Publications by authors named "David R Rubinow"

123 Publications

Reduction in left frontal alpha oscillations by transcranial alternating current stimulation in major depressive disorder is context-dependent in a randomized clinical trial.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Jul 14. Epub 2021 Jul 14.

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC; Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill, Chapel Hill, NC; Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC. Electronic address:

Background: Left frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for non-invasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind placebo controlled clinical trial.

Methods: In this current study, we aimed to replicate successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. 84 participants were randomized to receive verum or sham IAF-tACS. Electrical brain activity was recorded during rest and while viewing emotionally-salient images before and after stimulation to investigate if the modulation of alpha oscillation by tACS exhibited specificity with regards to valence.

Results: In agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared to placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants.

Conclusion: Together these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD.
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http://dx.doi.org/10.1016/j.bpsc.2021.07.001DOI Listing
July 2021

Comment on "Understanding the Clinical Effects and Mechanisms of Action of Neurosteroids".

Am J Psychiatry 2021 06;178(6):572-573

University of North Carolina School of Medicine, Chapel Hill (Rubinow); Sage Therapeutics, Cambridge, Mass. (Lasser, Kanes).

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http://dx.doi.org/10.1176/appi.ajp.2020.20121681DOI Listing
June 2021

The Cortisol and ACTH response to Dex/CRH testing in Women with and without Perimenopausal Depression.

J Clin Endocrinol Metab 2021 Jun 7. Epub 2021 Jun 7.

Behavioral Endocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.

Background: Abnormalities in the hypothalamic pituitary-adrenal (HPA) axis are frequent accompaniments of depression, and studies have documented the role of stress and stressful life events in the ontogeny of perimenopausal depressions (PMD). Since HPA axis function in women is further modulated by both aging and ovarian steroids, it is possible that a dysregulated HPA axis contributes to the increased risk of PMD.

Objective: We examined HPA axis function in perimenopausal women with and without depression using the combined dexamethasone-CRH (Dex/CRH) test.

Methods: Dex/CRH tests were performed on 20 women with PMD and 20 women who were also perimenopausal but without current or past depression (control women). Main outcome measures were plasma levels of cortisol and ACTH and 24-hour urinary free cortisol. Five women took chronic stable medications, otherwise all women were medically healthy, and both groups were comparable with respect to reproductive stage and age. Standardized symptom rating scales were administered to each woman prior to Dex/CRH testing.

Results: No group differences were present in either baseline or stimulated ACTH and cortisol secretion. Baseline plasma measures of estradiol, progesterone and 24-hour UFC levels similarly did not differ in PMD and control women.

Discussion: Despite reports of increased stress responsiveness in PMD, we observed no abnormalities of HPA axis activity associated with PMD compared with women without depression. These findings suggest that PMD is not uniformly associated with HPA dysregulation and could reflect underlying pathophysiologic processes that are distinct from women with non-reproductive-related depressions.
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http://dx.doi.org/10.1210/clinem/dgab407DOI Listing
June 2021

Altered estradiol-dependent cellular Ca homeostasis and endoplasmic reticulum stress response in Premenstrual Dysphoric Disorder.

Mol Psychiatry 2021 May 25. Epub 2021 May 25.

Laboratory of Neurogenetics, National Institute of Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.

Premenstrual Dysphoric Disorder (PMDD) is characterized by debilitating mood symptoms in the luteal phase of the menstrual cycle. Prior studies of affected women have implicated a differential response to ovarian steroids. However, the molecular basis of these patients' differential response to hormone remains poorly understood. We performed transcriptomic analyses of lymphoblastoid cell lines (LCLs) derived from women with PMDD and asymptomatic controls cultured under untreated (steroid-free), estradiol-treated (E2), and progesterone-treated (P4) conditions. Weighted gene correlation network analysis (WGCNA) of transcriptomes identified four gene modules with significant diagnosis x hormone interactions, including one enriched for neuronal functions. Next, in a gene-level analysis comparing transcriptional response to hormone across diagnoses, a generalized linear model identified 1522 genes differentially responsive to E2 (E2-DRGs). Among the top 10 E2-DRGs was a physically interacting network (NUCB1, DST, GCC2, GOLGB1) involved in endoplasmic reticulum (ER)-Golgi function. qRT-PCR validation reproduced a diagnosis x E2 interaction (F(1,24)=7.01, p = 0.014) for NUCB1, a regulator of cellular Ca and ER stress. Finally, we used a thapsigargin (Tg) challenge assay to test whether E2 induces differences in Ca homeostasis and ER stress response in PMDD. PMDD LCLs had a 1.36-fold decrease in Tg-induced XBP1 splicing response compared to controls, and a 1.62-fold decreased response (p = 0.005), with a diagnosis x treatment interaction (F(3,33)=3.51, p = 0.026) in the E2-exposed condition. Altered hormone-dependent in cellular Ca dynamics and ER stress may contribute to the pathophysiology of PMDD.
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http://dx.doi.org/10.1038/s41380-021-01144-8DOI Listing
May 2021

Subgenual cingulate resting regional cerebral blood flow in premenstrual dysphoric disorder: differential regulation by ovarian steroids and preliminary evidence for an association with expression of ESC/E(Z) complex genes.

