Lauren M. Osborne

Oxytocin receptor DNA methylation in postpartum depression

The oxytocin receptor (OXTR) is a key regulator of stress and anxiety and may be regulated by both psychosocial risk factors and gonadal hormones, making it an attractive candidate for study in postpartum depression (PPD). The objective of this study was to investigate both serum hormone and PPD specific DNA methylation variation in the OXTR. Illumina HM450 microarray data generated in a prospective PPD cohort identified significant associations (P=0.014) with PPD in an intronic region in the OXTR located 4bp proximal to an estrogen receptor (ER) binding region. Pyrosequencing confirmed moderate evidence for an interaction of CpGs in the region with childhood abuse status to mediate PPD. These CpGs located on chr3 at positions 8810078 and 8810069 exhibited significant associations with postpartum depression scores from an independent cohort of 240 women with no prior psychiatric history. Hormone analysis suggested a PPD specific negative correlation of DNA methylation in the region with serum estradiol levels. Estradiol levels and OXTR DNA methylation exhibited a significant interaction to associate with the ratio of allopregnanolone to progesterone. Cumulatively, the data corroborate our previous hypotheses of a PPD specific increased sensitivity of epigenetic reprogramming at estrogen target genes and suggests that OXTR epigenetic variation may be an important mediator of mood relevant neuroactive steroid production.

Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels

DNA methylation variation at HP1BP3 and TTC9B is modified by estrogen exposure in the rodent hippocampus and was previously shown to be prospectively predictive of postpartum depression (PPD) when modeled in antenatal blood. The objective of this study was to replicate the predictive efficacy of the previously established model in women with and without a previous psychiatric diagnosis and to understand the effects of changing hormone levels on PPD biomarker loci. Using a statistical model trained on DNA methylation data from N=51 high-risk women, we prospectively predicted PPD status in an independent N=51 women using first trimester antenatal gene expression levels of HP1BP3 and TTC9B, with an area under the receiver operator characteristic curve (AUC) of 0.81 (95% CI: 0.69–0.92, p<5 × 10−4). Modeling DNA methylation of these genes in N=240 women without a previous psychiatric diagnosis resulted in a cross-sectional prediction of PPD status with an AUC of 0.81 (95% CI: 0.68–0.93, p=0.01). TTC9B and HP1BP3 DNA methylation at early antenatal time points showed moderate evidence for association to the change in estradiol and allopregnanolone over the course of pregnancy, suggesting that epigenetic variation at these loci may be important for mediating hormonal sensitivity. In addition both loci showed PPD-specific trajectories with age, possibly mediated by age-associated hormonal changes. The data add to the growing body of evidence suggesting that PPD is mediated by differential gene expression and epigenetic sensitivity to pregnancy hormones and that modeling proxies of this sensitivity enable accurate prediction of PPD.

Associations Among Child Abuse, Depression, and Interleukin-6 in Pregnant Adolescents: Paradoxical Findings

Objective Limited data exist on child abuse–related immune variation during pregnancy, despite implications for maternal and infant health and extensive data showing that abuse history and depression are related to increased inflammation in other populations. This study examined associations among child abuse, depression, circulating levels of inflammatory markers, and perinatal health in pregnant adolescents, a group at high risk for childhood abuse and poor birth outcomes. Methods Pregnant teenagers (n = 133; 14–19 years; 89.5% Latina) reported on abuse and depression and had two blood draws (24–27 and 34–37 gestational weeks, second and third trimesters, respectively) for interleukin-6 (IL-6) and C-reactive protein; birth outcomes were collected. Results Abuse and depression interacted to predict higher IL-6 at second trimester (B = 0.006, p = .011) such that severely abused adolescents with high depression had higher IL-6 relative to severely abused adolescents with low depression; depression did not differentiate IL-6 levels for those with low abuse severity. Abuse and IL-6 also interacted to predict gestational age at birth (B = 0.004, p = .040) such that those with low abuse and high IL-6 and those with high abuse and low IL-6 had infants with earlier gestational age at birth. Cortisol at the second trimester mediated the association between IL-6 and gestational age at birth (indirect effect estimate=−0.143, p < .039). Conclusions Depression severity distinguished IL-6 levels among more severely abused pregnant Latina adolescents, but it was unrelated to IL-6 among less severely abused adolescents. Cortisol explained the relationship between IL-6 and earlier gestational age at birth. Multiple adversities and inflammation may influence birth outcomes and potentially affect intergenerational health.

