Maternal adverse childhood experiences impact fetal adrenal volume in a sex-specific manner.

BACKGROUND: The mechanisms by which parental early life stress can be transmitted to the next generation, in some cases in a sex-specific manner, are unclear. Maternal preconception stress may increase susceptibility to suboptimal health outcomes via in utero programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis. METHODS: We recruited healthy pregnant women (N = 147), dichotomized into low (0 or 1) and high (2+) adverse childhood experience (ACE) groups based on the ACE Questionnaire, to test the hypothesis that maternal ACE history influences fetal adrenal development in a sex-specific manner. At a mean (standard deviation) of 21.5 (1.4) and 29.5 (1.4) weeks gestation, participants underwent three-dimensional ultrasounds to measure fetal adrenal volume, adjusting for fetal body weight (waFAV). RESULTS: At ultrasound 1, waFAV was smaller in high versus low ACE males (b = - 0.17; z = - 3.75; p < .001), but females did not differ significantly by maternal ACE group (b = 0.09; z = 1.72; p = .086). Compared to low ACE males, waFAV was smaller for low (b = - 0.20; z = - 4.10; p < .001) and high ACE females (b = - 0.11; z = 2.16; p = .031); however, high ACE males did not differ from low (b = 0.03; z = .57; p = .570) or high ACE females (b = - 0.06; z = - 1.29; p = .196). At ultrasound 2, waFAV did not differ significantly between any maternal ACE/offspring sex subgroups (ps ≥ .055). Perceived stress did not differ between maternal ACE groups at baseline, ultrasound 1, or ultrasound 2 (ps ≥ .148). CONCLUSIONS: We observed a significant impact of high maternal ACE history on waFAV, a proxy for fetal adrenal development, but only in males. Our observation that the waFAV in males of mothers with a high ACE history did not differ from the waFAV of females extends preclinical research demonstrating a dysmasculinizing effect of gestational stress on a range of offspring outcomes. Future studies investigating intergenerational transmission of stress should consider the influence of maternal preconception stress on offspring outcomes.

Randomized controlled trial of transcranial magnetic stimulation in pregnant women with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) affects 10% of pregnancies. Because transcranial magnetic stimulation (TMS) is a nonmedication option, psychiatric patients who do not tolerate or prefer to avoid antidepressants are good candidates for TMS. METHOD: In a randomized controlled trial of twenty-two women with MDD in the second or third trimester of pregnancy, subjects were randomized to active TMS (n=11) or sham TMS (n=11). This study took place at a single academic center. Subjects received 20 sessions of TMS to the right dorsolateral prefrontal cortex at 1 Hz as a single train of 900 pulses per session at 100% motor threshold. Estradiol and progesterone and were measured before session 1 and after session 20. RESULTS: Results demonstrated significantly decreased Hamilton Depression Rating Scale (HDRS-17) scores for the active compared to the sham group (p=0.003). Response rates were 81.82% for the active and 45.45% for the sham coil (p=0.088). Remission rates were 27.27% for the active 18.18% for the sham coil (p=0.613). Late preterm birth (PTB) occurred in three women receiving active TMS. All other maternal and delivery outcomes were normal. CONCLUSIONS: Right-sided, low frequency TMS was effective in reducing depressive symptoms in this sample of pregnant women. There may be a possibility that TMS is associated with late PTB although a larger sample size would be needed for adequate power to detect a true difference between groups. This study demonstrated that TMS is low risk during pregnancy although larger trials would provide more information about the efficacy and safety of TMS in this population. This trial shows that an RCT of a biologic intervention in pregnant women with psychiatric illness can be conducted.

Pregnancy and the Acceptability of Computer-Based Versus Traditional Mental Health Treatments.

