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.

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.

[Diagnosis and admission center : Establishment and evaluation of an integrated translational infrastructure for clinical psychiatric research]. / Diagnose- und Aufnahmezentrum : Etablierung und Evaluation einer integrierten translationalen Infrastruktur für die klinisch-psychiatrische Forschung.

The routine in-depth characterization of patients with methods of clinical and scale-based examination, neuropsychology, based on biomaterials, and sensor-based information opens up transformative possibilities on the way to personalized diagnostics, treatment and prevention in psychiatry, psychotherapy, and psychosomatics. Effective integration of the additional temporal and logistical effort into everyday care as well as the acceptance by patients are critical to the success of such an approach but there is little evidence on this to date. We report here on the establishment of the Diagnosis and Admission Center (DAZ) at the Central Institute of Mental Health (ZI) in Mannheim. The DAZ is an outpatient unit upstream of other care structures for clinical and scientific phenotyping across diagnoses as a starting point for data-driven, individualized pathways to further treatment, diagnostics or research. We describe the functions, goals, and implementation of the newly created clinical scientific translational structure, provide an overview of the patient populations it has reached, and provide data on its acceptance. In this context, the close integration with downstream clinical processes enables a better coordinated and demand-oriented allocation. In addition, DAZ enables a faster start of disorder-specific diagnostics and treatment. Since its launch in April 2021 up to the end of 2022, 1021 patients underwent psychiatric evaluation at DAZ during a pilot phase. The patient sample corresponded to a representative sample from standard care and the newly established processes were regarded as helpful by patients. In summary, the DAZ uniquely combines the interests and needs of patient with the collection of scientifically relevant data.

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.

Association of hypertension, type 2 diabetes mellitus and dyslipidemia with the duration of inpatient treatments and recurrence of schizophrenia.

OBJECTIVE: People with schizophrenia have an increased cardiovascular risk with higher mortality than the general population. Only a few studies have investigated the impact of cardiovascular risk on the later course of schizophrenia. This study aims to explore the association of cardiovascular risk factors, as detected during an index inpatient treatment for schizophrenia, with the duration of psychiatric inpatient treatments and number of inpatient admissions in the subsequent 10 years, in patients with schizophrenia. METHODS: Cardiovascular risk factors of 736 patients with schizophrenia, identified through retrospective chart review, were assessed by hypertension, type 2 diabetes mellitus and dyslipidemia during an index inpatient stay. The duration of inpatient treatments, assessed by the total duration of psychiatric inpatient treatments in days, and the number of inpatient admissions, over the next 10 years were assessed and analyzed for an association with cardiovascular risk factors. RESULTS: Hypertension associated with longer duration of inpatient treatments and higher number of inpatient admissions. Type 2 diabetes mellitus and dyslipidemia associated with a higher number of psychiatric inpatient treatments. Hypertension remained significantly associated with the duration of inpatient treatments (ß = 0.174; p < 0.001) and the number of inpatient treatments (ß = 0.144; p < 0.001), when adjusting for age, sex and BMI. CONCLUSION: Out of the investigated cardiovascular risk factors documented during an index inpatient stay for schizophrenia, only hypertension associated with an increased duration of in-hospital stay and an increased number of re-hospitalizations during the subsequent ten years when adjusting for confounders. Screening for hypertension should be considered in all patients with schizophrenia.

The Impact of Childhood Traumatization on Diabetes Mellitus Type 2 Risk in World War II Refugees and Their Offspring.

OBJECTIVE: Type 2 diabetes mellitus (T2D) is a chronic disease that is influenced by different factors. The extent to which degree adverse childhood events (ACEs) can modify the potential to development of T2D is still not explored and therefore represents one of the central questions of the childhood escape-late life outcome (DRKS00012419) study. In addition, transgenerational effects were considered in the analyses. METHODS: The study analyzed the association of self-reported traumatic experiences and T2D disease of refugees from East Prussia, who were displaced from their former homeland at the end of the World War II. In addition, an independent sample consisting of participants of first-generation offspring of refugees was analyzed. RESULTS: Of the 242 refugees, all aged between 73 and 93 years, 17.36% reported T2D disease, whereas among the offspring ( n = 272), aged between 47 and 73 years, it was 5.5%, meaning reduced T2D prevalence for both generations compared with the German population of comparable age. In the refugee generation, emotional neglect showed a negative association with development of T2D in later life. In women, separation from close caregivers in childhood showed a negative association with later T2D. In contrast, experiencing emotional abuse in childhood showed a positive association with later T2D. The offspring generation showed no associations of adverse childhood events and reported T2D diagnoses in later life. CONCLUSIONS: Our results demonstrate that individual trauma in childhood is responded to with different mechanisms that can lead to both increased and decreased reported T2D diagnoses in adulthood and thus should by no means be considered in a generalized manner.