Transl Psychiatry 2021 04 8;11(1):206. Epub 2021 Apr 8.

Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, NIMH IRP, NIH, Bethesda, MD, USA.

Substantial evidence suggests that circulating ovarian steroids modulate behavior differently in women with PMDD than in those without this condition. However, hormonal state-related abnormalities of neural functioning in PMDD remain to be better characterized. In addition, while altered neural function in PMDD likely co-exists with alterations in intrinsic cellular function, such a relationship has not been explored. Here, we investigated the effects of ovarian steroids on basal, resting regional cerebral blood flow (rCBF) in PMDD, and, in an exploratory analysis, we tested whether the rCBF findings were linked to the expression of ESC/E(Z) genes, which form an essential ovarian steroid-regulated gene-silencing complex. Resting rCBF was measured with oxygen-15 water PET (189 PET sessions in 43 healthy women and 20 women with PMDD) during three self-as-own-control conditions: GnRH agonist (Lupron)-induced ovarian suppression, estradiol add-back, and progesterone add-back. ESC/E(Z) gene expression data were obtained from RNA-sequencing of lymphoblastoid cell lines performed in a previous study and were examined in relation to hormone-induced changes in rCBF. In the rCBF PET data, there was a significant diagnosis-by-hormone interaction in the subgenual cingulate (P = 0.05), an important neuroanatomical hub for regulating affective state. Whereas control women showed no hormonally-related changes in resting rCBF, those with PMDD showed decreased resting rCBF during both estradiol (P = 0.02) and progesterone (P = 0.0002) add-back conditions. In addition, in PMDD, ESC/E(Z) gene expression correlated with the change in resting rCBF between Lupron-alone and progesterone conditions (Pearson r = -0.807, P = 0.016). This work offers a formulation of PMDD that integrates behavioral, neural circuit, and cellular mechanisms, and may provide new targets for future therapeutic interventions.
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http://dx.doi.org/10.1038/s41398-021-01328-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032707PMC
April 2021

Disinhibition of right inferior frontal gyrus underlies alpha asymmetry in women with low testosterone.

Biol Psychol 2021 04 8;161:108061. Epub 2021 Mar 8.

Department of Psychiatry, University of North Carolina at Chapel Hill, 304 MacNider Hall, 101 Manning Drive, Chapel Hill, NC, 27599, USA; Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill, 6201 Mary Ellen Jones Building, 116 Manning Drive, Chapel Hill, NC, 27599, USA; Department of Neurology, University of North Carolina at Chapel Hill, 170 Manning Drive, Chapel Hill, NC, 27599, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, 5200 Medical Biomolecular Research Building, 111 Mason Farm Road, Chapel Hill, NC, 27599, USA; Department of Biomedical Engineering, University of North Carolina at Chapel Hill, 10010 Mary Ellen Jones, 116 Manning Drive, Chapel Hill, NC, 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, 116 Manning Drive, Chapel Hill, NC, 27599, USA. Electronic address:

Asymmetrical expression of alpha oscillations in the frontal cortex, increased left relative to right, is a phenotype associated with increased behavioral inhibition and mood-related psychiatric illnesses. However, investigations of frontal alpha asymmetry in mood-disorders have yielded inconsistent findings. A better understanding of factors that contribute to individual differences is required to establish a useful biomarker for the diagnosis and treatment of mood and stress related disorders. A novel factor is hormone concentration, as steroid hormones play a prominent role in regulating mood and stress. To investigate this question, concentrations of testosterone and estradiol were sampled. Multiple linear regression revealed that low levels of testosterone correlated with greater frontal alpha asymmetry in women. Source localization found that frontal asymmetry was driven by decreased alpha power in right inferior frontal gyrus that correlated with increased behavioral inhibition in women. Together, these findings might explain inconsistencies in previous investigation on frontal alpha asymmetry.
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http://dx.doi.org/10.1016/j.biopsycho.2021.108061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113111PMC
April 2021

One Small Step for PMDD, One Large Step for Affective Disorders.

Authors:
David R Rubinow

Am J Psychiatry 2021 03;178(3):215-217

Departments of Psychiatry and Medicine, School of Medicine, University of North Carolina at Chapel Hill.

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http://dx.doi.org/10.1176/appi.ajp.2020.20121793DOI Listing
March 2021

The short-term effects of estradiol, raloxifene, and a phytoestrogen in women with perimenopausal depression.

Menopause 2021 01 15;28(4):369-383. Epub 2021 Jan 15.

Department of Psychiatry, University of North Carolina, Chapel Hill, NC.

Objective: We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD).

Methods: Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure.

Results: Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (P = 0.34) or Beck Depression Inventory (P = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (P = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (P = 0.0005), and less consistently with placebo (P = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE-15.3 (4.5), raloxifene-16.0 (3.7), Rimostil-14.0 (2.7), and placebo-15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE-5.2(1.1), raloxifene-5.8(1.2), Rimostil-11.2(1.4), and placebo-7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (P values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo.

