In our earlier studies we have developed experimental models for the triggering of symptoms in both premenstrual dysphoric disorder (PMD) and postpartum depression that we continue to employ in our efforts to identify both the underlying biology of these conditions as well as the development of new safe and effective therapies for women with these conditions. We have extended and replicated our earlier findings by demonstrating that women with PMD (n = 35), who respond to gonadotropin releasing hormone (GnRH) agonist-induced ovarian suppression experience a recurrence of PMD after the initial re-exposure to combined estradiol and progesterone. However, recurrent symptoms do not occur once hormone levels are stabilized over the subsequent two months of continuous replacement therapy. These observations are of both clinical and scientific importance, as they identify promising phenotypes and suggest the physiologic basis for the susceptibility to experience PMD and will also provide alternative hormone-based therapies for women with this condition. Approximately 60-70% of women with PMD show symptomatic improvement in response to the GnRH agonist-induced ovarian suppression. We identified a suite of statistical descriptors of pre-treatment mood rating data to have high sensitivity and specificity for predicting the clinical response to ovarian suppression in PMD by applying chaos-based Approximate Entropy (ApEn) modeling to mood rating data. Relatively regular and non-spiky pre-trial dynamics of mood ratings predict a positive response to ovarian suppression with high probability. In contrast to our findings with ovarian suppression, no statistical measure distinguished responders from nonresponders to fluoxetine. Thus, these data suggest that the pattern of symptom cyclicity predicts a differential response to hormonal therapy versus a psychotropic agent. These statistical measures may have broad applicability to behavioral studies for many psychiatric disorders, facilitating the prediction of response to treatment. As an indirect measure of the relevance of declining ovarian steroid secretion in PPD, we examine the efficacy of estradiol in the treatment of PPD. Women with PPD are randomized in a double-blind, parallel design to receive either 17 beta estradiol (100 mcgs daily by skin patch) or placebo for six weeks. Preliminary results suggest that mood rating scores are improved compared with both baseline and scores in women receiving placebo. Differences between estradiol and placebo treatments were apparent by four weeks, reminiscent of the relatively rapid antidepressant effects of estradiol therapy in depressed perimenopausal women. If these findings are confirmed in a larger sample, estradiol treatment may not only provide a safe and effective alternative to traditional antidepressants in women with postpartum depression, but it may also suggest the relevant hormonal trigger for the development of this condition. In addition to our studies on the behavioral effects of changes in sex steroids across the menstrual cycle and during the postpartum, we employ methodologies to investigate the underlying biological mechanisms of these conditions including studies employing positron emission tomography (PET), structural magnetic resonance imaging (MRI), and functional magnetic resonance imaging (fMRI). Our neuroimaging protocols demonstrated for the first time in humans a differential reward-related pattern of brain activation in the orbital frontal cortex and the amygdala during the luteal phase compared with the follicular phase of the menstrual cycle using fMRI technology. We also perform O15 PET studies in women who are participating in the GnRH agonist-induced hypogonadism study. In this study, cognitive activation is achieved using the N-back test which allows us to vary the cognitive load and the effort required to perform the task. We observed that women with PMD show abnormal prefrontal recruitment, specifically greater activation than controls throughout the DLPFC bilaterally, as well as in the medial frontal gyrus, the inferior parietal lobule, and the cerebellum independent of hormone state. These findings are robust and observable in both 015 PET and fMRI techniques. In both imaging modalities, patients activations correlated negatively with a measure of PMD functional impairment (i.e., global assessment of functional impairment GAF scores), the greater the overactivation, the greater the disability lower GAF scores) throughout working memory/executive function pathway: most prominently in the DLPFC, as well as in the inferior and superior parietal lobules. Future findings in these studies may identify disturbances of a process that is critical to the clinical phenomenology of PMD, a functional disturbance of the normal modulatory effect of gonadal steroids, and a locus of the disturbance. Our therapeutic clinical trials have demonstrated that the 5-alpha reductase