Women’s Mood Disorders

Do APOE4+ women stand to benefit from menopausal hormone therapy? Piloting an experimental therapeutics approach to accelerate progress in dementia prevention research. 2023 Award: $44,875 Menopausal hormone replacement therapy (HRT) is not currently recommended to reduce risk for Alzheimer’s disease. However, emerging evidence suggests women who are APOE-4 carriers (the “Alzheimer’s gene”) may benefit from early initiation of HRT during the menopausal transition to reduce Alzheimer’s risk. We will pilot a short-term randomized, placebo-controlled trial to determine the potential efficacy of perimenopausal estrogen treatment to improve cognitive and brain markers associated with Alzheimer’s Disease in APOE-4 carriers compared to non-carriers. Need/Problem: Menopausal hormone replacement therapy (HRT) is not currently recommended to reduce risk for Alzheimer’s disease. However, emerging evidence suggests women who are APOE-4 carriers (the “Alzheimer’s gene”) may benefit from early initiation of HRT during the menopausal transition [...]

The Other Postpartum: Depression, Anxiety, and Post-Traumatic Stress Disorder following Stillbirth and Neonatal Death 2023 Award: $45,791 Each year, 1% of all live birth will be stillborn or result in neonatal death. The women and families that suffer these losses are at increased risk of anxiety, depression, and PTSD; however, their outcomes remain understudied, underrecognized, and undertreated. The grant allows us to begin to prospectively follow these women to begin to lay the groundwork for further investigation into biological risks, prevention, and best interventions. Need/Problem: Stillbirth and neonatal demise affects 1% of all live births. The repercussions of these losses have been understudied and undertreated, leaving many women and families to suffer without clear guidance and treatment options. Grant Summary: We will prospectively map the course depression, anxiety, and Post Traumatic Stress Disorder (PTSD) following stillbirth and neonatal loss and, for [...]

Mechanisms of Brexanolone Therapeutics in Post-Partum Depression: Expanded follow-up study 2023 Award: $100,000 Brexanolone is the first FDA approved medication for postpartum depression. This medication has a different mechanism of action than typical antidepressants and we will be investigating brexanolone’s impact on the systemic inflammatory pathways. Better understanding of why brexanolone is so effective for postpartum depression may provide a better understanding of postpartum depression itself and development of more accessible therapeutics. Need/Problem: Brexanolone is recently the first FDA approved medication for postpartum depression, which happens to be the most common complication of childbirth. This medication is an exciting development in psychiatry, in that it is rapidly acting, given by IV infusion over 60 hours, and has a vastly different mechanism of action than typical antidepressants. Despite these successes, there are limitations in that it requires a multiple day [...]

Probing the neurophysiological mechanisms underlying sex-specific testosterone-mood relationships during puberty: A randomized controlled trial using a smartphone-based training program 2023 Award: $45,080 Female and male adolescents may respond differently to pubertal changes in testosterone. This study will examine whether brain activity associated with emotion regulation may link testosterone change with different symptom profiles. Further, we will test the effects of a smartphone-based training program on brain dynamics underlying emotion regulation and symptoms of depression – the first step in developing new intervention and treatment approaches for adolescent psychopathology. Need/Problem: The pubertal transition marks an abrupt divergence between the sexes in rates of depression and other internalizing disorders in female adolescents, and externalizing disorders (i.e., attention-deficit/hyperactivity disorder (ADHD)) in male adolescents. The COVID-19 pandemic has further widened the gender gap in adolescent mental health, with a concerning escalation in depression, [...]

Hormone Flux and the Emergence of Irritability During Pregnancy: Investigating the Trajectory and Neurobiological Correlates of an Underrecognized Mood State2022 Award: $40,000Irritability is common in perinatal depression, however we do not know when irritability emerges during pregnancy and the neurobiological pathways underlying symptom progression are poorly understood. In this study we will investigate how hormone changes across pregnancy relate to the onset of irritability in women at risk for perinatal depression. We will also evaluate how hormone changes relate to neural and behavioral responses to threat and frustration, key components of irritability. Investigating the emergence and neurobiological correlates of irritability in perinatal depression is a critical first step to shed led light on this often underrecognized mood state and identify potential targets for prevention and intervention efforts that support the wellbeing of women and children.Need/Problem: Irritability is common in reproductive [...]

