Neurobehavioral follow-up of children exposed to selective serotonin reuptake inhibitors in utero.

BACKGROUND: Systematic data regarding long-term neurobehavioral effects of maternal antidepressant use during pregnancy are sparse. The aim of this study was to evaluate the impact of gestational exposure to antidepressants on later neurodevelopmental function. METHODS: This study describes a cohort of mother-child dyads (44 mothers, 54 children) in which maternal depressive symptoms and medication exposures were prospectively collected across pregnancy and the postpartum period. Children age 6 to 17 were assessed using validated instruments across domains of childhood behavior and executive memory and functioning. RESULTS: No associations were found between maternal use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and atypical neurodevelopment of children. Borderline clinical or clinical ranges of internalizing symptoms were associated with exposure to a higher maternal depressive symptom burden during pregnancy compared with those in the normal range. Compared with age- and sex-matched controls, the SSRI-exposed group showed superior performance on executive function tasks; findings did not demonstrate elevated risk for abnormal neurodevelopment in children age 6 to 17 exposed to SSRIs in utero. Deviations from the norm were instead associated with higher in utero exposure to maternal depression burden. CONCLUSIONS: This study highlights the need for rigorous studies of long-term outcomes after fetal antidepressant exposure.

Subclonal landscape of cancer drives resistance to immune therapy.

Tumor mutation burden (TMB) is often used as a biomarker for immunogenicity and prerequisite for immune checkpoint inhibitor (ICI) therapy. However, it is becoming increasingly evident that not all tumors with high TMB respond to ICIs as expected. It has been shown that the ability of T-cells to infiltrate the tumor microenvironment and elicit a specific immune response is dependent not only on the TMB, but also on intra-tumor heterogeneity and the fraction of low-frequency subclonal mutations that make up the tumor. High intra-tumor heterogeneity leads to inefficient recognition of tumor neoantigens by T-cells due to their diluted frequency and spatial heterogeneity. Clinical studies have shown that tumors with a high degree of intra-tumor heterogeneity respond poorly to ICI therapy, and previous cytotoxic treatment may increase the intra-tumor heterogeneity and render second-line ICI therapy less effective. This paper reviews the role of ICI therapy when following chemotherapy or radiation to determine if they may be better suited as first-line therapy in patients with high TMB, low intra-tumor heterogeneity, and high PD-1, PD-L1, or CTLA-4 expression.

The Course of ADHD during Pregnancy.

OBJECTIVE: The aim of this study was to characterize the course of ADHD during pregnancy. METHOD: Women ages 18 to 45 were followed prospectively at <20 weeks, 24 weeks, and 36 weeks pregnant. Three groups emerged: women who discontinued, maintained, or adjusted their ADHD medications. ADHD symptoms were recorded using the AISRS. Anxiety, depression, stress, and functional impairment were monitored. RESULTS: A total of 25 women with ADHD were eligible for analysis. No significant difference observed between three groups in AISRS scores. Significant differences found between medication discontinuers vs adjusters for both mood and family functioning (EPDS, 5.3, p < .0001; WFIRS, 3.3, p = .0309). Significant differences also found between discontinuers vs maintainers for mood and family functioning (EPDS, 4.98, p = .0009; WFIRS, 3.09, p = .0197). CONCLUSION: This preliminary study provides novel insight into the course of ADHD during pregnancy, underscoring mood and family functioning as critical domains that may contribute to growing use of psychostimulants during pregnancy.

Adenomatous polyposis coli in cancer and therapeutic implications.

Inactivating mutations of the adenomatous polyposis coli (APC) gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests APCmutations are also found in gastric, breast and other cancers. The APC gene, located on chromosome 5q, is responsible for negatively regulating the b-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3b, and CK1. In the event of an APC mutation, b-catenin accumulates, translocates to the cell nucleus and increases the transcription of Wnt target genes that have carcinogenic consequences in gastrointestinal epithelial stem cells. A literature review was conducted to highlight carcinogenesis related to APC mutations, as well as preclinical and clinical studies for potential therapies that target steps in inflammatory pathways, including IL-6 transduction, and Wnt pathway signaling regulation. Although a range of molecular targets have been explored in murine models, relatively few pharmacological agents have led to substantial increases in survival for patients with colorectal cancer clinically. This article reviews a range of molecular targets that may be efficacious targets for tumors with APC mutations.

