David Rubinow

• Chair at University of North Carolina at Chapel Hill

Mating and other behaviors emerge during adolescence through the coordinated actions of steroid hormone signaling throughout the nervous system and periphery. In this study, we investigated the transcriptional dynamics of the medial preoptic area (MPOA), a critical region for reproductive behavior, using single-cell RNA sequencing (scRNAseq) and in...

Objective: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. Method: Meta-analyses were conducted on 18 cohorts of Eur...

Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal phase of the menstrual cycle. Although menstrual-related affective dysfunction is responsible for considerable functional impairment and reduction in quality of life worldwide, cur...

The hormonal changes of pregnancy and parturition can trigger robust changes in affective state, particularly among patients with a history of postpartum depression. However, more work is needed to elucidate the temporal dynamics of symptom emergence. The current study explored how quickly hormone-sensitive (HS+) individuals can be differentiated f...

Suicide is a leading cause of death among females of reproductive age. The menstrual cycle is a plausible yet understudied trigger for acute suicide risk. Cross-sectional studies have demonstrated a greater frequency of suicide attempts and deaths in the weeks before and after the onset of menses compared to other cycle phases. Here, using prospect...

Brexanolone, a formulation of the neurosteroid allopregnanolone (ALLO), is approved for treating postpartum depression (PPD) and is being investigated for therapeutic efficacy across numerous neuropsychiatric disorders. Given ALLO’s beneficial effects on mood in women with PPD compared to healthy control women, we sought to characterize and compare...

Background: Psychological trauma exposure and posttraumatic stress disorder (PTSD) have been associated with advanced epigenetic age. However, whether epigenetic aging measured at the time of trauma predicts the subsequent development of PTSD outcomes is unknown. Moreover, the neural substrates underlying posttraumatic outcomes associated with epi...

Postpartum depression (PPD) is a leading cause of morbidity and mortality among women. Clinically, the administration and withdrawal of supraphysiologic estradiol and progesterone (E2 + P) can cause affective symptom reoccurrence in women with a history of PPD, but not matched controls. To investigate the cellular basis underlying this differential...

Female suicide attempts peak peri-menstrually—around the onset of menses—when the ovarian steroids estradiol (E2) and progesterone (P4) fall rapidly. Given preclinical evidence that withdrawal from either E2 or P4 can provoke behaviors consistent with elevated suicide risk, we hypothesized that withdrawal from one or both of these steroids contribu...

Background Brexanolone is currently the only treatment specifically approved for postpartum depression (PPD) in the United States, based on the results from one Phase 2 and two Phase 3 double-blind, randomized, controlled trials in the HUMMINGBIRD program. Methods Adults with PPD randomized to a 60-h infusion of brexanolone 90 μg/kg/h (BRX90) or p...

Background The menopausal transition (perimenopause) is associated with an increased risk of major depression, characterized by anxiety and anhedonia phenotypes. Greater estradiol (E2) variability predicts the development of perimenopausal depression, especially within the context of stressful life events (SLEs). While transdermal E2 (TE2) reduces...

Postpartum depression (PPD) affects 1 in 7 women and has negative mental health consequences for both mother and child. However, the precise biological mechanisms behind the disorder are unknown. Therefore, we performed the largest transcriptome-wide association study (TWAS) for PPD (482 cases, 859 controls) to date using RNA-sequencing in whole bl...

Peripubertal females are at elevated risk for developing affective illness compared to males, yet biological mechanisms underlying this sex-disparity are poorly understood. Female risk for depression remains elevated across a woman’s reproductive lifespan, implicating reproductive hormones. A sensitivity to normal hormone variability during reprodu...

Sex differences in the rates of affective disorders have been recognized for decades. Studies of physiologic sex-related differences in animals and humans, however, have generally yielded little in terms of explaining these differences. Furthermore, the significance of these findings is difficult to interpret given the dynamic, integrative, and hig...

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 transc...

Prefrontal cortex exerts control over sensory and motor systems via cross-frequency coupling. However, it is unknown whether these signals play a role in reward-based decision-making and whether such dynamic network configuration is altered in a major depressive episode. We recruited men and women with and without depression to perform a streamline...

Pubertal maturation aids development of emotion, cognition, and reproduction. We investigated transcriptional dynamics in the medial preoptic area (MPOA), a hypothalamic center for reproductive behaviors, in male and female mice at single-cell resolution (scRNAseq) during puberty. Defined subsets of neurons expressing Slc32a1 and Esr1 (Vgat+ Esr1+)...

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 i...

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...

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...

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 th...

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...

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...

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);...

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....

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 c...

Objective Cardiometabolic diseases are the number one cause of mortality, accounting for over one third of all deaths in the US. 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 tha...

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-estr...

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...

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 peri- and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease. Methods: Healthy perimenopausal and early po...

