Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder.

The serotonin deficit hypothesis explanation for major depressive disorder (MDD) has persisted among clinicians and the general public alike despite insufficient supporting evidence. To combat rising mental health crises and eroding public trust in science and medicine, researchers and clinicians must be able to communicate to patients and the public an updated framework of MDD: one that is (1) accessible to a general audience, (2) accurately integrates current evidence about the efficacy of conventional serotonergic antidepressants with broader and deeper understandings of pathophysiology and treatment, and (3) capable of accommodating new evidence. In this article, we summarize a framework for the pathophysiology and treatment of MDD that is informed by clinical and preclinical research in psychiatry and neuroscience. First, we discuss how MDD can be understood as inflexibility in cognitive and emotional brain circuits that involves a persistent negativity bias. Second, we discuss how effective treatments for MDD enhance mechanisms of neuroplasticity-including via serotonergic interventions-to restore synaptic, network, and behavioral function in ways that facilitate adaptive cognitive and emotional processing. These treatments include typical monoaminergic antidepressants, novel antidepressants like ketamine and psychedelics, and psychotherapy and neuromodulation techniques. At the end of the article, we discuss this framework from the perspective of effective science communication and provide useful language and metaphors for researchers, clinicians, and other professionals discussing MDD with a general or patient audience.

All "Roads" Lead to Rocksalt Structure.

Rocksalt is the most common crystal structure among binary compounds. Moreover, no long-lived, metastable polymorphs are observed in compounds with the rocksalt ground state. We investigate the absence of polymorphism via first-principles random structure sampling and transformation kinetics modeling of three rocksalt compounds: MgO, TaC, and PbTe. Random structure sampling reveals that for all three systems the rocksalt basin of attraction covers much more of configuration space than any other, making it statistically the most significant structure. The kinetics modeling shows that virtually all other relevant structures, including most of the 457 known A1B1 prototypes, transform rapidly to rocksalt, making it the only option at ambient conditions. These results explain the absence of polymorphism in binary rocksalts, answer why rocksalt is the structure of choice for high-entropy ceramics and disordered ternary nitrides, and help understand/predict metastable states in crystalline solids more generally.

Mechanistically Guided Materials Chemistry: Synthesis of Ternary Nitrides, CaZrN2 and CaHfN2.

Recent computational studies have predicted many new ternary nitrides, revealing synthetic opportunities in this underexplored phase space. However, synthesizing new ternary nitrides is difficult, in part because intermediate and product phases often have high cohesive energies that inhibit diffusion. Here, we report the synthesis of two new phases, calcium zirconium nitride (CaZrN2) and calcium hafnium nitride (CaHfN2), by solid state metathesis reactions between Ca3N2 and MCl4 (M = Zr, Hf). Although the reaction nominally proceeds to the target phases in a 1:1 ratio of the precursors via Ca3N2 + MCl4 → CaMN2 + 2 CaCl2, reactions prepared this way result in Ca-poor materials (CaxM2-xN2, x < 1). A small excess of Ca3N2 (ca. 20 mol %) is needed to yield stoichiometric CaMN2, as confirmed by high-resolution synchrotron powder X-ray diffraction. In situ synchrotron X-ray diffraction studies reveal that nominally stoichiometric reactions produce Zr3+ intermediates early in the reaction pathway, and the excess Ca3N2 is needed to reoxidize Zr3+ intermediates back to the Zr4+ oxidation state of CaZrN2. Analysis of computationally derived chemical potential diagrams rationalizes this synthetic approach and its contrast from the synthesis of MgZrN2. These findings additionally highlight the utility of in situ diffraction studies and computational thermochemistry to provide mechanistic guidance for synthesis.

Cognitive Problems in Perimenopause: A Review of Recent Evidence.

