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

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $485,915

## Abstract

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.

## Key facts

- **NIH application ID:** 10975641
- **Project number:** 1R01MH134904-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Liisa Victoria Hantsoo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $485,915
- **Award type:** 1
- **Project period:** 2024-09-11 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975641

## Citation

> US National Institutes of Health, RePORTER application 10975641, 1/2 Allopregnanolone and Dynamic GABA-A Receptor Plasticity in Selective Serotonin Reuptake Inhibitor Responsive Premenstrual Dysphoric Disorder (1R01MH134904-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10975641. Licensed CC0.

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