Stress during pregnancy and fetal serum BDNF in cord blood at birth.

INTRODUCTION: Adverse environments during pregnancy impact neurodevelopment including cognitive abilities of the developing children. The mediating biological alterations are not fully understood. Maternal stress may impact the neurotrophic regulation of the offspring as early as in utero and at birth. Brain-derived neurotrophic factor (BDNF) is essential for neurodevelopment. Short-term higher levels of BDNF in mice upon stressors associate with lower BDNF later in life, which itself associates with depression in animals and humans. Stress including glucocorticoids may impact BDNF, but there is a lack of data at birth. This study investigated if stress near term associates with fetal BDNF at birth in humans. METHODS: Pregnant women near term who underwent primary cesarean sections (at 38.80±0.64 weeks), were included in this study (n=41). Stress at the end of pregnancy was assessed before the cesarean section by determining maternal depressive symptoms (EDPS), maternal state and trait anxiety (STAI-S and STAI-T), maternal prenatal distress (PDQ), stress over the past month (PSS), prenatal attachment to the offspring (PAI), maternal social support (F-Sozu), maternal early life stress (CTQ), socioeconomic status, and the glucocorticoids cortisol and cortisone (n=40) in amniotic fluid at birth. The association with fetal BDNF was analyzed. Cord blood serum of n=34 newborns at birth was analyzed for BDNF and newborn anthropometrics (weight, length and head circumference per gestational age at birth) were assessed. The association of fetal BDNF with anthropometrics at birth was analyzed. RESULTS: After a BDNF-outlier (>3 SD) was removed, higher fetal BDNF associated significantly with maternal depressive symptoms (r=0.398, p=0.022), with lower socioeconomic status as assessed by the average number of people per room in the household (r=0.526, p=0.002) and with borderline significance with net income per person in the household (r=-0.313, p=0.087) in the bivariate analyses. In multivariable analysis, BDNF stayed positively associated with maternal depressive symptoms (ß=0.404, 95% CI [7.057, 306.041], p=0.041) and lower net income per person in the household (ß=-0.562, 95% CI [-914.511, -60.523], p=0.027) when controlling for maternal age, maternal pre-pregnancy BMI, fetal sex and gestational age. Fetal BDNF did not associate with newborn anthropometrics with the outlier removed in bivariate analyses or in multivariable analyses when controlling for maternal BMI and fetal sex. CONCLUSION: Maternal depressive symptoms and lower socioeconomic status associated with higher fetal BDNF when controlling for confounders. Fetal BDNF did not associate with newborn anthropometrics with the outlier removed. Further studies should investigate how early altered BDNF associate with the development and possibly psychopathology of the offspring.

Fetal Sex as Moderating Factor for the Relationship Between Maternal Childhood Trauma and Salivary Kynurenic Acid and Tryptophan in Pregnancy: A Pilot Study.

Traumatic experiences and fetal development influence tryptophan (TRP) and its neuroactive byproduct, kynurenic acid (KYNA). Maternal TRP metabolite levels during pregnancy vary by fetal sex, with higher concentrations in mothers carrying male fetuses. This pilot study aimed to explore the relationship between offspring sex, maternal childhood trauma, and maternal salivary KYNA and TRP levels during pregnancy. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine KYNA and TRP levels in maternal saliva samples collected from 35 late-pregnancy participants. Maternal childhood trauma was assessed using the Childhood Trauma Questionnaire, including subscales for emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. Among mothers pregnant with boys, salivary KYNA significantly correlated with physical and emotional neglect, and salivary TRP with emotional neglect. No significant correlations were found in mothers who delivered female offspring. Significant associations of childhood trauma and offspring sex were found for salivary KYNA but not TRP concentrations. Mothers with higher trauma levels who delivered boys exhibited higher levels of salivary KYNA compared to those with lower trauma levels. Moreover, mothers with higher trauma levels who delivered boys had higher salivary KYNA levels than those with higher trauma levels who delivered girls. This pilot study provides evidence of an association between maternal childhood trauma and TRP metabolism, measured in saliva, especially in mothers pregnant with boys. However, longitudinal studies with larger sample sizes are required to confirm these results.

