Premenstrual dysphoric disorder (PMDD), a distinct disorder that effects at least 3% of menstruating women, is associated with significant functional impairment. That PMDD is preferentially responsive to selective serotonin reuptake inhibitor (SSRI) treatment provides strong evidence that serotonergic dysfunction is involved in the pathophysiology, as well as, treatment of PMDD. However, there are substantial clinical and preclinical data to implicate the gamma-aminobutyric acid (GABA) system as a mediator of the clinical efficacy of SSRIs in this disorder. Using proton magnetic resonance spectroscopy (IH-MRS), our group has found that women with PMDD have abnormal central GABAergic regulation in response to menstrual cycle-related fluctuations in neuroactive steroids. Cortical GABA concentrations fluctuate across the menstrual cycle in a diagnosis- and phase-specific fashion with the greatest disparity in cortical GABA levels during the follicular phase, when women with PMDD had significantly lower cortical GABA levels than healthy menstruating controls. Presently, it is unclear whether inhibition of serotonin reuptake or alternatively SSRI modulation of GABAergic function is crucial in the therapeutic action of SSRIs in the treatment of PMDD. In support of the latter, animal and human studies have shown that SSRI administration enhances central production of the potent GABAA receptor agonist, allopregnanolone (ALLO). At baseline, women with PMDD fail to demonstrate a normal GABAergic response to endogenous or exogenous exposure to ALLO. Further, we have found that successful SSRI treatment is associated with an increase in occipital cortical GABA levels during the follicular phase in women with PMDD, essentially """"""""righting"""""""" the abnormal cyclic changes in GABA seen in these women prior to treatment. Therefore, the overarching goal of this proposal is two-fold; to confirm these early 1H-MRS findings in a group of women undergoing fluoxetine treatment for PMDD and to determine the impact of fluoxetine treatment on the relationship between occipital cortex GABA levels and plasma ALLO levels across the menstrual cycle. We anticipate that our findings will provide further support for the role of GABA and neurosteroids in the pathogenesis and treatment of PMDD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Brain Disorders and Clinical Neuroscience 5 (BDCN)
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Brady, Linda S
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Yale University
Schools of Medicine
New Haven
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O'Brien, Patrick Michael Shaughn; Bäckström, Torbjorn; Brown, Candace et al. (2011) Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus. Arch Womens Ment Health 14:13-21
Epperson, Cynthia Neill; Pittman, Brian; Czarkowski, Kathryn Ann et al. (2007) Luteal-phase accentuation of acoustic startle response in women with premenstrual dysphoric disorder. Neuropsychopharmacology 32:2190-8
Epperson, C Neill; Gueorguieva, Ralitza; Czarkowski, Kathryn A et al. (2006) Preliminary evidence of reduced occipital GABA concentrations in puerperal women: a 1H-MRS study. Psychopharmacology (Berl) 186:425-33