Conclusions: This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha).
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http://dx.doi.org/10.1097/GME.0000000000001724DOI Listing
January 2021

Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors.

J Clin Lipidol 2021 Jan-Feb;15(1):151-161.e0. Epub 2020 Nov 24.

Diabetes Institute, Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, 750 Republican St, Seattle WA 98109, USA. Electronic address:

Background: The cardiovascular (CV) safety of estrogen replacement therapy (ERT) in perimenopausal women remains uncertain. Although exogenous estrogens increase HDL cholesterol (HDL-C), estrogen-mediated effects on alternative metrics of HDL that may better predict CV risk are unknown.

Objective: To determine the effects of transdermal ERT on HDL composition and cholesterol efflux capacity (CEC), as well as the relationships between these metrics and CV risk factors.

Methods: Fasting plasma samples were analyzed from 101 healthy, perimenopausal women randomized to receive either transdermal placebo or transdermal estradiol (100 μg/24 h) with intermittent micronized progesterone. At baseline and after 6 months of treatment, serum HDL CEC, HDL particle concentration, HDL protein composition, insulin resistance and brachial artery flow-mediated dilatation (FMD) were measured.

Results: No difference between groups was found for change in plasma HDL-C (p = 0.69). Between-group differences were found for changes in serum HDL total CEC [median change from baseline -5.4 (-17.3,+8.4)% ERT group versus +5.8 (-6.3,+16.9)% placebo group, p = 0.01] and ABCA1-specific CEC [median change from baseline -5.3 (-10.7,+6.7)% ERT group versus +7.4 (-1.5,+18.1)% placebo group, p = 0.0002]. Relative to placebo, transdermal ERT led to reductions in LDL-C (p < 0.0001) and insulin resistance (p = 0.0002). An inverse correlation was found between changes in serum HDL total CEC and FMD (β = -0.26, p = 0.004).

Conclusions: Natural menopause leads to an increase in serum HDL CEC, an effect that is abrogated by transdermal ERT. However, transdermal ERT leads to favorable changes in major CV risk factors.
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http://dx.doi.org/10.1016/j.jacl.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887026PMC
November 2020

HPA axis regulation and epigenetic programming of immune-related genes in chronically stressed and non-stressed mid-life women.

Brain Behav Immun 2021 02 19;92:49-56. Epub 2020 Nov 19.

Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA; Carolina Stress Initiative, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Electronic address:

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been associated with altered immune function, but the underlying molecular mechanisms are unclear. Epigenetic processes, including DNA methylation, respond to the glucocorticoid end-products of the HPA axis (cortisol in humans) and could be involved in this neuroendocrine-immune crosstalk. Here we examined the extent to which variations in HPA axis regulation are associated with peripheral blood DNA (CpG) methylation changes in 57 chronically stressed caregivers and 67 control women. DNA methylation was determined with the Illumina 450k array for a panel of genes involved in HPA axis and immune function. HPA axis feedback was assessed with the low-dose dexamethasone suppression test (DST), measuring the extent to which cortisol secretion is suppressed by the synthetic glucocorticoid dexamethasone. After multiple testing correction in the entire cohort, higher post-DST cortisol, reflecting blunted HPA axis negative feedback, but not baseline waking cortisol, was associated with lower DNA methylation at eight TNF and two FKBP5 CpG sites. Caregiver group status was associated with lower methylation at two IL6 CpG sites. Since associations were most robust with TNF methylation (32% of the 450k-covered sites), we further examined functionality of this epigenetic signature in cultured peripheral blood mononuclear cells in 33 participants; intriguingly, lower TNF methylation resulted in higher ex vivo TNF mRNA following immune stimulation. Taken together, our findings link chronic stress and HPA axis regulation with epigenetic signatures at immune-related genes, thereby providing novel insights into how aberrant HPA axis function may contribute to heightened inflammation and disease risk.
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http://dx.doi.org/10.1016/j.bbi.2020.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897273PMC
February 2021

In vitro model of perimenopausal depression implicates steroid metabolic and proinflammatory genes.

Mol Psychiatry 2020 Aug 12. Epub 2020 Aug 12.

Laboratory of Neurogenetics, NIAAA, Rockville, MD, USA.