Speech Features as Predictors of Momentary Depression Severity in Patients With Depressive Disorder Undergoing Sleep Deprivation Therapy: Ambulatory Assessment Pilot Study.

BACKGROUND: The use of mobile devices to continuously monitor objectively extracted parameters of depressive symptomatology is seen as an important step in the understanding and prevention of upcoming depressive episodes. Speech features such as pitch variability, speech pauses, and speech rate are promising indicators, but empirical evidence is limited, given the variability of study designs. OBJECTIVE: Previous research studies have found different speech patterns when comparing single speech recordings between patients and healthy controls, but only a few studies have used repeated assessments to compare depressive and nondepressive episodes within the same patient. To our knowledge, no study has used a series of measurements within patients with depression (eg, intensive longitudinal data) to model the dynamic ebb and flow of subjectively reported depression and concomitant speech samples. However, such data are indispensable for detecting and ultimately preventing upcoming episodes. METHODS: In this study, we captured voice samples and momentary affect ratings over the course of 3 weeks in a sample of patients (N=30) with an acute depressive episode receiving stationary care. Patients underwent sleep deprivation therapy, a chronotherapeutic intervention that can rapidly improve depression symptomatology. We hypothesized that within-person variability in depressive and affective momentary states would be reflected in the following 3 speech features: pitch variability, speech pauses, and speech rate. We parametrized them using the extended Geneva Minimalistic Acoustic Parameter Set (eGeMAPS) from open-source Speech and Music Interpretation by Large-Space Extraction (openSMILE; audEERING GmbH) and extracted them from a transcript. We analyzed the speech features along with self-reported momentary affect ratings, using multilevel linear regression analysis. We analyzed an average of 32 (SD 19.83) assessments per patient. RESULTS: Analyses revealed that pitch variability, speech pauses, and speech rate were associated with depression severity, positive affect, valence, and energetic arousal; furthermore, speech pauses and speech rate were associated with negative affect, and speech pauses were additionally associated with calmness. Specifically, pitch variability was negatively associated with improved momentary states (ie, lower pitch variability was linked to lower depression severity as well as higher positive affect, valence, and energetic arousal). Speech pauses were negatively associated with improved momentary states, whereas speech rate was positively associated with improved momentary states. CONCLUSIONS: Pitch variability, speech pauses, and speech rate are promising features for the development of clinical prediction technologies to improve patient care as well as timely diagnosis and monitoring of treatment response. Our research is a step forward on the path to developing an automated depression monitoring system, facilitating individually tailored treatments and increased patient empowerment.

A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation.

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P < 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.

LC-MS/MS-based quantification of tryptophan, kynurenine, and kynurenic acid in human placental, fetal membranes, and umbilical cord samples.

Tryptophan breakdown metabolites formed along the kynurenine pathway play a significant role in pregnancy and fetal development. To understand their involvement, it is crucial to quantify the levels of tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA) in relevant biological samples such as the placenta, fetal membranes, and umbilical cord. This study used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine TRP, KYN, and KYNA levels. The LC-MS/MS method was optimized for high sensitivity and specificity, demonstrating good reproducibility with a precision of < 10% CV and an accuracy of 85-115%. The lower limit of quantification for both TRP and KYN was 0.5 µg/ml, while for KYNA, it was 0.5 ng/mL. The method exhibited linearity within the examined range of concentrations in the homogenate, ranging from 0.5 to 30 µg/ml for TRP and KYN and from 0.5 to 25 ng/ml for KYNA. Using this method, we found significant differences in the concentrations of these substances in investigated maternal-fetal compartments. Placenta samples exhibited higher KYN and lower KYNA concentrations than the umbilical cord and fetal membrane, indicating a potentially important role for kynurenines in late pregnancy. Collectively, this finding may facilitate further research and provide inside into the involvement of the kynurenine pathway of TRP metabolism in fetal development.

Reduced urine pregnenolone concentration after clinical response in patients with depression: An open-label short-term prospective study.