PURPOSE OF REVIEW: To review recent research regarding cognitive problems during perimenopause, including which menopause-related symptoms, demographic variables, stress exposures, and neural biomarkers are associated with cognitive problems and which interventions demonstrate efficacy at improving cognitive performance. RECENT FINDINGS: Cognitive problems are common during perimenopause and have a significant impact on a substantial proportion of women. Evidence continues to indicate that verbal learning and verbal memory are the cognitive functions that are most negatively affected during perimenopause, and new research suggests that perimenopause may also be associated with deficits in processing speed, attention, and working memory. Recent research suggests that the cognitive profiles of women transitioning through perimenopause are heterogenous - with some showing strengths and others demonstrating weaknesses in particular cognitive domains. Depression, sleep problems, and vasomotor symptoms in perimenopause may be associated with cognitive difficulties. Recent neuroimaging studies are identifying changes in activity patterns within brain regions that correlate with cognitive performance in perimenopause, but future causal studies are needed to understand the neural mechanisms of cognitive problems during this time. Although clinical treatment studies for cognitive concerns have historically focused on postmenopause, some small trials in perimenopausal samples have been conducted recently but are frequently underpowered. Current guidelines from the North American Menopause Society do not support the use of hormone therapy at any age for cognitive problems. Animal research demonstrates that estradiol and levonorgestrel combined may alleviate working memory problems. Much progress has been made in understanding how perimenopause impacts cognition, and more research is needed to better identify who is at highest risk and how to meaningfully prevent and alleviate cognitive problems during this reproductive stage. Larger-scale randomized intervention trials specifically during perimenopause are urgently needed to address cognitive concerns in this population of women. More consistent reproductive staging, inclusion of covariates, and analyses examining perimenopause specifically would improve study quality and the ability to draw clear conclusions from this research.

Progesterone Increases Nicotine Withdrawal and Anxiety in Male but Not Female Smokers During Brief Abstinence.

INTRODUCTION: Although exogenous progesterone may hold promise as a treatment for nicotine use disorders, it is unclear whether it is similarly effective in males and females. This study examined the effects of progesterone on nicotine use disorder comprehensively using behavioral, psychological, and neural measures in male and female smokers exposed to brief abstinence. AIMS AND METHODS: Thirty-three male and 33 female non-treatment-seeking smokers participated in a double-blind, randomized, placebo-controlled crossover study of 200 mg of progesterone or placebo daily over a four-day abstinence period. Smoking behavior and subjective effects of nicotine were assessed at baseline and after final drug administration. Nicotine withdrawal, smoking urges, mood states, and neural response to smoking cues were measured at baseline, after the first drug administration, and after the final drug administration. RESULTS: No main effect of drug (progesterone vs. placebo) emerged for any outcome. Significant sex by drug interactions emerged for nicotine withdrawal (p = .020), perceived strength of nicotine (p = .040), and perceived bad effects of nicotine (p = .029). Males receiving progesterone reported worse nicotine withdrawal (p = .046) and a trend towards decreased bad effects of nicotine (p = .070). Males on progesterone also reported greater tension and anxiety relative to placebo (p = .021). Females on progesterone perceived nicotine's effects as being stronger relative to placebo (p = .046). CONCLUSIONS: Progesterone causes sex-dependent effects on smoking-related outcomes during brief abstinence. Specifically, progesterone in males may increase rather than decrease nicotine withdrawal and negative affect during abstinence, potentially hindering efforts to quit smoking. IMPLICATIONS: In male and female smokers undergoing a brief period of abstinence, we examined the effects of progesterone on smoking outcomes. While progesterone had limited effects in female smokers, in males, it worsened nicotine withdrawal and negative affect. Our findings emphasize the importance of analyzing sex differences in future studies examining progesterone as a potential treatment and suggest that progesterone in males could potentially exacerbate aspects of nicotine dependence. CLINICALTRIALS.GOV REGISTRATION: NCT01954966. https://clinicaltrials.gov/ct2/show/NCT01954966.

Selective Serotonin Reuptake Inhibitors (SSRIs) in Pregnancy: An Updated Review on Risks to Mother, Fetus, and Child.

PURPOSE OF REVIEW: To provide an updated summary and appraisal of work from 2019 to 2022 examining risks of selective serotonin reuptake inhibitor (SSRI) use in pregnancy. RECENT FINDINGS: Perinatal SSRI exposure does not increase risk of major malformations or gestational diabetes after accounting for underlying maternal illness. SSRIs are associated with small increase in risk of pre-eclampsia, postpartum hemorrhage, preterm delivery, persistent pulmonary hypertension of the newborn, and neonatal intensive care unit admissions, though absolute risk of these outcomes is low. While data suggests no increased risk of neurodevelopmental disorders in offspring, mixed evidence indicates increased risk of adverse cognitive outcomes and affective disorders. Recent evidence suggest low absolute risk of clinically relevant negative outcomes with perinatal SSRI exposure when compared to untreated perinatal depression. However, study design and ability to control for confounding remains an ongoing research challenge, highlighting need for ongoing rigorous study design and analysis.