inhibitor, dutasteride, a medication that inhibits neurosteroid synthesis has no effect on either the symptoms of PMD or the luteinizing hormone (LH) surge prior to ovulation. Preliminary evidence employing a higher dose of dutasteride (i.e., 2.5 mg daily) to enhance central nervous system penetration also suggest that neither alterations in the plasma levels nor a deficiency of neurosteroids, such as allopregnanolone, play a critical role in the pathophysiology of PMD. We collaborate with Drs. Rima Kaddurah-Daouk at Duke University and Thomas Hankemeier at Leiden University to more comprehensively examine the profile of steroid and steroid metabolites with a metabolomics platform employing liquid chromatography-tandem mass spectroscopys. Our strategy is to perform metabolomic studies in women with PMD who respond to Lupron with elimination of symptoms and who experience return of symptoms during progesterone or estradiol replacement. Thus, we wish to specifically examine the effects of both estradiol and progesterone on the pattern of steroid metabolites in women with PMD and an asymptomatic comparison group. Our metabolomic and neuroimaging studies will be complemented by a new series of functional genomic studies performed in collaboration with David Goldmans laboratory at NIAAA, in which we employ lymphoid and fibroblast cell-lines obtained from women with PMD and controls who participate in our Lupron studies. We hypothesize that the capacity for phenotypic differences between women with and those without PMD will be preserved in their cellular function. These experiments will allow us to explore the nature of the differential behavioral response by examining protein expression and changes in cellular behaviors associated with the exposure to physiologic levels of either estradiol or progesterone across the two different behavioral phenotypes. Preliminary results show that women with PMD express more estrogen receptor (ER) alpha (but not beta) compared with controls (consistent with our genomic findings of differential ER alpha allele frequency in PMD compared with controls observed in a prior study). Finally, we have completed our study of HPA axis function in women with and without premenstrual dysphoria under conditions of GnRH agonist-induced hypogonadism and estradiol and progesterone replacement. In contrast to the prevalence of HPA axis abnormalities in depressive illness, we have demonstrated the absence of HPA axis regulatory abnormalities in women with PMD. Thus PMD is not characterized by abnormal HPA axis responsivity, nor does PMD appear to share biological markers with depression. We also demonstrated that even under conditions of dexamethasone suppression, progesterone results in an increase in stimulated measures of both cortisol and ACTH secretion (in both women with and those without PMD).

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Gordon, Jennifer L; Rubinow, David R; Eisenlohr-Moul, Tory A et al. (2018) Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial. JAMA Psychiatry 75:149-157
Di Florio, A; Putnam, K; Altemus, M et al. (2017) The impact of education, country, race and ethnicity on the self-report of postpartum depression using the Edinburgh Postnatal Depression Scale. Psychol Med 47:787-799
Eisenlohr-Moul, Tory A; Girdler, Susan S; Johnson, Jacqueline L et al. (2017) Treatment of premenstrual dysphoria with continuous versus intermittent dosing of oral contraceptives: Results of a three-arm randomized controlled trial. Depress Anxiety 34:908-917
Dubey, N; Hoffman, J F; Schuebel, K et al. (2017) The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Mol Psychiatry 22:1172-1184
Putnam, Karen T; Wilcox, Marsha; Robertson-Blackmore, Emma et al. (2017) Clinical phenotypes of perinatal depression and time of symptom onset: analysis of data from an international consortium. Lancet Psychiatry 4:477-485
Schmidt, Peter J; Martinez, Pedro E; Nieman, Lynnette K et al. (2017) Premenstrual Dysphoric Disorder Symptoms Following Ovarian Suppression: Triggered by Change in Ovarian Steroid Levels But Not Continuous Stable Levels. Am J Psychiatry 174:980-989
Nguyen, T V; Reuter, J M; Gaikwad, N W et al. (2017) The steroid metabolome in women with premenstrual dysphoric disorder during GnRH agonist-induced ovarian suppression: effects of estradiol and progesterone addback. Transl Psychiatry 7:e1193
Martinez, Pedro E; Rubinow, David R; Nieman, Lynnette K et al. (2016) 5?-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder. Neuropsychopharmacology 41:1093-102
Schiller, Crystal Edler; Johnson, Sarah L; Abate, Anna C et al. (2016) Reproductive Steroid Regulation of Mood and Behavior. Compr Physiol 6:1135-60
Kepple, Alyson L; Lee, Ellen E; Haq, Nazli et al. (2016) History of postpartum depression in a clinic-based sample of women with premenstrual dysphoric disorder. J Clin Psychiatry 77:e415-20

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