BACKGROUND: Identifying biological alterations in patients with depression, particularly those that differ between responders and non-responders, is of interest to clinical practice. Biomarker candidates involve neuroactive steroids, including pregnenolone (PREG) and allopregnanolone (ALLO). However, alterations in PREG and ALLO associated with treatment response are understudied. This study's main aim was to evaluate the effects of antidepressant treatment, clinical response, and treatment duration on PREG and ALLO in depression. MATERIALS AND METHODS: In a 4-week, open-label trial, participants were allocated randomly to the venlafaxine (n = 27) or mirtazapine (n = 30) group. Urine concentrations of PREG and ALLO were assessed through gas chromatography-mass spectrometry. Participants collected night urine between 10:30 p.m. and 8:00 a.m. Two primary outcomes were analyzed. Firstly, the effect of treatment (mirtazapine or venlafaxine), clinical response (operationalized through the Hamilton Depression Rating Scale), and time (baseline compared to 28 days) on the urine concentrations of PREG or ALLO in depression. Finally, the effect of clinical response and time on the urine concentration of PREG or ALLO, independently of the antidepressant given (mirtazapine or venlafaxine). Linear mixed models were carried out. RESULTS: There was no significant difference in PREG and ALLO concentrations between baseline and 28 days in responders and non-responders when investigating the venlafaxine or the mirtazapine group. However, we found a significant reduction of urine PREG concentration after 28 days of treatment in responders who received either venlafaxine or mirtazapine (estimate = -0.56; p = 0.016; 95CI [-1.003; -0.115]; Cohen's d = -0.61). CONCLUSIONS: Our main results indicate that responders in depression show reduced urinary PREG concentrations after 4-weeks of therapy, independently of the antidepressant used. More studies are needed to confirm these findings.

Psychological, endocrine and polygenic predictors of emotional well-being during the COVID-19 pandemic in a longitudinal birth cohort.

The COVID-19 pandemic severely affected the lives of families and the well-being of both parents and their children. Various factors, including prenatal stress, dysregulated stress response systems, and genetics may have influenced how the stress caused by the pandemic impacted the well-being of different family members. The present work investigated if emotional well-being during the COVID-19 pandemic could be predicted by developmental stress-related and genetic factors. Emotional well-being of 7-10 year-old children (n = 263) and mothers (n = 241) (participants in a longitudinal German birth cohort (POSEIDON)) was assessed during the COVID-19 pandemic using the CRISIS questionnaire at two time periods (July 2020-October 2020; November 2020-February 2021). Associations of the children's and mothers' well-being with maternal perceived stress, of the children's well-being with their salivary and morning urine cortisol at 45 months, and polygenic risk scores (PRSs) for depression, schizophrenia, loneliness were investigated. Lower emotional well-being was observed in both children and mothers during compared to before the pandemic, with the children's but not the mothers' emotional well-being improving over the course of the pandemic. A positive association between the child and maternal emotional well-being was found. Prenatally assessed maternal perceived stress was associated with a lower well-being in children, but not in mothers. Cortisol measures and PRSs were not significantly associated with the children's emotional well-being. The present study confirms that emotional well-being of children and mothers are linked, and were negatively affected by the COVID-19 pandemic, with differences in development over time.

Effects of left anodal transcranial direct current stimulation on hypothalamic-pituitary-adrenal axis activity in depression: a randomized controlled pilot trial.

The main objective of this study was to evaluate the effect of left anodal transcranial direct current stimulation (tDCS) on hypothalamic-pituitary-adrenal axis (HPAA) activity in individuals with depression. We conducted a 3-week, randomized, triple-blind pilot trial with 47 participants (dropout rate: 14.89%) randomly assigned to either the tDCS or control group (sham stimulation). Salivary cortisol was used as an HPAA activity marker since cortisol is the effector hormone of the HPAA. The primary outcome was the effect of tDCS on the diurnal cortisol pattern (DCP and area under the curve with respect to ground -AUCg-). Secondary outcomes included tDCS effects on cortisol awakening response (CAR) and cortisol decline (CD), as well as the variation of cortisol concentrations between the initiation of tDCS and 2 weeks later. Intention-to-treat and per-protocol analyses were conducted. Our primary outcome showed an absent effect of tDCS on DCP and AUCg. Additionally, tDCS had an absent effect on CAR, CD, and cortisol concentration variation before-after stimulation. Our pilot study suggests that anodal tDCS showed an absent effect on HPAA activity in individuals with depression. More studies are needed to confirm these findings.

