The Mood, Mother and Child Study: Protocol for a Prospective Longitudinal Study and Randomized Controlled Trial.

BACKGROUND: Perinatal depression affects >400,000 mother-child dyads in the United States every year and is associated with numerous adverse maternal and child developmental outcomes. Previous research implicates the dysregulation of oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis functioning in mothers and children as potential mechanisms mediating or moderating the transmission of risk associated with maternal depression. OBJECTIVE: The Mood, Mother and Child study will examine the psychobiological sources of risk and resilience within mother-child dyads affected by maternal depression. This manuscript describes (1) the study rationale and aims, (2) the research design and procedures and how they were altered in response to the COVID-19 pandemic, and (3) the data analysis plan to test the study hypotheses. METHODS: This is a prospective longitudinal study with an embedded randomized controlled trial that examines (1) correlations among postpartum depression and anxiety symptoms, maternal and child oxytocin and HPA axis functioning, and child developmental outcomes and (2) the causal relationship between exogenous oxytocin and HPA reactivity. This study is funded by the National Institute of Child Health and Human Development with institutional review board approval. RESULTS: Recruitment and data collection have commenced, and the expected results will be available in 2024. Analyses are presented for testing the proposed hypotheses. CONCLUSIONS: The unique combination of a prospective longitudinal research design with an embedded randomized controlled trial will allow the Mood, Mother and Child study to apply a developmental lens to the study of maternal depression and anxiety symptoms from birth to middle childhood and the psychobiological mechanisms promoting risk and resiliency for both mother and child outcomes. This will be the first study that simultaneously evaluates (1) the role of oxytocin using multiple methodologies, (2) the causal relationships between exogenous oxytocin and HPA axis functioning among mothers with differing levels of depression and anxiety symptoms, and (3) the multiple mediating and moderating roles of parenting behaviors and maternal and child psychobiological characteristics. The goals of these aims are to provide insights into the psychobiological effects of oxytocin in women and inform future clinical trials to treat perinatal mood disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT03593473; https://classic.clinicaltrials.gov/ct2/show/NCT03593473. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51132.

Effects of AFQ056 on language learning in fragile X syndrome.

BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.

Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study.

OBJECTIVE: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). METHODS: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks. RESULTS: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified. CONCLUSIONS: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02110706.

Universal screening for substance use by Peer Support Specialists in the Emergency Department is a pathway to buprenorphine treatment.

INTRODUCTION: Evidence suggests emergency department (ED)-initiated buprenorphine as efficacious in connecting ED patients to Medications for Opioid Use Disorder (MOUD) utilizing peer support specialists (PSS). However, there are no reports of implementation of ED-initiated buprenorphine in practice. Such information is crucial to support the adoption of ED-initiated buprenorphine. METHODS: In this quality improvement pilot study, a PSS screened ED patients over age 18 with the Tobacco, Alcohol, Prescription medication, and other Substance use - 1 (TAPS-1). The PSS considered the patient a positive screen if the patient met the following criteria: risky weekly alcohol use, illicit drugs, or prescription drugs. For patients who screened positive, the PSS delivered a brief intervention and assessed interest in treatment. An ED clinician assessed patients who screened positive for heroin/opioid use and were interested in treatment for buprenorphine induction. RESULTS: From January through June 2019, 1037 patients were screened for risky substance use, and, of these, 238 (23%) screened positive. The distribution of primary substance used was: 51% alcohol, 26% cannabis, 7.5% cocaine, 7.5% heroin, and 3.3% prescription opioids. Of the 23 patients who screened positive for heroin/opioid use and requested treatment, seven were admitted to the hospital. Of the remaining 16 patients, 14 patients wanted buprenorphine treatment, seven were provided buprenorphine in the ED, and four of these attended their intake appointments for community-based MOUD treatment. CONCLUSION: ED-initiated buprenorphine facilitated by a PSS is feasible and requires coordination and planning. Approaches to ED-initiated buprenorphine that screen only for opioid use will miss many patients interested in substance use treatment.

Telemedicine works for treating substance use disorder: The STAR clinic experience during COVID-19.

The coronavirus disease 2019 has exposed many opportunities for improvement in treatment for substance use disorders. Regulators can ensure higher quality treatment for addiction when acknowledging telemedicine as a necessary treatment option and amending regulations to allow for telehealth parity across the United States.