BRCA1/2 signaling and homologous recombination deficiency in breast and ovarian cancer.

Patients who have mutations of the genes BRCA1 or BRCA2 are at an increased risk for developing breast and ovarian cancer. BRCA1/2 function as tumor suppressor genes, responsible for regulating DNA repair, and play an essential role in homologous recombination. Mutation of BRCA1/2 results in homologous recombination deficiency and genomic instability which drives oncogenesis and cancer proliferation. Recently, BRCA1/2 gene expression has been implicated in regulating immune response. Here we discuss the signaling pathway of BRCA1/2 in relation to breast and ovarian cancer, with emphasis on how dysregulation facilitates the path to malignancy and current treatment options.

A prenatal supplement with methylfolate for the treatment and prevention of depression in women trying to conceive and during pregnancy.

BACKGROUND: Women often seek antidepressant alternatives for major depressive disorder (MDD) in anticipation of or during pregnancy. In this preliminary study, EnBrace HR, a prenatal supplement containing methylfolate, was investigated for depressive relapse prevention and for acute treatment of MDD in women planning pregnancy or during pregnancy. METHODS: This 12-week open-label study included women with histories of MDD who were planning pregnancy or pregnant < 28 weeks. At enrollment, Group 1 participants were well (not depressed) and planned to discontinue antidepressants for pregnancy. Group 2 participants were depressed. Primary outcome variables by group included MDD relapse and depressive symptoms, verified with the Mini-International Neuropsychiatric Interview and the Montgomery-Åsberg Depression Rating Scale (MADRS), respectively. Biomarkers of inflammation and the folate cycle were collected. RESULTS: Group 1 participants (N = 11) experienced lower rates of depressive relapse (27.3% P = .005) than expected from a historical comparison group and no significant changes in MADRS scores. Group 2 participants (N = 6) experienced significant improvements in MADRS scores (P = .001), with 5 (83.3%) improving >50% and 1 improving 33.3%. One adverse event occurred, a hospitalization for depression. CONCLUSIONS: Results suggest EnBrace HR is a well-tolerated intervention with potential efficacy for prevention and treatment of perinatal depression. Larger controlled trials are necessary.

Course of major depressive disorder after pregnancy and the postpartum period.

BACKGROUND: Maternal major depressive disorder (MDD) has an adverse effect on child development and increases risk for child psychopathology. It is paramount to understand the course of maternal depression during the childhood years particularly before, during, and after pregnancy. OBJECTIVE: To follow the course of MDD in women with prior histories of depression followed during an index pregnancy. METHODS: Subjects were women with histories of MDD who had participated in prior prospective, observational studies during pregnancy. In the follow-up, participants completed a structured interview that addressed (1) the course of MDD since their index pregnancy, (2) new psychiatric diagnoses, and (3) the course of MDD and treatment across subsequent pregnancies. RESULTS: Out of 129 eligible women, 48.8% participated (N = 63) with an average/mean time of 12.9 years (SD = 1.9, 8.8-16.7) elapsed since participation in the prior pregnancy studies. Although approximately one third reported sustained remission from MDD since the pregnancy during which they had been originally followed, of the remaining two thirds of women who reported subsequent depressive episodes, almost one fifth (∼12% of the total sample) endorsed depression more than 50% of the time following their index pregnancy. A total of 6.3% of the women with previous validated diagnoses of MDD reported new diagnoses of bipolar disorder. Women reported similar treatment choices regarding the use of antidepressants during pregnancies subsequent to the one followed in the previous study. CONCLUSION: Women with MDD experienced high rates of recurrent depression across the childbearing years. This represents a critical variable for clinical care and research.