Improvement of depressive symptoms, after a suicide attempt, with dextromethorphan/bupropion combination treatment in a patient with treatment-resistant depression and psychiatric comorbidities.

We admitted a 42-year-old patient with severe treatment-resistant depression and with psychiatric comorbidities. The patient attempted suicide 5 weeks after admission. Subsequently, we initiated dextromethorphan/bupropion based on prior evidence. As a result, the patient demonstrated an improvement in mood symptoms and a reduction in suicide risk, leading to her discharge.

Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills.

Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.

Urbanicity, behavior problems and HPA axis regulation in preschoolers.

Growing up in cities is associated with increased risk for developing mental health problems. Stress exposure and altered stress regulation have been proposed as mechanisms linking urbanicity and psychopathology, with most research conducted in adult populations. Here, we focus on early childhood, and investigate urbanicity, behavior problems and the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, a central circuit of the stress system, in a sample of N = 399 preschoolers aged 45 months. Urbanicity was coded dichotomously distinguishing between residences with more or less than 100,000 inhabitants. Behavior problems were measured using the Child Behavior Checklist (CBCL) 1½ - 5. Cortisol stress reactivity was assessed using an age-appropriated game-like stress task, and cortisol in the first morning urine was measured to assess nocturnal HPA axis activity. Urbanicity was not associated with behavior problems, urinary cortisol or the cortisol stress response. Neither urinary cortisol nor salivary cortisol response after stress exposure were identified as mediators of the relationship between urbanicity and behavior problems. The findings suggest no strong association of urbanicity with behavior problems and HPA axis regulation in preschool age. To our knowledge, this is the youngest sample to date studying the relationship between urbanicity and behavior problems as well as HPA axis regulation. Future research should examine at which age associations can first be identified and which mechanisms contribute to these relationships.

Microbiome profiles are associated with cognitive functioning in 45-month-old children.

Prenatal, perinatal, and postnatal factors have been shown to shape neurobiological functioning and alter the risk for mental disorders later in life. The gut microbiome is established early in life, and interacts with the brain via the brain-immune-gut axis. However, little is known about how the microbiome relates to early-life cognitive functioning in children. The present study, where the fecal microbiome of 380 children was characterized using 16S rDNA and metagenomic sequencing aimed to investigate the association between the microbiota and cognitive functioning of children at the age of 45 months measured with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Overall the microbiome profile showed a significant association with cognitive functioning. A strong correlation was found between cognitive functioning and the relative abundance of an unidentified genus of the family Enterobacteriaceae. Follow-up mediation analyses revealed significant mediation effects of the level of this genus on the association of maternal smoking during pregnancy and current cigarette smoking with cognitive function. Metagenomic sequencing of a subset of these samples indicated that the identified genus was most closely related to Enterobacter asburiae. Analysis of metabolic potential showed a nominally significant association of cognitive functioning with the microbial norspermidine biosynthesis pathway. Our results indicate that alteration of the gut microflora is associated with cognitive functioning in childhood. Furthermore, they suggest that the altered microflora might interact with other environmental factors such as maternal cigarette smoking. Interventions directed at altering the microbiome should be explored in terms of improving cognitive functioning in young children.

Childhood trauma and insulin-like growth factors in amniotic fluid: An exploratory analysis of 79 women.