Genome-wide gene expression changes in postpartum depression point towards an altered immune landscape.

Maternal postpartum depression (PPD) is a significant public health concern due to the severe negative impact on maternal and child health and well-being. In this study, we aimed to identify genes associated with PPD. To do this, we investigated genome-wide gene expression profiles of pregnant women during their third trimester of pregnancy and tested the association of gene expression with perinatal depressive symptoms. A total of 137 women from a cohort from the University of North Carolina, USA were assessed. The main phenotypes analysed were Edinburgh Postnatal Depression Scale (EPDS) scores at 2 months postpartum and PPD (binary yes/no) based on an EPDS cutoff of 10. Illumina NextSeq500/550 transcriptomic sequencing from whole blood was analysed using the edgeR package. We identified 71 genes significantly associated with postpartum depression scores at 2 months, after correction for multiple testing at 5% FDR. These included several interesting candidates including TNFRSF17, previously reported to be significantly upregulated in women with PPD and MMP8, a matrix metalloproteinase gene, associated with depression in a genome-wide association study. Functional annotation of differentially expressed genes revealed an enrichment of immune response-related biological processes. Additional analysis of genes associated with changes in depressive symptoms from recruitment to 2 months postpartum identified 66 genes significant at an FDR of 5%. Of these genes, 33 genes were also associated with depressive symptoms at 2 months postpartum. Comparing the results with previous studies, we observed that 15.4% of genes associated with PPD in this study overlapped with 700 core maternal genes that showed significant gene expression changes across multiple brain regions (P = 7.9e-05) and 29-53% of the genes were also associated with estradiol changes in a pharmacological model of depression (P values range = 1.2e-4-2.1e-14). In conclusion, we identified novel genes and validated genes previously associated with oestrogen sensitivity in PPD. These results point towards the role of an altered immune transcriptomic landscape as a vulnerability factor for PPD.

Oxytocin during breastfeeding and maternal mood symptoms.

This study aimed to quantify the relationship between postpartum depression and anxiety, oxytocin, and breastfeeding. We conducted a longitudinal prospective study of mother-infant dyads from the third trimester of pregnancy to 12 months postpartum. A sample of 222 women were recruited to complete the Beck Depression Inventory II and Spielberger State-Trait Anxiety Inventory-state subscale, participate in observed infant feeding sessions at 2 and 6 months postpartum, and provide venous blood samples during feeding. Maternal venous oxytocin levels in EDTA-treated plasma and saliva were determined by enzyme immunoassay with extraction and a composite measure of area under the curve (AUC) was used to define oxytocin across a breastfeeding session. Linear regression was used to estimate associations between postpartum depression and anxiety as predictors and oxytocin AUC during breastfeeding as the outcome at both 2 and 6 months postpartum. Mixed models accounting for correlations between repeated oxytocin measures were used to quantify the association between current depression and/or anxiety symptoms and oxytocin profiles during breastfeeding. We found no significant differences in oxytocin AUC across a feed between depressed or anxious women and asymptomatic women at either 2 or 6 months postpartum. Repeated measures analyses demonstrated no differences in oxytocin trajectories during breastfeeding by symptom group but possible differences by antidepressant use. Our study suggests that external factors may influence the relationship between oxytocin, maternal mood symptoms, and infant feeding.

The Mood, Mother, and Infant Study: Associations Between Maternal Mood in Pregnancy and Breastfeeding Outcome.