Technology-Based Approaches for Supporting Perinatal Mental Health.

PURPOSE OF REVIEW: This review explores advances in the utilization of technology to address perinatal mood and anxiety disorders (PMADs). Specifically, we sought to assess the range of technologies available, their application to PMADs, and evidence supporting use. RECENT FINDINGS: We identified a variety of technologies with promising capacity for direct intervention, prevention, and augmentation of clinical care for PMADs. These included wearable technology, electronic consultation, virtual and augmented reality, internet-based cognitive behavioral therapy, and predictive analytics using machine learning. Available evidence for these technologies in PMADs was almost uniformly positive. However, evidence for use in PMADs was limited compared to that in general mental health populations. Proper attention to PMADs has been severely limited by issues of accessibility, affordability, and patient acceptance. Increased use of technology has the potential to address all three of these barriers by facilitating modes of communication, data collection, and patient experience.

Discontinuation of hormonal contraception due to changes in mood and decreases in sexual desire: the role of adverse childhood experiences.

PURPOSE: To evaluate if adverse childhood experiences are associated with hormonal contraception discontinuation due to mood and sexual side effects. MATERIALS AND METHODS: Women, ages 18-40 (N = 826), with current and/or previous hormonal contraceptive use completed surveys on demographics, contraceptive history, and the Adverse Childhood Experiences Questionnaire. We characterised women into high (≥2 adverse experiences) and low (0 or 1) adverse childhood experience groups. We calculated risk ratios for associations between adverse childhood experiences and outcomes of interest using log binomial generalised linear models, and adjusted for relevant demographic variables. RESULTS: Women in the high adverse childhood experiences group (n = 355) were more likely to report having discontinued hormonal contraception due to decreases in sexual desire (adjusted risk ratio 1.44, 1.03-2.00, p = .030). Covariates included age, current hormonal contraception use, and various demographic variables associated with discontinuation. Adverse childhood experiences were not associated with mood or sexual side effects among current (n = 541) hormonal contraceptive users. CONCLUSIONS: Self-reported adverse childhood experiences were associated with greater likelihood of discontinuing hormonal contraception due to behavioural side effects, particularly decreases in sexual desire. Identification of risk factors for behavioural side effects can assist patients and clinicians in making informed choices on contraception that minimise risk of early discontinuation.

Neuropsychiatric effects of tamoxifen: Challenges and opportunities.

Epidemiological, clinical, and basic research over the past thirty years have described the benefits of estrogen on cognition, mood, and brain health. Less is known about tamoxifen, a selective estrogen receptor modifier (SERM) commonly used in breast cancer which is able to cross the blood-brain barrier. In this article, we review the basic pharmacology of tamoxifenas well as its effects on cognition and mood. The literature reveals an overall impairing effect of tamoxifen on cognition in breast cancer patients, hinting at central antiestrogen activity. On the other hand, tamoxifen demonstrates promising effects in psychiatric disorders, like bipolar disorder, where its therapeutic action may be independent of interaction with estrogen receptors. Understanding the neuropsychiatric properties of SERMs like tamoxifen can guide future research to ameliorate unwanted side-effects and provide novel options for difficult to treat disorders.

Stress exposure and psychopathology alter methylation of the serotonin receptor 2A (HTR2A) gene in preschoolers.

Serotonin signaling pathways play a key role in brain development, stress reactivity, and mental health. Epigenetic alterations in the serotonin system may underlie the effect of early life stress on psychopathology. The current study examined methylation of the serotonin receptor 2A (HTR2A) gene in a sample of 228 children including 119 with child welfare documentation of moderate to severe maltreatment within the last 6 months. Child protection records, semistructured interviews in the home, and parent reports were used to assess child stress exposure, psychiatric symptoms, and behavior. The HTR2A genotype and methylation of HTR2A were measured at two CpG sites (-1420 and -1224) from saliva DNA. HTR2A genotype was associated with HTR2A methylation at both CpG sites. HTR2A genotype also moderated associations of contextual stress exposure and HTR2A methylation at site -1420. Contextual stress was positively associated with -1420 methylation among A homozygotes, but negatively associated with -1420 methylation among G homozygotes. Posttraumatic stress disorder and major depressive disorder symptoms were negatively associated with methylation at -1420, but positively associated with methylation at -1224. Results support the view that the serotonin system is sensitive to stress exposure and psychopathology, and HTR2A methylation may be a mechanism by which early adversity is biologically encoded.