The estimated 20-30% of women who develop perimenopausal depression (PMD) are at an increased risk of cardiovascular and all-cause mortality. The therapeutic benefits of estradiol (E2) and symptom-provoking effects of E2-withdrawal (E2-WD) suggest that a greater sensitivity to changes in E2 at the cellular level contribute to PMD. We developed an in vitro model of PMD with lymphoblastoid cell lines (LCLs) derived from participants of a prior E2-WD clinical study. LCLs from women with past PMD (n = 8) or control women (n = 9) were cultured in three experimental conditions: at vehicle baseline, during E2 treatment, and following E2-WD. Transcriptome analysis revealed significant differences in transcript expression in PMD in all experimental conditions, and significant overlap in genes that were changed in PMD regardless of experimental condition. Of these, chemokine CXCL10, previously linked to cardiovascular disease, was upregulated in women with PMD, but most so after E2-WD (p < 1.55 × 10). CYP7B1, an enzyme intrinsic to DHEA metabolism, was upregulated in PMD across experimental conditions (F = 19.93, p < 0.0001). These transcripts were further validated via qRT-PCR. Gene networks dysregulated in PMD included inflammatory response, early/late E2-response, and cholesterol homeostasis. Our results provide evidence that differential behavioral responsivity to E2-WD in PMD reflects intrinsic differences in cellular gene expression. Genes such as CXCL10, CYP7B1, and corresponding proinflammatory and steroid biosynthetic gene networks, may represent biomarkers and molecular targets for intervention in PMD. Finally, this in vitro model allows for future investigations into the mechanisms of genes and gene networks involved in the vulnerability to, and consequences of, PMD.
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http://dx.doi.org/10.1038/s41380-020-00860-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878574PMC
August 2020

IL-6 Response to Psychosocial Stress Predicts 12-month Changes in Cardiometabolic Biomarkers in Perimenopausal Women.

J Clin Endocrinol Metab 2020 10;105(10)

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Objective: Cardiometabolic diseases are the number one cause of mortality, accounting for over one third of all deaths in the United States. Cardiometabolic risk further increases with psychosocial stress exposure and during menopausal transition in women. Because disease risk and stress burden are associated with aberrant immune signaling, we hypothesized that responses of interleukin-6 (IL-6) to psychosocial stress may predict longitudinal cardiometabolic outcomes in perimenopausal women.

Methods: We conducted post hoc analyses in 151 perimenopausal or early postmenopausal women participants in a previously completed study. At study onset, participants underwent the Trier Social Stress Test (TSST), and plasma IL-6 was measured repeatedly before and during the 1 hour post-TSST. Subsequently, participants were randomly assigned to either hormonal treatment (HT) or placebo and followed for 12 months to determine longitudinal changes in cardiometabolic biomarkers.

Results: Greater IL-6 reactivity to stress, measured with baseline-adjusted area under the curve, predicted 12-month decrease in flow-mediated dilatation of the brachial artery (P = 0.0005), a measure of endothelial-dependent vascular function, but not in endothelial-independent function measured with nitroglycerin-mediated dilatation (P = 0.17). Greater baseline IL-6 levels predicted 12-month increase in insulin resistance based on the homeostatic model assessment of insulin resistance score (P = 0.0045) and in the number of criteria met for metabolic syndrome (P = 0.0008). These predictions were not moderated by HT.

Conclusions: Greater baseline IL-6 levels as well as its reactivity to stress may predict worsening in distinct cardiometabolic biomarkers as women transition to menopause. Interleukin-6 reactivity predicts decline in endothelial-dependent vascular function, whereas baseline IL-6 presages accumulation of metabolic risk.
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http://dx.doi.org/10.1210/clinem/dgaa476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465560PMC
October 2020

Test-statistic inflation in methylome-wide association studies.

Epigenetics 2020 11 19;15(11):1163-1166. Epub 2020 May 19.

Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University , Richmond, VA, USA.

Recent years have seen a surge of methylome-wide association studies (MWAS). We observed that many of these studies suffer from test statistic inflation that is most likely caused by commonly used quality control (QC) pipelines not going far enough to remove technical artefacts. To support this claim, we reanalysed GEO datasets with an improved QC pipeline that reduced test-statistic inflation parameter lambda from the original mean/median of 20.16/15.17 to 3.07/1.14. Furthermore, the mean/median number of methylome-wide significant findings was reduced by 65,688/57,805 loci after more thorough QC. To avoid such false positives we argue for more extensive QC and that reporting the test-statistic inflation parameter lambda become standard for all MWAS allowing readers to better assess the risk of false discoveries.
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http://dx.doi.org/10.1080/15592294.2020.1758382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595582PMC
November 2020

A case study of weekly tACS for the treatment of major depressive disorder.

Brain Stimul 2020 May - Jun;13(3):576-577. Epub 2019 Dec 17.

Department of Psychiatry, University of North Carolina at Chapel Hill, United States; Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill, United States; Neurobiology Curriculum, University of North Carolina at Chapel Hill, United States; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, United States; Department of Biological Engineering, University of North Carolina at Chapel Hill, United States; Neuroscience Center, University of North Carolina at Chapel Hill, United States; Department of Neurology, University of North Carolina at Chapel Hill, United States. Electronic address:

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http://dx.doi.org/10.1016/j.brs.2019.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210803PMC
December 2019

The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease.

J Clin Endocrinol Metab 2020 05;105(5)

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: The arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE + IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease.