Purpose: We sought to determine the role of depression and anxiety in breastfeeding cessation. Materials and Methods: Participants underwent a baseline visit with a structured clinical interview in the third trimester of pregnancy. Monthly phone interviews assessed current mood symptoms and infant feeding status. We assessed the association between baseline mood and infant feeding outcomes using Cox proportional hazards regression, adjusting for infant feeding intention and sociodemographic confounders. Results: We enrolled 222 mother-infant dyads in late pregnancy, of whom 206 completed assessments through 12 months postpartum. We enriched our study with symptomatic women by enrolling 87 women with current depression or anxiety (Current), 64 women with a history of depression or anxiety (Past), and 71 women with no psychiatric history (Never). In multivariable-adjusted analyses, baseline diagnosis was not associated with breastfeeding outcome, but baseline symptoms of depression (Beck Depression Inventory ≥11) or anxiety (Spielberger State Anxiety ≥40) were associated with earlier introduction of formula (depression: adj hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.01-2.30; anxiety: 1.70, 95% CI 1.01-2.87); and any cessation of breastfeeding (depression: adj HR 2.02, 95% CI 1.23-3.31; anxiety: 1.83, 95% CI 1.00-3.33), as were depression symptoms among women who were being treated with antidepressants, compared with untreated asymptomatic women (formula: adj HR 2.27, 95% CI 1.29-4.02; cessation: 2.32, 95% CI 1.17-4.61). History of childhood trauma (adj HR 1.34, 95% CI 1.12-1.61), disordered eating symptoms (adj HR 1.22, 95% CI 1.02-1.46), and poor sleep quality in pregnancy (adj HR 1.32, 95% CI 1.09-1.60) were independently associated with earlier introduction of formula. Conclusions: Baseline mood symptoms were independently associated with earlier formula introduction and cessation of breastfeeding. History of childhood trauma, disordered eating symptoms and poor sleep quality were associated with earlier formula introduction. Targeted support may enable women with these symptoms to achieve their feeding goals.

HPA axis reactivity to pharmacologic and psychological stressors in euthymic women with histories of postpartum versus major depression.

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-dependent phenomenon. This study sought the following: (1) to determine if euthymic postpartum women with a history of depression have an abnormal HPA axis reactivity to pharmacologic and psychological challenges and (2) to compare HPA reactivity in women with histories of PPD versus MDD. As a secondary objective, we wanted to determine the influence of trauma history on HPA axis function. Forty-five parous (12-24 months postpartum), euthymic women with history of MDD (n = 15), PPD (n = 15), and controls (n = 15) completed pharmacologic (dexamethasone/corticotropin-releasing hormone (CRH) test [DEX/CRH]) and psychological (Trier social stress test [TSST]) challenges during the luteal phase. Outcome measures were cortisol and adrenocorticotropic hormone (ACTH) response after DEX/CRH, and blood pressure, heart rate, epinephrine, norepinephrine, and cortisol response during the TSST. All groups had robust cortisol and ACTH response to DEX/CRH and cortisol response to TSST. Groups did not differ significantly in cortisol or ACTH response to DEX/CRH or in blood pressure, heart rate, epinephrine, norepinephrine, or cortisol response to TSST. Cortisol/ACTH ratio did not differ significantly between groups. Trauma history was associated with decreased cortisol response to DEX/CRH in women with histories of MDD, which was not significant after correction (F 8,125, p = 0.02, Greenhouse-Geisser corrected p = 0.11). Currently euthymic women with histories of MDD or PPD did not demonstrate residual abnormal stress responsivity following administration of either a pharmacologic or psychological stressor.

Double-blind, placebo-controlled pilot study of adjunctive quetiapine SR in the treatment of PMS/PMDD.

OBJECTIVE: Premenstrual dysphoric disorder (PMDD), a more severe form of premenstrual syndrome (PMS), afflicts 5-8% of reproductive age women and results in significant functional impairment. We conducted a double-blind, placebo-controlled trial of adjunctive quetiapine in patients with PMS/PMDD who had inadequate response to selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor therapy for their symptoms. METHODS: A PMS/PMDD diagnosis was confirmed by 2-month prospective diagnostic assessment of PMS/PMDD using the Prospective Record of the Impact and Severity of Premenstrual Symptoms (PRISM) calendar. Women were randomized equally to receive quetiapine sustained-release (SR) or placebo (25-mg starting dose) during the luteal phase for 3 months. Outcome variables included the Hamilton Depression and Anxiety Scales, Clinical Global Impression Scale, and PRISM. RESULTS: Twenty women were enrolled in the treatment phase. Although the study was underpowered, greater reductions in luteal phase mood ratings were observed in the quetiapine group on the 17-item Hamilton Depression Rating Scale, Clinical Global Impression improvement rating, and PRISM daily score. The quetiapine group showed most improvement in symptoms of mood lability, anxiety, and irritability. CONCLUSION: This small double-blind study suggests that adjunctive treatment with quetiapine SR may be a useful addition to selective serotonin reuptake inhibitor therapy in women with PMS/PMDD by reducing symptoms and improving quality of life.

Maternal neuroendocrine serum levels in exclusively breastfeeding mothers.

