMDD are suboptimal in their effectiveness. Research over the past two decades has suggested that the interaction between allopregnanolone, a neurosteroid derivative of progesterone, and the gamma-aminobutyric acid (GABA) system represents an important relationship underlying symptom genesis in reproductive-related mood disorders, including PMDD. The objective of this narrative review is to discuss the plausible link between changes in GABAergic transmission secondary to the fluctuation of allopregnanolone during the luteal phase and mood impairment in susceptible individuals. As part of this discussion, we explore promising findings from early clinical trials of several compounds that stabilize allopregnanolone signaling during the luteal phase, including dutasteride, a 5-alpha reductase inhibitor; isoallopregnanolone, a GABA-A modulating steroid antagonist; and ulipristal acetate, a selective progesterone receptor modulator. We then reflect on the implications of these therapeutic advances, including how they may promote our knowledge of affective regulation more generally. We conclude that these and other studies of PMDD may yield critical insight into the etiopathogenesis of affective disorders, considering that (1) symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics, and (2) GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signaling in the brain.

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    Christopher Sikes-Keilp & David R. Rubinow

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Dr. Rubinow is on the Scientific Advisory Board of (and has received honoraria and stock options from) Sage Therapeutics. He is also on the Scientific Advisory Boards of Sensorium Therapeutics and Embarq Neuro. He also has consulted to Arrivo Therapeutics. Dr. Sikes-Keilp reports no conflicts of interest.

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Sikes-Keilp, C., Rubinow, D.R. GABA-ergic Modulators: New Therapeutic Approaches to Premenstrual Dysphoric Disorder. CNS Drugs 37, 679–693 (2023). https://doi.org/10.1007/s40263-023-01030-7

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