Methods: Healthy perimenopausal and early postmenopausal women, ages 45 to 60 years, were enrolled in this randomized, double-blind, placebo-controlled trial. Women were randomized to receive TE (0.1 mg/day) + IMP (200 mg/day for 12 days) or identical placebo patches and pills for 12 months. Outcomes included: change in stress reactivity composite z-score (combining inflammatory, cortisol, and hemodynamic responses to a standardized psychological laboratory stressor); flow-mediated dilation (FMD) of the brachial artery (an index of vascular endothelial function); baroreflex sensitivity; and metabolic risk (presence of the metabolic syndrome or insulin resistance), all assessed at baseline and at months 6 and 12.

Results: Of 172 women enrolled, those assigned to TE + IMP tended to have higher resting baroreflex sensitivity than those assigned to placebo across the 6- and 12-month visits. Although treatment groups did not differ in terms of the other prespecified outcomes, a significant treatment-by-age interaction was found for FMD and stress reactivity such that an age-related decrease in FMD and increase in stress reactivity were seen among women assigned to placebo but not those assigned to TE + IMP. Women on TE + IMP also had lower resting diastolic blood pressure, lower levels of low-density lipoprotein cholesterol, and higher baroreflex sensitivity during stress testing.

Conclusions: TE + IMP tended to improve cardiac autonomic control and prevented age-related changes in stress reactivity and endothelial function among healthy perimenopausal and early postmenopausal women.
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http://dx.doi.org/10.1210/clinem/dgz262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096310PMC
May 2020

Effects of perimenopausal transdermal estradiol on self-reported sleep, independent of its effect on vasomotor symptom bother and depressive symptoms.

Menopause 2019 11;26(11):1318-1323

University of North Carolina at Chapel Hill, Chapel Hill, NC.

Objective: The aim of this study was to determine the efficacy of transdermal estradiol (E2) plus intermittent progesterone (EPT) for improving self-reported sleep in perimenopausal women, after controlling for vasomotor symptoms (VMS) bother and depressive symptoms.

Methods: Using a double-blind, placebo-controlled design, 172 healthy women meeting STRAW+10 criteria for being in the menopausal transition or early postmenopause were randomized to 12 months of transdermal E2 (0.1 mg/d) + 200 mg progesterone (12 d every 3 mo) or placebo. Using standard questionnaires, self-reported sleep, depression, and VMS bother were obtained at baseline and bimonthly postrandomization.

Results: Controlling for baseline levels, EPT (vs placebo) led to reductions in minutes to fall asleep (estimate = -0.12, P = 0.002) and number of awakenings (estimate = -0.24, P = 0.04) over the 12 months. Controlling for changes in VMS bother and depressive symptoms, EPT still predicted reductions in minutes to fall asleep (estimate = -0.28, P = 0.02) and number of awakenings (estimate = -0.11, P = 0.02) over the 12 months.

Conclusions: We extend existing research by demonstrating that hormone therapy (HT) in subjective sleep cannot be fully explained by improvements in VMS bother or depressive symptoms. Research to examine the mechanism (s) underlying HT's effects on sleep would have public health significance for perimenopausal women and also advance our general understanding of the pathophysiology of impaired sleep.
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http://dx.doi.org/10.1097/GME.0000000000001398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294069PMC
November 2019

Trial of SAGE-217 in Patients with Major Depressive Disorder.

N Engl J Med 2019 09;381(10):903-911

From Sage Therapeutics, Cambridge (H.G.-B., C.S., A.J.S., H.L., R.L., S.M.P., J.J., J.J.D., S.J.K.), Kaul Consulting, Concord (I.K.), and the University of Massachusetts Medical School and UMass Memorial Healthcare, Worcester (A.J.R.) - all in Massachusetts; the Atlanta Center for Medical Research, Atlanta (R.R.); Washington University School of Medicine, St. Louis (C.F.Z., S.M.P.); and the University of North Carolina School of Medicine, Chapel Hill (D.R.R.).

Background: Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown.

Methods: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse).

Results: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence.

Conclusions: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.).
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http://dx.doi.org/10.1056/NEJMoa1815981DOI Listing
September 2019

Transdermal estradiol for postpartum depression: results from a pilot randomized, double-blind, placebo-controlled study.

Arch Womens Ment Health 2020 06 1;23(3):401-412. Epub 2019 Aug 1.

Section on Behavioral Endocrinology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.