Lower allopregnanolone during pregnancy predicts postpartum depression: An exploratory study

Current evidence is mixed on the role of progesterone and its metabolites in perinatal mood and anxiety disorders. We measured second and third trimester (T2 and T3) progesterone (PROG) and allopregnanolone (ALLO) levels by ELISA and postpartum depression (PPD) by clinician interview (DSM-IV criteria) in 60 pregnant women with a prior diagnosis of a mood disorder. Methods included multivariate and logistic regression with general linear mixed effect models. We found that, after adjustment, every additional ng/mL of T2 ALLO resulted in a 63% (95% CI 13% to 84%, p=0.022) reduction in the risk of developing PPD. Our findings extend previous work connecting ALLO and depression within pregnancy, and indicate that the relationship between pregnancy ALLO and PPD is worth further exploration in a larger sample.

Beyond screening: A review of pediatric primary care models to address maternal depression

Depression is one of the most debilitating chronic disorders in the United States, affecting 15 million children in homes with depressed mothers, many of whom endure household chaos, inconsistent nurturing, inadequate safety practices, and harsh discipline. Depressed mothers are under diagnosed and undertreated, yet there is broad consensus about the importance of identifying and managing maternal depression, as reflected in recommendations by pediatric and obstetric professional organizations to routinely screen for perinatal depression. Screening was shown to be acceptable to women and most pediatric providers, and adding a screening component need not impair clinic efficiency. Screening, however, is not sufficient, and there are few models in the literature to guide medical practices in implementing successful interventions to identify, treat, and prevent maternal depression, particularly in the pediatric setting. We reviewed the literature and identified six studies that evaluated models for screening and managing mothers’ depression in pediatric primary care settings. Some of these interventions have promise, but no studies characterized health outcomes of the depressed mothers and children. We discuss the components of these models, their implementation, and the practice and research needed to create effective pediatrics-based systems to reduce the negative effects of maternal depression on mothers, children, and families.