BACKGROUND: Recent recommendations urge increased depression screening in pregnant and postpartum women, potentially increasing demand for treatment. Computer-based psychotherapy treatments may address some of perinatal women's unique mental health treatment needs and barriers. MATERIALS AND METHODS: We conducted a quantitative survey of pregnant women (≥12 weeks of gestation) on preferences regarding computer-based therapies compared with traditional therapies (psychotherapy and medication). Nonpregnant women and men served as comparison groups. Participants were provided descriptions of three computer-based therapies: video telehealth therapy (VTT), computer-assisted therapy (CAT), and self-guided online therapy (SGO). Participants were asked to select all options that they would consider for treatment as well as first choice preference. The Patient Health Questionnaire-9 (PHQ-9) assessed current depressive symptomatology, and the Mini International Neuropsychiatric Interview (MINI) assessed psychiatric history. RESULTS: Participants included pregnant females (n = 111), nonpregnant females (n = 147), and males (n = 54). Among pregnant women, 77.5% (n = 86) indicated that they would consider some form of computer-based therapy for mental health treatment during pregnancy; VTT was the most commonly considered, followed by CAT and SGO. When asked to select their preferred intervention, traditional talk therapy was the first choice among all three groups, controlling for treatment history and PHQ-9 score. About one-third of pregnant women chose some form of computer-based therapy as their top choice. CONCLUSIONS: While computer-based therapies were acceptable to most pregnant women in this sample, traditional talk therapy was the preferred option. Future research should consider how to tailor computer-based therapies to the unique needs of perinatal women.

Adverse Childhood Experiences and Risk for First-Episode Major Depression During the Menopause Transition.

OBJECTIVE: Stress exposures may have a differential impact on risk and resilience for depression depending on their timing across development. We sought to determine whether adverse childhood experiences (ACEs) and their onset with respect to puberty contribute to the increased risk observed in first-episode major depressive disorder (MDD) during the menopause transition. METHODS: Participants were from the Penn Ovarian Aging Study cohort, which is composed of women from Philadelphia County, Pennsylvania, who underwent behavioral, cognitive, and endocrine evaluations approximately yearly from 1996 to 2012 and completed the Adverse Childhood Experiences Questionnaire at study end point (n = 243). ACEs that first occurred 2 or more years before menarche were considered prepubertal. Incident menopause MDD was defined as first observed onset of the disorder in the perimenopause to postmenopause transition using the Structured Clinical Interview for DSM-III-R and the Primary Care Evaluation of Mental Disorders. RESULTS: Incident menopause MDD occurred in 48% of the 100 women who reported lifetime MDD. Women reporting ≥ 2 total ACEs were at significantly greater risk for lifetime MDD (adjusted odds ratio [aOR] = 2.05, P = .034) and incident menopause MDD (aOR = 2.58, P = .03) compared to those reporting 0 ACEs; women with ≥ 2 postpubertal ACEs were 2.3 times more likely to experience incidence menopause MDD (P = .024) after controlling for race, smoking, body mass index, and employment. Experiencing only 1 ACE in the prepubertal window, regardless of additional ACEs in postpuberty, was associated with reduced risk for lifetime and incident menopause MDD. CONCLUSIONS: Timing and number of adverse experiences with respect to puberty differentially impacted risk and resilience for MDD across the female life span and during the menopause transition in this community cohort.

Preadolescent Adversity Programs a Disrupted Maternal Stress Reactivity in Humans and Mice.

BACKGROUND: Adverse childhood experiences (ACEs) are one of the greatest predictors of affective disorders for women. Periods of dynamic hormonal flux, including pregnancy, exacerbate the risk for affective disturbance and promote hypothalamic-pituitary-adrenal (HPA) axis dysregulation, a key feature of affective disorders. Little is understood as to how stress experienced in late childhood, defined as preadolescence, alters the programming unique to this period of brain maturation and its interaction with the hormonal changes of pregnancy and postpartum. METHODS: Preadolescent female mice were exposed to chronic stress and examined for changes in their HPA axis during pregnancy and postpartum, including assessment of maternal-specific stress responsiveness and transcriptomics of the paraventricular nucleus of the hypothalamus. Translationally, pregnant women with low or high ACEs were examined for their maternal stress responsiveness. RESULTS: As predicted, preadolescent stress in mice resulted in a significant blunting of the corticosterone response during pregnancy. Transcriptomic analysis of the paraventricular nucleus revealed widespread changes in expression of immediate early genes and their targets, supporting the likely involvement of an upstream epigenetic mechanism. Critically, in our human studies, the high ACE women showed a significant blunting of the HPA response. CONCLUSIONS: This unique mouse model recapitulates a clinical outcome of a hyporesponsive HPA stress axis, an important feature of affective disorders, during a dynamic hormonal period, and suggests involvement of transcriptional regulation in the hypothalamus. These studies identify a novel mouse model of female ACEs that can be used to examine how additional life adversity may provoke disease risk or resilience.

Depression and Anxiety During Pregnancy: Evaluating the Literature in Support of Clinical Risk-Benefit Decision-Making.