Accurate, Traceable, and Verifiable Time Synchronization for World Financial Markets.

The National Institute of Standards and Technology (NIST), through a collaboration with Perseus, a global provider of telecommunication services, is providing accurate, traceable, and verifiable time synchronization to stock exchanges in the United States, Europe, and Asia. The paper describes why accurate time is necessary for fair and equitable financial markets and summarizes current and proposed future synchronization requirements in the financial sector. We discuss reference time sources and provide a technical overview of how NIST transfers time to data center hosted stock exchange. We also discuss how Perseus distributes NIST time to financial market customers and describes how the time is verified. Measurement data are presented, along with a discussion of measurement uncertainty.

A Low-Cost Time Transfer Receiver for Contributions to Coordinated Universal Time.

This paper describes a low-cost time transfer receiver that allows timing laboratories, including national metrology institutes and other designated institutions, to contribute data to the computation of Coordinated Universal Time (UTC). The time transfer receiver compares a laboratory's local realization of UTC, to signals broadcast by Global Positioning System (GPS) satellites. It stores the measurement results in a format compatible with international standards, and sends data via the Internet to the Bureau International des Poids et Mesures (BIPM) for inclusion in the UTC computation. In addition to being inexpensive, the receiver was designed to be easy to use, allowing recently established timing laboratories to begin contributing to UTC with a minimal investment in training.

Acute cerebrovascular accident in an 18-year-old male with von Willebrand disease.

Compared to the older populations, stroke is an infrequent occurrence in children, adolescents, and young adults. Furthermore, individuals who have hypocoagulability disorders, such as von Willebrand disease (vWD), appear to possess a degree of protection against thrombotic events. Here, we describe an 18-year-old male with a history of vWD who presented to the emergency department with left sided hemiparesis that occurred shortly after being placed in a headlock while wrestling. MRI revealed a right paramedian pontine stroke. The relationship between vWD and stroke is discussed as well as the role of neck trauma in vertebral artery injury. While vWD does appear to decrease the incidence of thrombotic events, such patients are still at risk, especially in the context of common inciting events such as neck trauma.

Probabilistic prediction of material stability: integrating convex hulls into active learning.

Active learning is a valuable tool for efficiently exploring complex spaces, finding a variety of uses in materials science. However, the determination of convex hulls for phase diagrams does not neatly fit into traditional active learning approaches due to their global nature. Specifically, the thermodynamic stability of a material is not simply a function of its own energy, but rather requires energetic information from all other competing compositions and phases. Here we present convex hull-aware active learning (CAL), a novel Bayesian algorithm that chooses experiments to minimize the uncertainty in the convex hull. CAL prioritizes compositions that are close to or on the hull, leaving significant uncertainty in other compositions that are quickly determined to be irrelevant to the convex hull. The convex hull can thus be predicted with significantly fewer observations than approaches that focus solely on energy. Intrinsic to this Bayesian approach is uncertainty quantification in both the convex hull and all subsequent predictions (e.g., stability and chemical potential). By providing increased search efficiency and uncertainty quantification, CAL can be readily incorporated into the emerging paradigm of uncertainty-based workflows for thermodynamic prediction.

Relationship between functional connectivity and weight-gain risk of antipsychotics in schizophrenia.

BACKGROUND: The mechanisms by which antipsychotic medications (APs) contribute to obesity in schizophrenia are not well understood. Because AP effects on functional brain connectivity may contribute to weight effects, the current study investigated how AP-associated weight-gain risk relates to functional connectivity in schizophrenia. METHODS: Fifty-five individuals with schizophrenia (final N = 54) were divided into groups based on previously reported AP weight-gain risk (no APs/low risk [N = 19]; moderate risk [N = 17]; high risk [N = 18]). Resting-state functional magnetic resonance imaging (fMRI) was completed after an overnight fast ("fasted") and post-meal ("fed"). Correlations between AP weight-gain risk and functional connectivity were assessed at the whole-brain level and in reward- and eating-related brain regions (anterior insula, caudate, nucleus accumbens). RESULTS: When fasted, greater AP weight-gain risk was associated with increased connectivity between thalamus and sensorimotor cortex (pFDR = 0.021). When fed, greater AP weight-gain risk was associated with increased connectivity between left caudate and left precentral/postcentral gyri (pFDR = 0.048) and between right caudate and multiple regions, including the left precentral/postcentral gyri (pFDR = 0.001), intracalcarine/precuneal/cuneal cortices (pFDR < 0.001), and fusiform gyrus (pFDR = 0.008). When fed, greater AP weight-gain risk was also associated with decreased connectivity between right anterior insula and ventromedial prefrontal cortex (pFDR = 0.002). CONCLUSIONS: APs with higher weight-gain risk were associated with greater connectivity between reward-related regions and sensorimotor regions when fasted, perhaps relating to motor anticipation for consumption. Higher weight-gain risk APs were also associated with increased connectivity between reward, salience, and visual regions when fed, potentially reflecting greater desire for consumption following satiety.