Postpartum depression (PPD) is a common complication following delivery, though evidence-based treatment options are limited. This study explores the feasibility and efficacy of outpatient PPD treatment with transdermal estradiol (TE). In a pilot, double-blind, placebo-controlled trial, women with PPD were randomized to receive transdermal 17β-estradiol (100 mcg/day) or placebo patch. Over 6 weeks, women completed weekly ratings on the Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS), and Hamilton Depression Scale (HAM-D). Primary outcome measures were treatment response (> 50% decrease from baseline BDI) and remission (BDI < 10) at 6 weeks, and secondary outcome measures included severity on all scales at weeks 3 and 6. Of 12 recruited women, 6 received TE and 6 received placebo. By week 6, 5 women receiving TE responded to treatment and 4 showed symptom remission, compared to 2 responders and 1 remitter in the placebo group. This difference was not significant (p = 0.24). In a mixed-model of BDI ratings, TE was associated with a 9.2 point decrease at 3 weeks (95%CI - 19.5 to + 1.0, p = 0.074) and a 10.5 point decrease at 6 weeks (95%CI - 21.0-0.0, p = 0.049) compared to placebo, though these differences did not survive multiple comparisons correction. Analogous effects were found for HAM-D but not EPDS scores. Interestingly, no significant difference in plasma estradiol levels existed between groups. We were unable to demonstrate a significant therapeutic benefit of TE compared with placebo in PPD. Although limited by under-recruitment and loss to follow-up, our results suggest TE is a feasible option for outpatient PPD management, with preliminary evidence (based on secondary outcomes) for efficacy. Therapeutic effects may be seen as early as 3 weeks and may not directly depend on peripheral measures of estradiol.
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http://dx.doi.org/10.1007/s00737-019-00991-3DOI Listing
June 2020

Brexanolone injection for post-partum depression treatment - Authors' reply.

Lancet 2019 08 26;394(10196):380. Epub 2019 Jun 26.

Sage Therapeutics, Cambridge, MA, USA.

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http://dx.doi.org/10.1016/S0140-6736(19)30703-2DOI Listing
August 2019

Double-blind, randomized pilot clinical trial targeting alpha oscillations with transcranial alternating current stimulation (tACS) for the treatment of major depressive disorder (MDD).

Transl Psychiatry 2019 03 5;9(1):106. Epub 2019 Mar 5.

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Major depressive disorder (MDD) is one of the most common psychiatric disorders, but pharmacological treatments are ineffective in a substantial fraction of patients and are accompanied by unwanted side effects. Here we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) at 10 Hz, which we hypothesized would improve clinical symptoms by renormalizing alpha oscillations in the left dorsolateral prefrontal cortex (dlPFC). To this end, 32 participants with MDD were randomized to 1 of 3 arms and received daily 40 min sessions of either 10 Hz-tACS, 40 Hz-tACS, or active sham stimulation for 5 consecutive days. Symptom improvement was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary outcome. High-density electroencephalograms (hdEEGs) were recorded to measure changes in alpha oscillations as the secondary outcome. For the primary outcome, we did not observe a significant interaction between treatment condition (10 Hz-tACS, 40 Hz-tACS, sham) and session (baseline to 4 weeks after completion of treatment); however, exploratory analyses show that 2 weeks after completion of the intervention, the 10 Hz-tACS group had more responders (MADRS and HDRS) compared with 40 Hz-tACS and sham groups (n = 30, p = 0.026). Concurrently, we found a significant reduction in alpha power over the left frontal regions in EEG after completion of the intervention for the group that received per-protocol 10 Hz-tACS (n = 26, p < 0.05). Our data suggest that targeting oscillations with tACS has potential as a therapeutic intervention for treatment of MDD.
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http://dx.doi.org/10.1038/s41398-019-0439-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401041PMC
March 2019

Is there a role for reproductive steroids in the etiology and treatment of affective disorders?

Dialogues Clin Neurosci 2018 09;20(3):187-196

Behavioral Endocrinology Branch, National Institute of Mental Health, Magnuson Clinical Center, Bethesda, Maryland, USA.

A variety of hormones have been shown to play a role in affective disorders. Reproductive steroids are particularly informative in our efforts to understand the pathophysiology of affective dysregulation for several reasons: i) Reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, perinatal depression, perimenopausal depression) are wonderful clinical models for investigating the mechanisms by which affective state changes occur; ii) Reproductive steroids regulate virtually every system that has been implicated as disturbed in the ontogeny of affective disorders; iii) Despite the absence of a reproductive endocrinopathy a triggering role in the affective disturbance of reproductive mood disorders has been shown clearly for changes in reproductive steroids. The existing data, therefore, support a differential sensitivity to reproductive steroids in reproductive mood disorders such that an abnormal affective state is precipitated by normal changes in reproductive steroids. The therapeutic implications of these findings for affective illness are discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296393PMC
September 2018

Early Life Abuse Moderates the Effects of Intranasal Oxytocin on Symptoms of Premenstrual Dysphoric Disorder: Preliminary Evidence From a Placebo-Controlled Trial.

Front Psychiatry 2018 29;9:547. Epub 2018 Nov 29.

Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States.