BACKGROUND: Perinatal stress has adverse effects on fetal outcome, yet the effect of early maternal trauma on fetal outcome has scarcely been studied. We investigated effects of maternal childhood trauma and current environment on important regulators of prenatal growth, fetal insulin-like growth factor (IGF)-1 and IGF-2 in amniotic fluid and assessed the impact of IGFs on newborn anthropometrics. METHODS: 79 pregnant women in their second trimester who underwent amniocentesis (15.9 ± 0.9 weeks of gestational age) and their newborns at birth were analyzed. Maternal childhood trauma was assessed using the childhood trauma questionnaire (CTQ) and current environment was operationalized by assessing maternal psychosocial, physical health and endocrine measurements in amniotic fluid. RESULTS: In this exploratory analysis of 79 pregnant women, maternal childhood trauma, defined as reporting at least low scores on any of the CTQ subscales, negatively correlated with fetal IGF-1 (Mln = 3.48 vs. 2.98; p = 0.012) and IGF-2 (Mdnln = 4.99 vs. 4.70; p = 0.002). Trauma severity, defined as the overall trauma score, negatively correlated with fetal IGF-2 (r = -0.24; p = 0.037). From trauma subscales, maternal sexual abuse correlated with fetal IGF-1 (r = -0.32; p = 0.006) and IGF-2 (r = -0.39; p = 0.001). Maternal BMI negatively correlated with fetal IGF-1 (r = -0.26; p = 0.023) and IGF-2 (r = -0.29; p = 0.011). Newborn anthropometrics were operationalized by length, weight, sex, gestational age, length/gestational age and weight/gestational age at birth. Fetal weight at birth associated with a trend with fetal IGF-1 when controlling for BMI. Maternal hypothalamus-pituitary-adrenal axis activity and maternal exercise did not contribute significantly to predicting fetal IGFs. Maternal childhood trauma (ß = -0.27; p = 0.011) and BMI (ß = -0.24; p = 0.026) remained significantly associated with fetal IGF-1. Maternal childhood trauma (ß = -0.32; p = 0.003), maternal BMI (ß = -0.30; p = 0.005) and maternal sexual abuse (ß = -0.22; p = 0.049) remained significantly associated with fetal IGF-2 and with a trend with fetal IGF-1 (ß = -0.21; p = 0.076) when excluding women with gestational diabetes. CONCLUSION: Maternal childhood trauma and BMI associate negatively with fetal IGF-1 and IGF-2 in amniotic fluid. Controlling for maternal BMI, fetal weight at birth remains associated with a trend with fetal IGF-1. The presented data suggests that childhood trauma can affect endocrine measurements of the developing next generation, providing a mechanism by which adverse maternal life events are transmitted to the next generation.

Rhythm of Fetoplacental 11ß-Hydroxysteroid Dehydrogenase Type 2 - Fetal Protection From Morning Maternal Glucocorticoids.

CONTEXT: Excess glucocorticoids impact fetal health. Maternal glucocorticoids peak in early morning. Fetoplacental 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) inactivates cortisol to cortisone, protecting the fetus from high glucocorticoids. However, time-specific alterations of human fetoplacental 11ß-HSD2 have not been studied. OBJECTIVE: We hypothesized that fetoplacental 11ß-HSD2 activity shows time-specific alteration and acute affective or anxiety disorders impact fetoplacental 11ß-HSD2 activity. METHODS: In this observational study we investigated 78 pregnant European women undergoing amniocentesis (15.9 ± 0.9 weeks of gestation). Amniotic fluid was collected (8:00 to 16:30 hours) for analysis of fetoplacental 11ß-HSD2 activity, using cortisol (F):cortisone (E) ratio in amniotic fluid, E/(E + F). Fetoplacental 11ß-HSD2 rhythm and association with "acute affective or anxiety disorder" (patients with at least one of: a major depressive episode, specific phobia, panic disorder, generalized anxiety disorder, mixed anxiety and depressive disorder) and "acute anxiety disorder" (one of: panic disorder, generalized anxiety disorder, mixed anxiety, depressive disorder), assessed using Mini International Neuropsychiatric Interview, were investigated. RESULTS: Activity of 11ß-HSD2 correlated with time of amniocentesis, peaking in the morning (r = -0.398; P < 0.001) and increased with acute affective or anxiety disorder (mean [M] = 0.70 vs M = 0.74; P = 0.037) and acute anxiety disorder (M = 0.70 vs M = 0.75; P = 0.016). These associations remained significant when controlling for confounders. 11ß-HSD2 activity correlated negatively with pre-pregnancy body mass index (r = -0.225; P = 0.047). CONCLUSION: Our study indicates a time-specific alteration of fetoplacental 11ß-HSD2 activity with peaking levels in the morning, demonstrating a mechanism of fetal protection from the morning maternal glucocorticoid surge.

Association of Locomotor Activity During Sleep Deprivation Treatment With Response.