BACKGROUND: Low milk supply is a common cause of early weaning, and supply issues are associated with dysregulation of thyroid function and prolactin. However, hormone levels compatible with successful breastfeeding are not well defined, limiting interpretation of clinical lab results. In this study we sought to quantify ranges for thyroid-stimulating hormone (TSH), free thyroxine (T4), total T4, and prolactin in a cohort of exclusively breastfeeding women. MATERIALS AND METHODS: Women planning to breastfeed were recruited in the third trimester of pregnancy. Maternal endocrine function was assessed before and after a breastfeeding session at 2 and 8 weeks postpartum. We used paired t tests to determine whether values changed from the 2- to 8-week visit. RESULTS: Of 52 study participants, 28 were exclusively breastfeeding, defined as only breastmilk feeds in the prior 7 days, at both the 2- and 8-week study visits. Endocrine function changed with time since delivery: the TSH level was higher, whereas total T4, free T4, and prolactin levels were lower, at the 8-week visit than at the 2-week visit (by paired t test, p≤0.01). We found a wide range of prolactin values at the 8-week visit, with a 5th percentile value of 9 ng/dL before feeding and 74 ng/dL at 10 minutes after feeding. CONCLUSIONS: Neuroendocrine function changes during the first 8 weeks after birth, and a wide range of values is compatible with successful breastfeeding. Further studies are needed to define reference values in breastfeeding women.

Evaluating the clinical effectiveness of a specialized perinatal psychiatry inpatient unit.

Women experiencing severe perinatal mental illness during pregnancy or postpartum have unique needs when psychiatric hospitalization is indicated. Although many countries have established mother-baby psychiatric units, similar facilities have not been available in the US. In 2011, the University of North Carolina at Chapel Hill inaugurated the first Perinatal Psychiatry Inpatient Unit in the US. We describe the unique characteristics of the patient population and report clinical outcomes guiding development and refinement of treatment protocols. Ninety-two perinatal patients were admitted between September 2011 and September 2012, and 91 completed self-report measures at admission and discharge. Perinatal unipolar mood disorder was the most frequent primary diagnosis (60.43 %), and 11 patients (12 %) were admitted with psychosis. The data document clinically and statistically significant improvements in symptoms of depression, anxiety, and active suicidal ideation between admission and discharge (p < 0.0001), as assessed by the Edinburgh Postnatal Depression Scale, Patient Health Questionnaire, and Generalized Anxiety Disorder Scale. Overall functioning was also improved, demonstrated by a significant mean difference of -10.96 in total scores of the Work and Social Adjustment Scale (p < 0.0001). Data suggest that delivering specialized and targeted interventions for severe maternal mental illness in a safe and supportive setting produces positive patient outcomes.

REACH: an effective catalyst for scaling up priority nutrition interventions at the country level.

BACKGROUND: Renewed Efforts Against Child Hunger (REACH) is the joint United Nations initiative to address Millennium Development Goal (MDG) 10, Target 3, i.e., to halve the proportion of underweight children under 5 years old by 2015. The United Nations Food and Agriculture Organization (FAO), the World Health Organization (WHO), the United Nations Children's Fund (UNICEF), the World Food Programme (WFP), and the International Fund for Agricultural Development (IFAD) developed and tested a facilitation mechanism to act as a catalyst for scaling up multisectoral nutrition activities. OBJECTIVE: The UN-REACH partners developed pilot projects in Mauritania and Lao PDR from 2008 to 2010 and deployed facilitators to improve nutrition governance and coordination. Review missions were conducted in February 2011 to assess the REACH approach and what it achieved. METHODS: The UN review mission members reviewed documents, assessed policy and management indicators, conducted qualitative interviews, and discussed findings with key stakeholders, including the most senior UN nutrition directors from all agencies. RESULTS: Among other UN-REACH achievements, the Prime Minister of Mauritania agreed to preside over a new National Nutrition Development Council responsible for high-level decision-making and setting national policy objectives. REACH facilitated the completion of Lao's first national Nutrition Strategy and Plan of Action and formation of the multistakeholder Nutrition Task Force. During the REACH engagement, coordination, joint advocacy, situation analysis, policy development, and joint UN programming for nutrition were strengthened in Lao PDR and Mauritania. CONCLUSIONS: Improvements in the nutrition governance and management mechanisms in Mauritania and Lao PDR were observed during the period of REACH support through increased awareness of nutrition as a key development objective, establishment of governmental multisectoral coordinating mechanisms, improved government capacity, and new joint UN-government nutrition programming.