Reproductive Psychiatry: The Gap Between Clinical Need and Education

Over the past three decades, there have been substantial advances in our understanding of the strong influence of sex hormones on women’s mental and physical health. In particular, the literature clearly documents that fluctuating levels of reproductive hormones can manifest as premenstrual, perinatal, andperimenopausalpsychiatricdisorders inwomenwho arevulnerable to thesefluctuations (1–3).Theresearchover the past three decades came in response to a 1985 Public Health Service task force report onwomen’s health that noted deficits in our knowledge regarding key women’s health problems and that called for an expansion of biomedical and behavioral research to emphasize conditions unique to, or more prevalent in, women (4). In response, the National Institutes of Health (NIH) created a policy encouraging inclusion of women in clinical research. Because implementation of this policy was inconsistent and unmonitored, Congress passed legislation in 1993 mandating fair inclusion of women and minorities in clinical research.As a result, in 1994NIHbeganmandating that all grant applications either include women or justify the exclusion.This policywasupdated in 2001,with furtherguidance on reporting data by sex. Research resulting from these changes has dramatically expanded knowledge of the psychiatric sequelae of reproductive cycle transitions. Due to the accumulation of ample evidence, premenstrual dysphoric disorder, described in the medical literature since the time of Hippocrates, was finally included in DSM-5 (5). Perimenopause has also been recognized as a time of heightened risk for depressive and anxiety symptoms (6–10), and the role of hormonal and other novel interventions is being investigated(11). Importantly, depression has been found to be among the most prevalent perinatal illnesses, affecting up to 15% of women in the perinatal period (12–14). As of 2003, antidepressants were being used in approximately 13% of pregnancies—a rate that had climbed dramatically in the previous 10 years (15, 16); with the current U.S.birthrate, thatmeans thatmore than600,000fetusesevery year are exposed to depression and/or its treatments. The risks of untreated antenatal depression have been identified and include a lower likelihood of engaging in prenatal care; increased rates of smoking and alcohol use; poorer physical health; and higher rates of preeclampsia, gestational diabetes, preterm birth, and low birth weight (17, 18). Epigenetic effects of antenatal stress and depression on fetal development (“fetal programming”) are increasingly understood (19–21), as are the adverse long-term effects of postpartum depression on children (22–25). In addition to these risks, there is also considerable literature on the potential risks of treatments to both mother and fetus (26–28), as well as a body of literature concerning drug disposition and pharmacokinetic changes in pregnancy and postpartum that may require dosage adjustments (29–32). Clinicians who specialize in the field routinely use this new scientific information to craft individualized risk analyses for pregnant women who require treatment. This increased body of knowledge has led to the growth of international professional societies such as the Marcé International Society for Perinatal Mental Health and the International Society of Psychosomatic Obstetrics andGynecology. It has influenced public policy initiatives, including, for example, a number of statewide perinatal depression projects (33) and mandatory screenings (34). It has also begun to be disseminated into clinical practice via the emergence and growth of specialized clinical programs, which include outpatient and inpatient programs that offer perinatal consultations and ongoing treatment (35); perinatal care settings that integratemental health care (36); a peripartumday hospital (37); and, most recently, the first mother-baby inpatient unit in the United States (38). Such programs have been created by specialists out of necessity becausemany general psychiatrists havenot sufficientlymastered thisnewbodyofknowledgeand are unwilling or unable to treat pregnant and postpartum patients. While there is no doubt that such programs provide outstanding care (39, 40), they can neither begin to keep up with theclinical demandthat leads towaiting listsmonths long

Discovery and replication of a peripheral tissue DNA methylation biosignature to augment a suicide prediction model

BackgroundSuicide is the second leading cause of death among adolescents in the USA, and rates are rising. Methods to identify individuals at risk are essential for implementing prevention strategies, and the development of a biomarker can potentially improve prediction of suicidal behaviors. Prediction of our previously reported SKA2 biomarker for suicide and PTSD is substantially improved by questionnaires assessing perceived stress or anxiety and is therefore reliant on psychological assessment. However, such stress-related states may also leave a biosignature that could equally improve suicide prediction. In genome-wide DNA methylation data, we observed significant overlap between waking cortisol-associated and suicide-associated DNA methylation in blood and the brain, respectively.ResultsUsing a custom bioinformatic brain to blood discovery algorithm, we derived a DNA methylation biosignature that interacts with SKA2 methylation to improve the prediction of suicidal ideation in our existing suicide prediction model across both blood and saliva data sets. This biosignature was independently validated in the Grady Trauma Project cohort and interacted with HPA axis metrics in the same cohort. The biosignature showed a relationship with immune status by its correlation with myeloid-derived cell proportions in all data sets and with IL-6 measures in a prospective postpartum depression cohort. Three probes showed significant correlations with the biosignature: cg08469255 (DDR1), cg22029879 (ARHGEF10), and cg24437859 (SHP1), of which SHP1 methylation correlated with immune measures.ConclusionsWe conclude that this biosignature interacts with SKA2 methylation to improve suicide prediction and may represent a biological state of immune and HPA axis modulation that mediates suicidal behavior.

Reproductive Psychiatry Residency Training: A Survey of Psychiatric Residency Program Directors

ObjectiveThe reproductive life cycle has unique influences on the phenotypic expression of mental illness in women. Didactic and clinical training focused on these sex-specific influences should be a vital component of the education of future psychiatrists. The authors sought to determine the current state of and attitudes toward reproductive psychiatry in resident education.MethodsThe authors administered a web-based survey to psychiatry residency training directors. They assessed the availability of both mandated and optional didactic and clinical training experiences in reproductive psychiatry.ResultsFifty residency program directors answered the survey, for a response rate of 28%. More than half of residency program directors (59%) reported requiring some training in reproductive psychiatry. Both the breadth and depth of topics covered varied greatly among programs. Lack of time (48%) and lack of qualified faculty (26%) were the most frequently cited barriers to more training. Only 40% of residency directors surveyed agreed that all residents should be competent in reproductive psychiatry.ConclusionsThese findings suggest that specific training in reproductive psychiatry is inconsistent in US residency programs, and that training that does exist varies considerably in clinical time and content. Given that women comprise more than 50% of all psychiatric patients and most women will menstruate, give birth, and undergo menopause, future psychiatrists would benefit from more systematic instruction in this area. The authors propose the development of a national, standardized reproductive psychiatry curriculum to address this gap and aid in producing psychiatrists competent to treat women at all stages of life.