Disrupted circadian rhythms and sleep patterns are frequently observed features of psychiatric disorders, and especially mood disorders. Sleep deprivation treatment (SD) exerts rapid but transient antidepressant effects in depressed patients and has gained recognition as a model to study quick-acting antidepressant effects. It is of interest how locomotor activity patterns during SD might be associated with and potentially predict treatment response. The present study is an analysis of locomotor activity data, previously collected over a 24 h period, to examine the night of SD (Trautmann et al. 2018) as mood disorder patients suffering from a depressive episode (n = 78; after exclusions n = 59) underwent SD. In this exploratory analysis, the associations between response to SD, locomotor activity, and subjective mood during the 24 h period of SD were explored. Higher levels of activity overall were observed in non-responders (n = 18); in particular, non-responders moved more during the evening of SD until midnight and remained high thereafter. In contrast, activity in responders (n = 41) decreased during the evening and increased in the morning. Subjective mood was not found to be associated with locomotor activity. The window of data available in this analysis being limited, additional data from before and after the intervention are required to fully characterize the results observed. The present results hint at the possible utility of locomotor activity as a predictor and early indicator of treatment response, and suggest that the relationship between SD and locomotor activity patterns should be further investigated.

Longitudinal transcriptome-wide gene expression analysis of sleep deprivation treatment shows involvement of circadian genes and immune pathways.

Therapeutic sleep deprivation (SD) rapidly induces robust, transient antidepressant effects in a large proportion of major mood disorder patients suffering from a depressive episode, but underlying biological factors remain poorly understood. Research suggests that these patients may have altered circadian molecular genetic 'clocks' and that SD functions through 'resetting' dysregulated genes; additional factors may be involved, warranting further investigation. Leveraging advances in microarray technology enabling the transcriptome-wide assessment of gene expression, this study aimed to examine gene expression changes accompanying SD and recovery sleep in patients suffering from an episode of depression. Patients (N = 78) and controls (N = 15) underwent SD, with blood taken at the same time of day before SD, after one night of SD and after recovery sleep. A transcriptome-wide gene-by-gene approach was used, with a targeted look also taken at circadian genes. Furthermore, gene set enrichment, and longitudinal gene set analyses including the time point after recovery sleep, were conducted. Circadian genes were significantly affected by SD, with patterns suggesting that molecular clocks of responders and non-responders, as well as patients and controls respond differently to chronobiologic stimuli. Notably, gene set analyses revealed a strong widespread effect of SD on pathways involved in immune function and inflammatory response, such as those involved in cytokine and especially in interleukin signalling. Longitudinal gene set analyses showed that in responders these pathways were upregulated after SD; in non-responders, little response was observed. Our findings emphasize the close relationship between circadian, immune and sleep systems and their link to etiology of depression at the transcriptomic level.

Nightmares and Stress: A Longitudinal Study.

STUDY OBJECTIVES: In nightmare etiology, trait and state factors play important roles. However, the interaction of state and trait factors has never been studied in a longitudinal design. METHODS: The current sample included 406 pregnant women who were followed up approximately 6 months after giving birth (n = 375) and 4 years later (n = 302). A nightmare frequency scale and several stress-related questionnaires were presented at three measurement points. RESULTS: Despite the major life events in this sample, nightmare frequency was very stable over this time period and decreased slightly. In line with previous findings, cross-sectional analyses showed that stressors were associated with current nightmare frequency but longitudinal analyses indicated that previously measured nightmare frequency showed even stronger effects on current nightmare frequency. CONCLUSIONS: Because the nightmare frequencies were very stable, it would be desirable to carry out intervention studies treating nightmares as early as possible-even in childhood-and study whether nightmare occurrence is lower even years after the intervention. CITATION: Schredl M, Gilles M, Wolf I, Peus V, Scharnholz B, Sütterlin M, Bardtke S, Send TS, Samaras A, Deuschle M. Nightmares and stress: a longitudinal study. J Clin Sleep Med. 2019;15(9):1209-1215.

Peripheral levels of the anti-aging hormone Klotho in patients with depression.

