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. As a continuation of these studies, we have demonstrated that women with PMD 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 (but not placebo). 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. Additionally, a suite of statistical descriptors were identified to have very high sensitivity and specificity for predicting the clinical response to GnRH agonist-induced ovarian suppression in PMD by applying chaos-based Approximate Entropy modeling to mood rating data. 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 (both those nursing and those who are bottle-feeding their babies) 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 (both nursing and non-nursing mothers), 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 a number of methodologies to investigate the underlying biological mechanisms of these conditions including studies employing multimodal neuroimaging such as positron emission tomography (PET), structural magnetic resonance imaging (MRI), and functional magnetic resonance imaging (fMRI). Our neuroimaging protocols demonstrated for the first time 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. The paradigm employed disentangles transient reward error prediction (prefrontal cortex) from sustained response to receipt of the reward (ventral striatum). These data demonstrate, for the first time in humans, that ovarian steroids modulate reward system function, with increased follicular phase activation of the orbitofrontal cortex and amygdala during reward anticipation and of the midbrain, striatum, and left ventrolateral prefrontal cortex (VLPFC) during reward delivery. We have further investigated these finding across the menstrual cycle by employing the reward paradigm in women who are participating in the GnRH agonist-induced hypogonadism study in which we examine the effects of estradiol and progesterone separately compared with a hypogonadal state (see Annual Report for Project Z01-MH002874-03, The Neuroregulatory Effects of Gonadal Steroids in Humans). 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. Differences in brain activation between the 2-back and 0-back (control) tasks were compared across hormone conditions in women with and those without PMD. Preliminary results suggest that during the N-back testing, women with PMD show abnormal recruitment of the dorsolateral prefrontal cortex (DLPFC) with greater activation in the right DLPFC, and reduced activation in the left DLPFC an asymmetry not observed in the asymptomatic controls. Interestingly, scores on the global assessment of function scale, a measure of the severity of the functional impairment accompanying each womans PMD, correlate with activity within the medial frontal and precentral gyri. The lack of effect of hormonal state on these findings suggests that alterations in DLPFC could either reflect a substrate of vulnerability to develop PMD (i.e., vulnerability trait) or be a sequela of experiencing a chronic recurrent mood disorder. Indeed, asymmetries in the activity of the DLPFC (Right >Left) have been documented in major depression and could reflect alterations in attention to or judgment of emotional state. 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 efforts to identify markers of vulnerability to the development of PMD have identified the following findings: 1) Four single nucleotide polymorphisms in the estrogen receptor alpha gene positively associated with the disorder, and evidence for epistasis with the catechol-o-methyl transferase gene. This is the first demonstration of an association between a polymorphic genetic variant and PMD. 2) The absence of an increased prevalence of postpartum depression (relative to community-based samples) in women with prospectively confirmed PMD. 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. Thus our preliminary findings 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 since blocking the synthesis of these steroid metabolites has no effect on the timing or expression of PMD symptoms. Alternatively, the failure of dutasteride to inhibit ovulation in either group of women could suggest that the dose of dutasteride is not sufficient to disrupt CNS neurosteroid synthesis. Thus we have amended the protocol and are evaluating the effects of a higher dose of dutasteride (i.e., 2.5 mg daily) in women with PMD and an asymptomatic comparison group. Finally, the effects of dutasteride on the responcivity of hypothalamic-pituitary-adrenal axis await the results of hormone assays in the process of being completed.

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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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