Reproductive Psychiatry Fellowship Training: Identification and Characterization of Current Programs

While effects of female reproductive transitions on mental health have long been observed, the past three decades have seen a dramatic increase in focused research and clinical programming related to reproductive mental health. Stemming from a 1985 US Public Health Service task force report that described a dearth of knowledge regarding women’s health more broadly, US federal research policies have since encouraged or mandated the inclusion of women in clinical research [1]. As a result, knowledge regarding the identification, diagnosis, and treatment of women experiencing mental illness during the premenstrual, perinatal, and perimenopausal periods has increased substantially. Reproductive psychiatry, a specialized field of medicine that seeks to understand and treat mental health disorders related to female reproductive stages, has emerged in parallel with this expanded knowledge. The past three decades have seen a growth of professional societies such as the Marcé International Society for Perinatal Mental Health and the North American Society for Psychosocial Obstetrics and Gynecology. The Academy of Psychosomatic Medicine has consistently included reproductive psychiatry as a subspecialty track of their annual meetings since 2013 [2–5]. Concomitantly, there has been a growth of specialized clinical programs, including integrated outpatient services, perinatal psychiatric day hospitals, and inpatient units [6–8]. Despite these advances, educational opportunities in reproductive psychiatry remain limited and have not yet been systematically integrated into psychiatric residency training. Individual residency training programs vary widely in their training opportunities in this field [9]. Furthermore, as reproductive psychiatry is not a recognized subspecialty of the American Board of Psychiatry and Neurology, no accredited fellowships, consensual training objectives, standardized curricula, or subspecialty exams exist. While graduates of Psychosomatic Medicine fellowships are required by the Accreditation Council for Graduate Medical Education (ACGME) to demonstrate proficiency in the appropriate use of psychoactive medication in obstetrical conditions [10], the amount of focused clinical and didactic time offered in these fellowships to reproductive psychiatry is constrained by other training requirements. There are a growing number of nonaccredited post-graduate fellowships that offer in-depth training in Women’s Mental Health, a broader field that encompasses reproductive psychiatry as well as subjects such as gender-linked trauma, gender roles, pharmacokinetic sex differences, and brain sexual dimorphism. These non-accredited opportunities can, however, be difficult to identify and compare with one another as they have not yet been cataloged by any specific organization. An unpublished survey of 55 selfidentified reproductive psychiatrists done by our group at a 2015 national perinatal mental health conference revealed that only 23% (n=13) of participants had any formal fellowship training in the field (16% (n=9) completed women’s mental health fellowships and 7% (n=4) completed Psychosomatic Medicine fellowships), while 25% (n=14) of participants indicated they had completed a specialized residency experience and over 50% (n=28) indicated that they had been either self* Sarah Nagle-Yang Sarah.nagle-yang@uhhospitals.org

Antidepressants, pregnancy, and stigma: how we are failing mothers and babies.

There is considerable public debate over the use of antidepressants in pregnancy. In this article, we offer a commentary on Gail Robinsons important overview of the current controversies. Dr Ronbinson gives a thorough review of the literature, including the risks posed by both antidepressants and depression itself. We summarize her arguments and point out that, in the public conversation, the risks posed to a fetus from antidepressants are consistently overestimated while the risks of untreated depression are consistently underestimated because of the pervasive stigma against mental health. We review recent lay media analyses and urge our fellow physicians to make decisions about prescribing in pregnancy on the basis of evidence and individual patient needs rather than media and stigma.