Although intranasal oxytocin (OXT) has been proposed to be a promising treatment for some psychiatric disorders, little research has addressed individual difference factors that may predict response to OXT. One such factor is early life abuse (ELA), which has widespread influences on social-emotional processing and behavior. This single-blind, placebo-controlled crossover trial examined the role of ELA in shaping the effects of intranasal OXT (vs. placebo) on daily behavioral symptoms in women with three or more prospectively-diagnosed cycling symptoms of premenstrual dysphoric disorder (PMDD). Participants were ten women with PMDD ( = 8) or subthreshold PMDD ( = 2), who had experienced ELA prior to age 13 ( = 5) or no ELA ( = 5). They completed two study visits during the late luteal (premenstrual) phase: once following administration of intranasal OXT and once following intranasal placebo (counterbalanced). Participants then self-administered OXT or placebo at home three times per day for 5 days or until menstrual onset, and prospectively rated daily emotional symptoms of PMDD. Power was adequate to detect medium main and interactive effects. Among women with ELA, intranasal OXT (vs. placebo) increased the premenstrual emotional symptoms of PMDD, whereas among women without ELA, OXT decreased symptoms. This study adds to a growing literature highlighting the importance of considering historical social contexts and traits (such as ELA) as moderators of therapeutic response to OXT.
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http://dx.doi.org/10.3389/fpsyt.2018.00547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282546PMC
November 2018

Progesterone and plasma metabolites in women with and in those without premenstrual dysphoric disorder.

Depress Anxiety 2018 12 5;35(12):1168-1177. Epub 2018 Sep 5.

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: The molecular mechanisms underpinning the progesterone-triggering mood symptoms in women with premenstrual dysphoric disorder (PMDD) are unknown. Cell metabolism is a potential source of variability. Very little is known about the effect of progesterone sensitivity on the metabolome. In this study, we aimed to characterize the effects of progesterone on the global metabolic profile and explore the differences between women with PMDD and controls.

Methods: Plasma was obtained from 12 women with prospectively confirmed PMDD and 25 controls under two hormone conditions: (1) gonadal suppression induced by leuprolide acetate (3.75 mg IM monthly) and (2) add-back phase with leuprolide and progesterone (200 mg twice daily by vaginal suppository). The global metabolic profile was obtained using liquid and gas chromatography followed by mass spectrometry. Differences between groups and time points were tested using repeated measures analysis of variance. The false discovery rate was calculated to account for multiple testing.

Results: Amino acids and their derivatives represented 78% (28/36) of the known compounds that were found in significantly lower plasma concentrations after progesterone administration than during gonadal suppression. The concentration of tyrosine was nominally significantly decreased after progesterone add-back in controls, but not in cases (P = 0.02).

Conclusion: Plasma levels of some amino acids are decreased in response to progesterone. Albeit preliminary, evidence further suggests that progesterone has a different effect on the metabolic profiles of women with PMDD compared to controls. Further research is needed to replicate our findings in a larger sample and to identify the unknown compounds, especially those differentially expressed.
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http://dx.doi.org/10.1002/da.22827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440927PMC
December 2018

Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials.

Lancet 2018 09 31;392(10152):1058-1070. Epub 2018 Aug 31.

Sage Therapeutics, Cambridge, MA, USA.

Background: Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABA) receptors, for the treatment of moderate to severe post-partum depression.

Methods: We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18-45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20-25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either brexanolone 90 μg/kg per h (BRX90), brexanolone 60 μg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2).

Findings: Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference -5·5 [95% CI -8·8 to -2·2], p=0·0013 for the BRX60 group; -3·7 [95% CI -6·9 to -0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference -2·5 [95% CI -4·5 to -0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related.

Interpretation: Administration of brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder.

Funding: Sage Therapeutics, Inc.
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http://dx.doi.org/10.1016/S0140-6736(18)31551-4DOI Listing
September 2018

Sex differences and the neurobiology of affective disorders.

Neuropsychopharmacology 2019 01 9;44(1):111-128. Epub 2018 Jul 9.

Behavioral Endocrinology Branch, NIMH, Bethesda, MD, USA.

Observations of the disproportionate incidence of depression in women compared with men have long preceded the recent explosion of interest in sex differences. Nonetheless, the source and implications of this epidemiologic sex difference remain unclear, as does the practical significance of the multitude of sex differences that have been reported in brain structure and function. In this article, we attempt to provide a framework for thinking about how sex and reproductive hormones (particularly estradiol as an example) might contribute to affective illness. After briefly reviewing some observed sex differences in depression, we discuss how sex might alter brain function through hormonal effects (both organizational (programmed) and activational (acute)), sex chromosome effects, and the interaction of sex with the environment. We next review sex differences in the brain at the structural, cellular, and network levels. We then focus on how sex and reproductive hormones regulate systems implicated in the pathophysiology of depression, including neuroplasticity, genetic and neural networks, the stress axis, and immune function. Finally, we suggest several models that might explain a sex-dependent differential regulation of affect and susceptibility to affective illness. As a disclaimer, the studies cited in this review are not intended to be comprehensive but rather serve as examples of the multitude of levels at which sex and reproductive hormones regulate brain structure and function. As such and despite our current ignorance regarding both the ontogeny of affective illness and the impact of sex on that ontogeny, sex differences may provide a lens through which we may better view the mechanisms underlying affective regulation and dysfunction.
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http://dx.doi.org/10.1038/s41386-018-0148-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235863PMC
January 2019

Safety of Estradiol Treatment in Perimenopausal Asymptomatic Women-Reply.

JAMA Psychiatry 2018 05;75(5):529

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill.