Harnessing technology to improve sleep in frontline healthcare workers: A pilot study of electronic noise-masking earbuds on subjective and objective sleep measures.

Objective: This pilot study assessed the effects of electronic noise-masking earbuds on subjective sleep perception and objective sleep parameters among healthcare workers (HCWs) reporting sleep difficulties during the COVID-19 pandemic. Methods: Using a pre-post design, 77 HCWs underwent 3 nights of baseline assessment followed by a 7-night intervention period. Participants wore an at-home sleep monitoring headband to assess objective sleep measures and completed subjective self-report assessments. The difference in mean sleep measures from baseline to intervention was estimated in linear mixed models. Results: Compared to baseline assessments, HCWs reported significant improvements in sleep quality as measured by the Insomnia Severity Index (ISI) (Cohen's d = 1.74, p < 0.001) and a significant reduction in perceived sleep onset latency (SOL) during the intervention (M = 17.2 minutes, SD = 7.7) compared to baseline (M = 24.7 minutes, SD = 16.1), (Cohen's d = -0.42, p = 0.001). There were no significant changes in objective SOL (p = 0.703). However, there was a significant interaction between baseline objective SOL (<20 minutes vs >20 minutes) and condition (baseline vs intervention) (p = 0.002), such that individuals with objective SOL >20 minutes experienced a significant decrease in objective SOL during the intervention period compared to baseline (p = 0.015). Conclusions: HCWs experienced a significant improvement in perceived SOL and ISI scores after using the electronic noise-masking earbuds. Our data provide preliminary evidence for a nonpharmacological intervention to improve the sleep quality of HCWs which should be confirmed by future controlled studies.

Childhood stress, gender, and cognitive control: Midline theta power.

The emergence of psychiatric symptoms is a common consequence of childhood stress exposure. However, there are a dearth of reliable clinical hallmarks or physiological biomarkers to predict post-trauma symptom emergence. The objective of this study was to examine if childhood stressors and stress-related symptoms are associated with altered midline theta power (MTP) during cognitive control demands, and how these associations interact with gender and early adversity. N = 53 children (ages 9-13 years old) from a longitudinal study of children maltreated during early childhood and non-maltreated children participated in this study. EEG recorded neural activity during a Zoo-Themed Go/No-Go task. Stress-related symptoms, recent stressful events, and other adversity experiences were identified. MTP was analyzed with clinical variables in a series of follow-up analyses. The number of stressors in the past six months was negatively correlated with MTP in those with low preschool adversity, but not in those with high preschool adversity. MTP was higher in girls than in boys, and the associations of MTP with stressors and symptoms were moderated by gender. MTP was negatively associated with stressors in the past six months in girls, while in boys, MTP was associated with stress-related symptoms. Childhood stressful events were associated with reduced MTP during cognitive control demands, and this was finding was moderated by gender and early life adversity. These preliminary findings suggest that boys and girls may process stressful experiences in distinct ways, and preschool adversity may potentially blunt the interaction between current stress and neural dynamics. However, ongoing investigation is needed.

Adolescent social defeat decreases spatial working memory performance in adulthood.