(Abstracted from N Engl J Med 2019;381(10):903–911) Positive allosteric modification of GABA A receptors via SAGE-217, an oral synthetic neurosteroid, has been proposed as a treatment for major depressive disorder.

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 pa...

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 mee...

( Lancet . 2018;392:1058–1070) Postpartum depression is a common problem, with an overall prevalence in the United States of ∼11.5%. It is associated with impaired mother-infant attachment, increased maternal morbidity and poor outcomes for infants later in life, including lower academic achievement and an increased risk of depression. There is a n...

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

The risk of depression increases 2-3 fold for women during the menopause transition compared to premenopausal women. Additionally, peri/postmenopausal women with even minor depression are at an increased risk of cardiovascular mortality (Wassertheil-Smoller et al, 2004). Clinical studies show both the therapeutic benefits of estradiol (E2) in perim...

(Abstracted from Lancet 2018;392:1058–1070) Postpartum depression effects 10% to 20% of women who give birth worldwide, and approximately 40% to 80% of cases are considered moderate to severe. The burden of this disorder is multifactorial, with financial, social, and health-related consequences for mothers and families.

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 woul...

Background Race, psychiatric history, and adverse life events have all been independently associated with Postpartum Depression (PPD). However, the role these play together in Black and Latina women remains inadequately studied. Therefore, we performed a case-control study of PPD, including comprehensive assessments of symptoms and biomarkers, whil...

Background: 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...

The role of reproductive steroids in the pathophysiology or treatment of traditional affective disorders remains unestablished. However, there is strong evidence documenting roles of ovarian steroids in reproductive endocrine-related mood disorders including Premenstrual Dysphoric Disorder (PMDD). Studies in PMDD have consistently demonstrated the...

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 depre...

1 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...

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 (GABAA) receptors, for the treatment of moderate to severe post-partum depres...

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 i...

Postpartum depression (PPD) is a mood disorder that can have serious consequences for the mother and family. Brexanolone iv (USAN; formerly SAGE-547 Injection) showed antidepressant effects in preclinical studies, early Phase 2 studies, and first-ever Phase 3 studies in PPD.

INTRODUCTION A double-blind, placebo-controlled Phase 2 study of brexanolone (USAN; formerly SAGE-547 Injection), a positive allosteric modulator of GABAA receptors, demonstrated rapid and durable improvements in postpartum depression (PPD). The current study (NCT 02942017) is one of two randomized, multi-center, double-blind, placebo-controlled Ph...

INTRODUCTION A double-blind, placebo-controlled Phase 2 study of brexanolone (USAN; formerly SAGE-547 Injection), a positive allosteric modulator of GABAA receptors, demonstrated rapid and durable improvements in postpartum depression (PPD). The current study (NCT02942004) is one of two randomized, double-blind, placebo-controlled Phase 3 studies t...

In Reply Hugon-Rodin et al and Joffe and Hickey¹ raise questions about the safety and advisability of hormone therapy (HT) in the treatment and/or prevention of depression in perimenopausal women, as HT (in the wake of the Women’s Health Initiative²) is recommended only for the management of acute perimenopausal symptoms. In response to their conce...

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 th...

In the version of this article initially published, there were errors in data analysis and presentation. The corrected analysis and presentation do not change the results or interpretation of the data. Asterisk definitions have also been added for clarity as noted below. Changes with respect to the number of subjects reflect errors in reporting onl...

Background Race, psychiatric history, and adverse life events have all been independently associated with postpartum depression (PPD). However, the role these play together in Black and Latina women remains inadequately studied. Therefore, we performed a case–control study of PPD, including comprehensive assessments of symptoms and biomarkers, whil...

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., diffi...

Clinical evidence suggests that symptoms in premenstrual dysphoric disorder (PMDD) reflect abnormal responsivity to ovarian steroids. This differential steroid sensitivity could be underpinned by abnormal processing of the steroid signal. We used a pharmacometabolomics approach in women with prospectively confirmed PMDD (n=15) and controls without...

Background: Although traditionally dosed combined oral contraceptives (COCs) (21 days of active pills, 7 days of inactive pills) have not been demonstrated as superior to placebo for the treatment of premenstrual dysphoria (PMD), some randomized controlled trials (RCTs) indicate that oral contraceptives administered with a shortened or eliminated...

It is unclear whether women with a history of postpartum depression (PPD) have residual, abnormal hypothalamic-pituitary-adrenal (HPA) axis reactivity, as has been reported in major depression (MDD). Further unclear is whether the abnormalities in HPA axis reactivity associated with MDD represent a stable, underlying predisposition or a state-depen...

Background Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABAA) receptors,...

Background: The perinatal period is a time of high risk for onset of depressive disorders and is associated with substantial morbidity and mortality, including maternal suicide. Perinatal depression comprises a heterogeneous group of clinical subtypes, and further refinement is needed to improve treatment outcomes. We sought to empirically identif...