Klotho is a humoral factor with pleiotropic effects. Most notably, Klotho deficiency is associated with a phenotype comprising organ manifestations accompanying aging including atherosclerosis and cognitive impairment. Research on the role of Klotho in affective disorder is scarce, which is surprising in light of the fact that depression is associated with accelerated cellular aging as well as aging-related phenotypes and comorbidity observed in Klotho deficiency. Soluble α-Klotho (sKlotho) serum levels in patients with a major depressive episode and either undergoing electroconvulsive therapy (n = 16) or a monotherapy with an antidepressant (n = 37) were investigated. We measured the sKlotho serum levels in those patients before and after treatment and compared the baseline levels with those of age-matched healthy controls (n = 39). No group differences were found between the baseline sKlotho levels of patients and controls (573.5 pg/ml vs. 563.8 pg/ml; p = 0.80) and between pre- and post-treatment in the patients with depression (563.8 pg/ml vs. 561.8 pg/ml; p = 0.15), when treated either with electroconvulsive therapy or antidepressant. The major limitation of our study might be that peripheral material such as serum might not reliably reflect processes in the central nervous system. In sum, this first study on peripheral sKlotho levels in a clinical sample cannot confirm a global Klotho dysregulation in depression as it has been already suggested by others. Nonetheless, further preclinical and clinical studies on the involvement of Klotho in affective disorders should be carried out.

Response to therapeutic sleep deprivation: a naturalistic study of clinical and genetic factors and post-treatment depressive symptom trajectory.

Research has shown that therapeutic sleep deprivation (SD) has rapid antidepressant effects in the majority of depressed patients. Investigation of factors preceding and accompanying these effects may facilitate the identification of the underlying biological mechanisms. This exploratory study aimed to examine clinical and genetic factors predicting response to SD and determine the impact of SD on illness course. Mood during SD was also assessed via visual analogue scale. Depressed inpatients (n = 78) and healthy controls (n = 15) underwent ~36 h of SD. Response to SD was defined as a score of ≤ 2 on the Clinical Global Impression Scale for Global Improvement. Depressive symptom trajectories were evaluated for up to a month using self/expert ratings. Impact of genetic burden was calculated using polygenic risk scores for major depressive disorder. In total, 72% of patients responded to SD. Responders and non-responders did not differ in baseline self/expert depression symptom ratings, but mood differed. Response was associated with lower age (p = 0.007) and later age at life-time disease onset (p = 0.003). Higher genetic burden of depression was observed in non-responders than healthy controls. Up to a month post SD, depressive symptoms decreased in both patients groups, but more in responders, in whom effects were sustained. The present findings suggest that re-examining SD with a greater focus on biological mechanisms will lead to better understanding of mechanisms of depression.

Maternal hypothalamus-pituitary-adrenal (HPA) system activity and stress during pregnancy: Effects on gestational age and infant's anthropometric measures at birth.

BACKGROUND: Prenatal maternal stress might be a risk for the developing fetus and may have long-lasting effects on child and adult vulnerability to somatic and psychiatric disease. Over-exposure of the unborn to excess glucocorticoids and subsequent alteration of fetal development is hypothesized to be one of the key mechanisms linking prenatal stress with negative child outcome. METHODS: In this prospective longitudinal study, mothers-to-be (n = 405) in late pregnancy (36.8 ±â€¯1.9 weeks of gestational age) and their singleton neonates were studied. We investigated the impact of different prenatal stress indices derived from six stress variables (perceived stress, specific prenatal worries, negative life events, symptoms of depression, trait anxiety, neuroticism) and diurnal maternal saliva cortisol secretion on gestational age and anthropometric measures at birth. RESULTS: Maternal prenatal distress during late gestation was associated with significant reduction in birth weight (-217 g; p = .005), birth length (-1.2 cm; p = .005) and head circumference (-0.8 cm; p = .001). Prenatal stress was modestly but significantly associated with altered diurnal cortisol pattern (flattened cortisol decline and higher evening cortisol), which in turn was significantly related to reduced length of gestation. No evidence for a profound interaction between maternal cortisol level in late pregnancy and infant's anthropometric measures at birth (i.e., birth weight, length, head circumference) was found. CONCLUSION: Prenatal stress is associated with flattened circadian saliva cortisol profiles and reduced infant's anthropometric measures at birth. HPA system activity during pregnancy may be related to low gestational age. The effect of prenatal stress might be partly mediated by maternal-placental-fetal neuroendocrine mechanisms especially the dysregulation of diurnal cortisol profile.