Monitoring Affective State Change with Wearable Technology: Assessing Physiological and Behavioral Mechanisms in Premenstrual Dysphoric Disorder 2021 Award: $40,000 Real-time monitoring during the transition in to or out of depression (affective state change) is an important precursor to providing targeted interventions to reduce high-risk periods of suicide and early detection and treatment for depression relapse. In this project, we capitalize on widely used wearable technology that can passively collect such real-time data including variables known to be associated with affective state change. Premenstrual dysphoric disorder (PMDD) provides a depression model with monthly switching of affective state. Establishing the physiological variables related to mood transition in PMDD is a first critical step in identifying mechanisms of risk for depression and suicide to develop a prediction model that may be applied to other mental health conditions. Need/Problem: Depression rates are continuing [...]

The Comorbidity of Depression and Cardiovascular Disease in Midlife Women: Investigating novel biological pathways of risk 2021 Award: $39,617 The risk for developing depression and cardiovascular disease increases significantly in midlife women and this combination of illnesses is a leading cause of disability in this population.  Disruption in the physiological pathways involved in stress response may underlie the connection between these illnesses, though this has not been fully studied. The primary objective of this proposal is to examine whether dysfunction in the renin-angiotensin-aldosterone system and autonomic nervous system pathways may be a mechanistic link underlying the association between depression and cardiovascular disease in women. Need/Problem: Depression and cardiovascular disease (CVD) contribute significantly to the morbidity and mortality of women. About 20% of women are impacted by this comorbidity, which is also the leading cause of disability in women worldwide. The [...]

Mechanisms of Brexanolone Therapeutics in Postpartum Depression 2020 Award: $48,070 Depression is associated with abnormal activation of inflammatory immune signals in the blood and the brain.  We recently discovered that the endogenous steroid allopregnanolone inhibits these signals and therefore we hypothesize that this mechanism explains the therapeutic effects of the new drug Zulresso, which is a proprietary form of allopregnanolone.  We will test this idea in women with postpartum depression in hopes of discovering new ways to treat all forms of depression. Need/Problem: The first FDA-approved medication for post-partum depression is brexanolone, but it requires IV infusion for 60 hours in a medically supervised setting with oxygen monitoring. We need to understand the mechanism of action of brexanolone to allow development of a more affordable and convenient bioavailable treatment for post-partum depression. Grant Summary: We will examine whether the anti-depressant effects of brexanolone in patients with post-partum [...]

Microbiome and Methylation (M&M): A Source of Information for Precision Medicine 2020 Award: $42,000 Despite greater recognition of the need to treat Perinatal Depression and Anxiety that can affect one in five women, current treatment algorithms are still limited in the ability to personalize to individuals and the heterogenous factors that are playing a role for each woman. This project will identify profiles of the microbiome i.e., the composition and the function of the microbes that live within us and particularly in our guts, and methylation, i.e., the process by which methyl groups are added to allow for use of our genes, during the postpartum period are blueprints for the foundation of mental wellness for each woman, her child, and family. Need/Problem: Despite greater recognition of the need to treat Perinatal Depression and Anxiety that can affect one in [...]

Depression in the pubertal transition: Circadian rhythms and sleep impairment as mechanisms of risk 2020 Award: $37,920 Puberty is characterized by dramatic reproductive hormone instability, sleep and circadian rhythm disturbances, and an increased risk for depression, especially for girls. This study will examine the role of estrogen fluctuation in regulating sleep and circadian rhythms to understand risk for female-dominated adolescent depression. The pubertal transition is a critical developmental window offering a unique opportunity for identifying novel treatment targets and intervention efforts to diverge mental illness trajectories. Need/Problem: Adolescent girls have a three-fold greater risk for depression and a two-fold greater risk for sleep disorders compared with boys. The pubertal transition marks an abrupt divergence between the sexes in risk for depression and sleep disorders, implicating ovarian hormones (e.g., estrogen) as a common pathway of risk. With the prevalence of [...]