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http://dx.doi.org/10.1001/jamapsychiatry.2018.0368DOI Listing
May 2018

Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial.

JAMA Psychiatry 2018 02;75(2):149-157

Department of Psychiatry, University of North Carolina at Chapel Hill.

Importance: The menopause transition and early postmenopausal period are associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms. Although a few studies suggest that hormone therapy can effectively manage existing depression during this time, to our knowledge, there have been no studies testing whether hormone therapy can prevent the onset of perimenopausal and early postmenopausal depressive symptoms.

Objective: To examine the efficacy of transdermal estradiol plus intermittent micronized progesterone (TE+IMP) in preventing depressive symptom onset among initially euthymic perimenopausal and early postmenopausal women. A secondary aim was to identify baseline characteristics predicting TE+IMP's beneficial mood effects.

Design, Setting, And Participants: Double-blind, placebo-controlled randomized trial at the University of North Carolina at Chapel Hill from October 2010 to February 2016. Participants included euthymic perimenopausal and early postmenopausal women from the community, aged 45 to 60 years.

Interventions: Transdermal estradiol (0.1 mg/d) or transdermal placebo for 12 months. Oral micronized progesterone (200 mg/d for 12 days) was also given every 3 months to women receiving active TE, and identical placebo pills were given to women receiving placebo.

Main Outcome Measures: Scores on the Center for Epidemiological Studies-Depression Scale (CES-D), assessed at baseline and months 1, 2, 4, 6, 8, 10, and 12 after randomization, and the incidence of clinically significant depressive symptoms, defined as a CES-D score of at least 16.

Results: Of 172 participants, 130 were white (76%), and 70 were African American (19%), with a mean household income of $50 000 to $79 999. The mean age was 51 years, and 43 developed clinically significant depressive symptoms. Women assigned to placebo were more likely than those assigned to TE+IMP to score at least 16 on the CES-D at least once during the intervention phase (32.3% vs 17.3%; odds ratio [OR], 2.5; 95% CI, 1.1-5.7; P = .03) and had a higher mean CES-D score across the intervention period (P = .03). Baseline reproductive stage moderated the effect of treatment (β, -1.97; SEM, 0.80; P for the interaction = .03) such that mood benefits of TE+IMP vs placebo were evident among women in the early menopause transition (β, -4.2; SEM, 1.2; P < .001) but not the late menopause transition (β, -0.9; SEM, 0.3; P = .23) or among postmenopausal women (β, -0.3; SEM, 1.1; P = .92). Stressful life events in the 6 months preceding enrollment also moderated the effect of treatment on mean CES-D score such that the mood benefits of TE+IMP increased with a greater number of events (β, 1.22; SEM, 0.40; P = .003). Baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not moderate treatment effects.

Conclusions: Twelve months of TE+IMP were more effective than placebo in preventing the development of clinically significant depressive symptoms among initially euthymic perimenopausal and early postmenopausal women.

Trial Registration: clinicaltrials.gov Identifier: NCT01308814.
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http://dx.doi.org/10.1001/jamapsychiatry.2017.3998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838629PMC
February 2018

Perimenopausal depression and early menopause: cause or consequence?

Menopause 2017 12;24(12):1333-1335

Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, MD Department of Psychiatry, UNC School of Medicine, Chapel Hill, NC.

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http://dx.doi.org/10.1097/GME.0000000000001016DOI Listing
December 2017

Emotion-related impulsivity and rumination predict the perimenstrual severity and trajectory of symptoms in women with a menstrually related mood disorder.

J Clin Psychol 2018 04 12;74(4):579-593. Epub 2017 Sep 12.

University of North Carolina at Chapel Hill.

Objective: Women with menstrually related mood disorders (MRMDs) demonstrate clinically significant distress during the premenstrual week that remits with the onset of menses. Relatively little is known about psychosocial mechanisms of MRMDs. Given the core affective and behavioral symptoms of MRMDs, dysfunctional responses to emotion (e.g., difficulties with awareness and regulation of emotion; rumination and impulsive or maladaptive behavior in response to emotion) may be important factors to explore as cognitive and behavioral mechanisms in MRMDs. The purpose of the present study was to examine the associations of various dysfunctional responses to emotion (as measured using the Difficulties in Emotion Regulation Scale [DERS] and brooding on the Ruminative Responses Scale [RRS]) with premenstrual symptom severity and trajectory.

Method: A total of 54 women (mean age = 38.11; 65% Caucasian) with prospectively confirmed MRMDs completed the DERS and RRS, and provided 2-4 menstrual cycles of daily symptom reports.

Results: Only the emotion-related impulsivity subscale of the DERS was robustly associated with premenstrual symptom severity. Brooding rumination predicted a more rapid premenstrual increase and slower postmenstrual remission of some symptoms.

Conclusion: Both rumination and emotion-related impulsivity may be important treatment targets in cognitive behavioral interventions aimed at reducing symptom severity and cyclicity in MRMDs.
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http://dx.doi.org/10.1002/jclp.22522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847394PMC
April 2018
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