1/2 Allopregnanolone and Dynamic GABA-A Receptor Plasticity in Selective Serotonin Reuptake Inhibitor Responsive Premenstrual Dysphoric Disorder

PROJECT SUMMARY Premenstrual dysphoric disorder (PMDD) is a severe affective disorder impacting millions of women worldwide, thought to be due to impaired sensitivity to hormone fluctuations across the menstrual cycle. Low-dose selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for PMDD, but their mechanism in PMDD is poorly understood. Despite this morbidity and limited treatment options, research on PMDD’s pathophysiology and treatment lags behind that of other brain disorders. A potential aspect of PMDD’s pathophysiology is altered interaction between steroid hormones - specifically gamma-aminobutyric acid (GABA)ergic neuroactive steroids (NAS) - and their target, the GABA-A receptor (GABA-A-R). GABAergic NAS, such as the progesterone metabolite allopregnanolone, fluctuate across the menstrual cycle and are associated with luteal phase symptom emergence in PMDD. The proposed study will examine three aspects of GABAergic function in PMDD, to clarify its pathophysiology: 1) GABAergic NAS fluctuations, particularly allopregnanolone (ALLO) and its isomers, 2) GABA-A-R subunit expression, and 3) GABAergic neurosteroidogenic enzyme expression. A key focus of this placebo-controlled trial is to assess how these parameters are affected by low-dose SSRI treatment in women with PMDD, shedding light on treatment mechanism. In this multi-site study, we will assess 288 women with regular menstrual cycles (72 controls, 216 with PMDD), across the luteal phase of the menstrual cycle. In a second luteal phase, women with PMDD will be randomized to sertraline or placebo. We will capture three outcome measures: 1) plasma NAS changes within subjects at multiple timepoints across the luteal phase using precise gas chromatography/mass spectrometry (GC/MS) methods, 2) GABA-A-R subunit expression across the luteal phase in blood cells measured via real-time polymerase chain reaction (RT-qPCR), and 3) GABAergic neurosteroidogenic enzyme expression. We will compare controls versus women with PMDD, and within those with PMDD compare sertraline versus placebo. The study explores a mechanistic hypothesis about NAS dynamics and GABA-A-R plasticity in women with PMDD, and focuses on biologically relevant treatment target engagement. The multiple investigators bring complementary expertise; Drs. Hantsoo and Payne in prospective studies of reproductive affective disorders, and Dr. Pinna in applying state-of-the-art methods to study the impact of NAS on GABA-A-R function. This study represents a critical step in elucidating NAS and GABA-A-R dynamics in women with PMDD when treated with low-dose SSRIs, which may shed light on both pathophysiology and treatment response mechanisms. Understanding PMDD’s pathophysiology may also inform treatment development, i.e.GABA-modulating drugs that have recently emerged as treatments for postpartum depression. Assessing parameters affected by SSRI in PMDD could lead to developing a personalized medicine approach.