Obstetrical and neonatal outcomes after benzodiazepine exposure during pregnancy: Results from a prospective registry of women with psychiatric disorders.

OBJECTIVE: The goal of this analysis was to examine the effect of benzodiazepine use during pregnancy on maternal and neonatal outcomes in a cohort of women with psychiatric disorders. METHODS: 794 evaluable women from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications were followed across pregnancy (N = 144 exposed to benzodiazepines and N = 650 unexposed). Data obtained through maternal report and medical records included maternal outcomes (cesarean section, preeclampsia) and neonatal outcomes (birth weight, breathing difficulty, feeding difficulty, head circumference, 5-minute Apgar score, muscular and/or extrapyramidal symptoms, NICU admission, prematurity). RESULTS: In adjusted analyses, infants exposed to benzodiazepines in utero were more likely to be admitted to the NICU (OR: 2.02, 95% CI: 1.11, 3.66) and to have small head circumferences (OR: 3.89, 95% CI: 1.25, 12.03) compared to unexposed infants. Other neonatal adverse effects such as respiratory distress or muscular symptoms including hypotonia were not observed. There were no significant differences in adverse obstetrical outcomes. CONCLUSIONS: Infants exposed to benzodiazepines during pregnancy had an increased risk of NICU admissions and small head circumferences. Confounding from psychiatric symptoms and other variables cannot be ruled out as contributors to these findings.

Impact of experimentally manipulated sleep on adolescent simulated driving.

OBJECTIVE/BACKGROUND: Sleep restriction (SR) impairs adolescents' attention, which could contribute to high rates of driving crashes. Here, we examine the impact of experimental SR on adolescent drivers, considering whether that impact is moderated by the nature of the drive (urban/suburban vs. rural) or how vulnerable each adolescent is to attentional decline after SR. PARTICIPANTS/METHODS: A total of 17 healthy 16-18-year-old licensed drivers completed two five-night sleep conditions: SR (6.5 h in bed) versus extended sleep (ES; 10 h in bed) in counterbalanced order. After each, participants completed rural and urban/suburban courses in a driving simulator, and parents rated participants' attention in day-to-day settings. Vulnerability to SR was computed as cross-condition change in parent ratings. Dependent variables included standard deviation (SD) of lateral lane position (SDLP), mean speed, SD of speed, and crashes. Multivariate models examined the main and interaction effects of sleep condition, driving environment, and vulnerability to SR, covarying for years licensed. RESULTS: Although the effects for the other outcomes were nonsignificant, there were three-way interactions (sleep × drive × vulnerability) for mean speed and SDLP (p <0.02). During the rural drive, adolescents had less consistent lateral vehicle control in SR than ES, despite slower driving among those reported to be vulnerable to SR. During the urban/suburban drive, SR worsened SDLP only among adolescents reported to be vulnerable to SR. CONCLUSIONS: These preliminary findings suggest that even a moderate degree of SR may be a modifiable contributor to adolescent driving problems for some. This impact is widely present during monotonous rural drives and in a subgroup during interesting urban/suburban drives.

The Impact of Early Bedtimes on Adolescent Caloric Intake Varies by Chronotype.

PURPOSE: Adolescent sleep restriction is common and can lead to overeating. Here, we test whether lengthening sleep via early bedtimes affects dietary intake differently for adolescents accustomed to a later sleep phase ("night owls") versus an earlier sleep phase ("morning larks"). METHODS: Using a randomized cross-over design, 67 adolescents changed bedtimes to create five-night periods of sleep restriction (6.5 hours in bed) versus healthy sleep (10 hours in bed). Caloric intake was measured via validated interviews. Phase preference was based on participants' premanipulation sleep. RESULTS: Actigraphy verified that the manipulation altered sleep regardless of phase preference. Phase preference moderated the effect of the manipulation on cumulative caloric intake (p = .01-.03). Night owls showed little effect, but morning larks reduced their evening intake during healthy sleep. CONCLUSIONS: An "early to bed" approach confers little dietary benefit for night owls but may have a protective effect for adolescents who gravitate toward earlier bedtimes.