Depression and anxiety during pregnancy are common, and patients and providers are faced with complex decisions regarding various treatment modalities. A structured discussion of the risks and benefits of options with the patient and her support team is recommended to facilitate the decision-making process. This clinically focused review, with emphasis on the last 3 years of published study data, evaluates the major risk categories of medication treatments, namely pregnancy loss, physical malformations, growth impairment, behavioral teratogenicity, and neonatal toxicity. Nonpharmacological treatment options, including neuromodulation and psychotherapy, are also briefly reviewed. Specific recommendations, drawn from the literature and the authors' clinical experience, are also offered to help guide the clinician in decision-making.

Is third trimester serotonin reuptake inhibitor use associated with postpartum hemorrhage?

As serotonin reuptake inhibitor (SRI) use may decrease platelet function, previous research has shown a relationship between SRI use and an increased risk for bruising and bleeding. The literature regarding the association between SRI use during pregnancy and increased bleeding at delivery, referred to as postpartum hemorrhage (PPH), is mixed. In secondary analyses from two prospective observational studies of pregnant women with mood disorders, 263 women were exposed to an SRI (n = 51) or not (n = 212) in the third trimester. To be precise, we used the terminology estimated blood loss (EBL) >600 cc rather than the term PPH because the current definition of PPH differs. The occurrence of EBL >600 cc was determined using the Peripartum Events Scale (PES) completed from obstetrical records by a blinded medically trained member of the study team. EBL >600 cc occurred in 8.7% of women in this cohort. There was no statistically significant difference in the rates of EBL >600 cc in the 24 h after delivery in women taking SRIs during the third trimester (9.8%) compared to non-exposed women (8.5%). Utilizing generalizing estimating equations, the odds of EBL >600 cc in each group were not significantly different (OR 1.17, CI-0.41-3.32, p = 0.77). When the SRI group was limited to women with exposure at the time of delivery, the difference in the odds of EBL >600 cc was unchanged (OR 1.16, CI = 0.37-3.64, p = 0.79). In population, both third trimester and use at delivery of SRIs during pregnancy was not associated with an increased risk of excessive blood loss.

New onset executive function difficulties at menopause: a possible role for lisdexamfetamine.

RATIONALE: Reports of cognitive decline, particularly in the domains of executive functions (EFs), are common among menopausal women. OBJECTIVE: This study aims to determine the impact of the psychostimulant lisdexamfetamine (LDX) on subjective and objective cognitive function among menopausal women who report new-onset EF complaints. METHODS: Thirty-two healthy perimenopausal and early postmenopausal women experiencing mid-life-onset executive function difficulties as measured using the Brown Attention Deficit Disorder Scale (BADDS) were administered LDX 40-60 mg/day for 4 weeks in this double-blind, placebo-controlled, cross-over study. Diagnosis of lifetime ADHD was exclusionary. BADDS total and subscale scores and performance on verbal memory and working memory tasks were outcomes of interest. RESULTS: Analyses revealed a significant effect of LDX treatment over placebo for total BADDS scores (p = 0.0001) and for four out of the five BADDS subscales (all p < 0.004). LDX treatment also resulted in significant improvement in delayed paragraph recall (p = 0.018), but there was no significant effect of treatment on other cognitive measures. Systolic blood pressure (p = 0.017) and heart rate increased significantly (p = 0.006) when women were on LDX but remained, on average, within the normal range. CONCLUSIONS: LDX 40-60 mg/day was well tolerated and improved the subjective measures of executive function as well as objective measures of delayed verbal recall in this sample of healthy menopausal women.

Neuromodulation and antenatal depression: a review.

BACKGROUND: Depression during pregnancy affects 5%-8% of women. While the percentage of women in the US taking serotonin reuptake inhibitors during pregnancy has risen over the last decade, pregnant women continue to report that they prefer non-pharmacologic interventions. OBJECTIVE: We review the literature regarding neuromodulation techniques for major depressive disorder during pregnancy. The rationale for their use in this population, new developments, and future directions are discussed. METHODS: A literature search was conducted in PubMed Plus, Ovid Medline, and Embase to collect all articles on neuromodulation for the treatment of depression during pregnancy. Key search words included electroconvulsive therapy, transcranial magnetic stimulation, deep brain stimulation, transcranial direct current stimulation, neuromodulation, depression, and pregnancy. Given the sparse literature, all articles from 1960 to 2014 that addressed the use of neuromodulation in pregnancy were included. CONCLUSION: The data support the use of electroconvulsive therapy in all trimesters of pregnancy for major depressive disorder. New data are emerging for the use of transcranial magnetic stimulation in pregnancy, which is likely safe, but more data are needed before it can be recommended as a primary treatment modality during pregnancy. Other neuromodulation techniques have not been well studied in this population.