BACKGROUND: Adolescent social stress is associated with increased incidence of mental illnesses in adulthood that are characterized by deficits in cognitive focus and flexibility. Such enhanced vulnerability may be due to psychosocial stress-induced disruption of the developing mesocortical dopamine system, which plays a fundamental role in facilitating complex cognitive processes such as spatial working memory. Adolescent rats exposed to repeated social defeat as a model of social stress develop dopaminergic hypofunction in the medial prefrontal cortex as adults. To evaluate a direct link between adolescent social stress and later deficits in cognitive function, the present study tested the effects of adolescent social defeat on two separate tests of spatial working memory performance. METHODS: Adult rats exposed to adolescent social defeat and their controls were trained on either the delayed win-shift task or the delayed alternating T-Maze task and then challenged with various delay periods. To evaluate potential differences in motivation for the food reward used in memory tasks, consumption and conditioned place preference for sweetened condensed milk were tested in a separate cohort of previously defeated rats and controls. RESULTS: Compared to controls, adult rats defeated in adolescence showed a delay-dependent deficit in spatial working memory performance, committing more errors at a 90 s and 5 min delay period on the T-maze and win-shift tasks, respectively. Observed memory deficits were likely independent of differences in reward motivation, as conditioned place preference for the palatable food used on both tasks was similar between the adolescent social defeat group and control. CONCLUSIONS: The results demonstrate that severe social stressors during adolescence can produce long term deficits in aspects of cognitive function. Given the dependence of spatial working memory on prefrontal dopamine, pharmacologically reversing dopaminergic deficiencies caused by adolescent social stress has the potential to treat such cognitive deficits.

Adverse childhood experiences and hormonal contraception: Interactive impact on sexual reward function.

The current literature suggests that some women are uniquely vulnerable to negative effects of hormonal contraception (HC) on affective processes. However, little data exists as to which factors contribute to such vulnerability. The present study evaluated the impact of prepubertal adverse childhood experiences (ACEs) on reward processing in women taking HC (N = 541) compared to naturally cycling women (N = 488). Participants completed an online survey assessing current and past HC use and exposure to 10 different adverse childhood experiences (ACEs) before puberty (ACE Questionnaire), with participants categorized into groups of low (0-1) versus high (≥2) prepubertal ACE exposure. Participants then completed a reward task rating their expected and experienced valence for images that were either erotic, pleasant (non-erotic), or neutral. Significant interactions emerged between prepubertal ACE exposure and HC use on expected (p = 0.028) and experienced (p = 0.025) valence ratings of erotic images but not pleasant or neutral images. Importantly, follow-up analyses considering whether women experienced HC-induced decreases in sexual desire informed the significant interaction for expected valence ratings of erotic images. For current HC users, prepubertal ACEs interacted with HC-induced decreased sexual desire (p = 0.008), such that high ACE women reporting decreased sexual desire on HC showed substantially decreased ratings for anticipated erotic images compared to both high prepubertal ACE women without decreased sexual desire (p < 0.001) and low prepubertal ACE women also reporting decreased sexual desire (p = 0.010). The interaction was not significant in naturally cycling women reporting previous HC use, suggesting that current HC use could be impacting anticipatory reward processing of sexual stimuli among certain women (e.g., high prepubertal ACE women reporting HC-induced decreases in sexual desire). The study provides rationale for future randomized, controlled trials to account for prepubertal ACE exposure to promote contraceptive selection informed by behavioral evidence.

The role of the hypothalamic-pituitary-adrenal axis in depression across the female reproductive lifecycle: current knowledge and future directions.

The aim of this narrative review is to consolidate knowledge on the role of the hypothalamic-pituitary-adrenal (HPA) axis in depression pathophysiology at different reproductive stages across the female lifespan. Despite growing evidence about the impact of gonadal hormones on mood disorders, no previous review has examined the interaction between such hormonal changes and the HPA axis within the context of depressive disorders in women. We will focus on HPA axis function in depressive disorders at different reproductive stages including the menstrual cycle (e.g., premenstrual dysphoric disorder [PMDD]), perinatally (e.g., postpartum depression), and in perimenopausal depression. Each of these reproductive stages is characterized by vast physiological changes and presents major neuroendocrine reorganization. The HPA axis is one of the main targets of such functional alterations, and with its key role in stress response, it is an etiological factor in vulnerable windows for depression across the female lifespan. We begin with an overview of the HPA axis and a brief summary of techniques for measuring HPA axis parameters. We then describe the hormonal milieu of each of these key reproductive stages, and integrate information about HPA axis function in depression across these reproductive stages, describing similarities and differences. The role of a history of stress and trauma exposure as a contributor to female depression in the context of HPA axis involvement across the reproductive stages is also presented. This review advances the pursuit of understanding common biological mechanisms across depressive disorders among women. Our overarching goal is to identify unmet needs in characterizing stress-related markers of depression in women in the context of hormonal changes across the lifespan, and to support future research in women's mental health as it pertains to pathophysiology, early diagnosis, and treatment targets.