Psychiatric consultation to the postpartum mother.

The immediate postpartum period is a time of acute vulnerability to mental illness, which presents unique challenges for the psychiatric consultant. Because the postpartum hospital stay is typically brief, the consultant must have a working knowledge of postpartum physiology and the myriad forms of mental illness that may emerge in this vulnerable time, in order to quickly make a diagnosis and formulate a treatment plan. This review aims to characterize the most common reasons for postpartum consultation, review postpartum physiology and psychiatric conditions, and propose an evidence-based, practical approach to treatment. A literature search using the terms "postpartum," "obstetric," "consultation," and "psychiatry" yielded six studies that identified reasons for psychiatric consultation to the obstetrics and gynecology services. These studies informed the structure of the article such that we review the most common reasons for consultation and how to approach each issue. The most common reason for consultation is past psychiatric history, often in the absence of current symptoms. For each clinical situation, including depression, adverse birth events, and psychosis, we present a differential diagnosis, as well as risk factors, clinical signs, and recommended treatment.

Prenatal programming of mental illness: current understanding of relationship and mechanisms.

The British epidemiologist Dr. David J. Barker documented the relationship between infant birth weight and later onset of hypertension, coronary heart disease, insulin resistance, and type II diabetes. A stressful in utero environment can cause long-term consequences for offspring through prenatal programming. Prenatal programming most commonly occurs through epigenetic mechanisms and can be dependent on the type and timing of exposure as well as the sex of the fetus. In this review, we highlight the most recent evidence that prenatal programming is implicated in the development of psychiatric disorders in offspring exposed to maternal stress during pregnancy. Methodological differences between studies contribute to unavoidable heterogeneity in study findings. Current data suggest that fetal exposure to maternal hypothalamic-pituitary-adrenal axis dysregulation, excessive glucocorticoids, and inflammation with resulting epigenetic changes at both the placental and fetal levels are important areas of continued investigation.

Computer-assisted cognitive behavioral therapy for pregnant women with major depressive disorder.

BACKGROUND: Pregnant women with major depressive disorder (MDD) report that psychotherapy is a more acceptable treatment than pharmacotherapy. However, although results of several studies suggest that psychotherapy is an effective treatment for pregnant women, logistical barriers-including cost and traveling for weekly visits-can limit real-world utility. We hypothesized that computer-assisted cognitive behavior therapy (CCBT) would be both acceptable and would significantly decrease depressive symptoms in pregnant women with MDD. METHODS: As a preliminary test of this hypothesis, we treated 10 pregnant women with MDD using a standardized CCBT protocol. RESULTS: The pilot results were very promising, with 80% of participants showing treatment response and 60% showing remission after only eight sessions of CCBT. CONCLUSION: A larger, randomized controlled trial of CCBT in pregnant women with MDD is warranted.

Pharmacotherapy of postpartum depression: an update.

INTRODUCTION: Postpartum depression (PPD) is a common and serious illness that affects up to 14% of women in the first month after childbirth. We present an update on the pharmacologic treatment of PPD, although there continues to be a lack of large, randomized controlled trials (RCTs). AREAS COVERED: A review of the literature on the use of antidepressants, hormonal supplements and omega-3 fatty acids for the prevention and the treatment of PPD published since the original review in 2009 and the authors' opinion on the current status of the pharmacological treatment of PPD are covered. An electronic search was performed by using PubMed, Medline and PsychINFO. Inclusion criteria were: i) empirical articles in peer-reviewed English-language journals; ii) well-validated measures of depression; and iii) a uniform scoring system for depression among the sample. EXPERT OPINION: Since the last Expert Opinion review, four antidepressant treatment studies and one prevention study of PPD have been published. Six RCTs evaluating the use of omega-3 fatty acids (four for prevention and two for treatment) have been published. There continues to be lack of data regarding the pharmacotherapy of PPD. However, serotonin reuptake inhibitors should be considered first-line for women with PPD after it has been determined that the proper diagnosis is not bipolar disorder. It is important to individualize treatment for women with PPD and consider the risks and benefits of treatment while breastfeeding.

Elevated risk of adverse obstetric outcomes in pregnant women with depression.

In this study, we evaluated the association between prenatal depression symptoms adverse birth outcomes in African-American women. We conducted a retrospective cohort study of 261 pregnant African-American women who were screened with the Edinburgh Postnatal Depression Scale (EPDS) at their initial prenatal visit. Medical records were reviewed to assess pregnancy and neonatal outcomes, specifically preeclampsia, preterm birth, intrauterine growth retardation, and low birth weight. Using multivariable logistic regression models, an EPDS score ≥10 was associated with increased risk for preeclampsia, preterm birth, and low birth weight. An EPDS score ≥10 was associated with increased risk for intrauterine growth retardation, but after controlling for behavioral risk factors, this association was no longer significant. Patients who screen positive for depression symptoms during pregnancy are at increased risk for multiple adverse birth outcomes. In a positive, patient-rated depression screening at the initial obstetrics visit, depression is associated with increased risk for multiple adverse birth outcomes. Given the retrospective study design and small sample size, these findings should be confirmed in a prospective cohort study.

Central nervous system effects of prenatal selective serotonin reuptake inhibitors: sensing the signal through the noise.

RATIONALE: Women are increasingly prescribed selective serotonin reuptake inhibitors (SSRIs) during pregnancy, with potential implications for neurodevelopment. Whether prenatal SSRI exposure has an effect on neurodevelopment and behavior in the offspring is an important area of investigation. OBJECTIVES: The aim of this paper was to review the existing preclinical and clinical literature of prenatal SSRI exposure on serotonin-related behaviors and markers in the offspring. The goal is to determine if there is a signal in the literature that could guide clinical care and/or inform research. RESULTS: Preclinical studies (n = 4) showed SSRI exposure during development enhanced depression-like behavior. Half of rodent studies examining anxiety-like behavior (n = 13) noted adverse effects with SSRI exposure. A majority of studies of social behavior (n = 4) noted a decrease in sociability in SSRI exposed offspring. Human studies (n = 4) examining anxiety in the offspring showed no adverse effects of prenatal SSRI exposure. The outcome of one study suggested that children with autism were more likely to have a mother who was prescribed an SSRI during pregnancy. CONCLUSIONS: Preclinical findings in rodents exposed to SSRIs during development point to an increase in depression- and anxiety-like behavior and alteration in social behaviors in the offspring, though both the methods used and the findings were not uniform. These data are not robust enough to discourage use of SSRIs during human pregnancy, particularly given the known adverse effects of maternal mental illness on pregnancy outcomes and infant neurodevelopment. Future research should focus on consistent animal models and prospective human studies with larger samples.

The relationship between bipolar disorder, seasonality, and premenstrual symptoms.

Cyclical mood disorders characterized by shifting affective states include bipolar disorder, seasonal affective disorder, and premenstrual syndrome/premenstrual dysphoric disorder. In this article, we explore the relationship between these disorders and bring the reader up to date on the advances made in the past year in understanding the relationship between bipolar disorder, seasonality, and premenstrual symptoms.

An open label pilot study of transcranial magnetic stimulation for pregnant women with major depressive disorder.

OBJECTIVE: Despite the data that major depressive disorder (MDD) is common during pregnancy and that pregnant women prefer nonmedication treatment options, there is a paucity of research examining alternative treatments for this special population. We present the results of an open label pilot study examining treatment with transcranial magnetic stimulation (TMS) in pregnant women with MDD. METHODS: Ten women with MDD in the second or third trimester of pregnancy were treated with 20 sessions of 1-Hz TMS at 100% of motor threshold (MT) to the right dorsolateral prefrontal cortex. The total study dose was 6000 pulses. Antenatal monitoring was performed during treatment sessions 1, 10, and 20. RESULTS: Seven of ten (70%) subjects responded (decrease ≥50% in Hamilton Depression Rating Scale [HDRS-17] scores). No adverse pregnancy or fetal outcomes were observed. All infants were admitted to the well baby nursery and were discharged with the mother. Mild headache was the only common adverse event and was reported by 4 of 10 (40%) subjects. CONCLUSIONS: TMS appears to be a promising treatment option for pregnant women who do not wish to take antidepressant medications.