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.

Association of polygenic risk for schizophrenia with fast sleep spindle density depends on pro-cognitive variants.

Cognitive impairment is a common feature in schizophrenia and the strongest prognostic factor for long-term outcome. Identifying a trait associated with the genetic background for cognitive outcome in schizophrenia may aid in a deeper understanding of clinical disease subtypes. Fast sleep spindles may represent such a biomarker as they are strongly genetically determined, associated with cognitive functioning and impaired in schizophrenia and unaffected relatives. We measured fast sleep spindle density in 150 healthy adults and investigated its association with a genome-wide polygenic score for schizophrenia (SCZ-PGS). The association between SCZ-PGS and fast spindle density was further characterized by stratifying it to the genetic background of intelligence. SCZ-PGS was positively associated with fast spindle density. This association mainly depended on pro-cognitive genetic variants. Our results strengthen the evidence for a genetic background of spindle abnormalities in schizophrenia. Spindle density might represent an easily accessible marker for a favourable cognitive outcome which should be further investigated in clinical samples.

Efficacy of Augmentation of Cognitive Behavioral Therapy With Transcranial Direct Current Stimulation for Depression: A Randomized Clinical Trial.

Importance: Major depressive disorder (MDD) affects approximately 10% of the population globally. Approximately 20% to 30% of patients with MDD do not sufficiently respond to standard treatment. Therefore, there is a need to develop more effective treatment strategies. Objective: To investigate whether the efficacy of cognitive behavioral therapy (CBT) for the treatment of MDD can be enhanced by concurrent transcranial direct current stimulation (tDCS). Design, Setting, and Participants: The double-blind, placebo-controlled randomized clinical trial PsychotherapyPlus was conducted at 6 university hospitals across Germany. Enrollment took place between June 2, 2016, and March 10, 2020; follow-up was completed August 27, 2020. Adults aged 20 to 65 years with a single or recurrent depressive episode were eligible. They were either not receiving medication or were receiving a stable regimen of antidepressant medication (selective serotonin reuptake inhibitor and/or mirtazapine). A total of 148 women and men underwent randomization: 53 individuals were assigned to CBT alone (group 0), 48 to CBT plus tDCS (group 1), and 47 to CBT plus sham-tDCS (group 2). Interventions: Participants attended a 6-week group intervention comprising 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 mA for 30 minutes (anode over F3, cathode over F4). Main Outcomes and Measures: The primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to posttreatment in the intention-to-treat sample. Scores of 0 to 6 indicate no depression; 7 to 19, mild depression; 20 to 34, moderate depression; and 34 and higher, severe depression. Results: A total of 148 patients (89 women, 59 men; mean [SD] age, 41.1 [13.7] years; MADRS score at baseline, 23.0 [6.4]) were randomized. Of these, 126 patients (mean [SD] age, 41.5 [14.0] years; MADRS score at baseline, 23.0 [6.3]) completed the study. In each of the intervention groups, intervention was able to reduce MADRS scores by a mean of 6.5 points (95% CI, 3.82-9.14 points). The Cohen d value was -0.90 (95% CI, -1.43 to -0.50), indicating a significant effect over time. However, there was no significant effect of group and no significant interaction of group × time, indicating the estimated additive effects were not statistically significant. There were no severe adverse events throughout the whole trial, and there were no significant differences of self-reported adverse effects during and after stimulation between groups 1 and 2. Conclusions and Relevance: Based on MADRS score changes, this trial did not indicate superior efficacy of tDCS-enhanced CBT compared with 2 CBT control conditions. The study confirmed that concurrent group CBT and tDCS is safe and feasible. However, additional research on mechanisms of neuromodulation to complement CBT and other behavioral interventions is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT02633449.

Adverse childhood experiences and late-life diurnal HPA axis activity: Associations of different childhood adversity types and interaction with timing in a sample of older East Prussian World War II refugees.

Adverse childhood experiences (ACEs) have been associated with unfavorable health outcomes throughout the life up to old age. Mechanisms through which ACEs impact later life health are still not entirely clear. There is growing evidence for the idea that alterations in the hypothalamic pituitary adrenal (HPA) axis might cause the effects of ACEs on later health consequences. Only few studies have investigated associations between ACEs and diurnal HPA axis functioning in older adults. Therefore, we investigated the impact of type and timing of ACEs linked to flight of war on diurnal HPA axis activity in a sample of East Prussian World War II refugees aged 74-91 years. We calculated a dichotomous variable according to the (minimum) age at trauma: early ACE (eACE; 0-5 years) and late ACE (lACE; 6-17 years). Multiple linear regression analysis using different ACEs linked to flight of war (war-related trauma, individual experience of violence, neglect) as well as age at trauma and the interactions of ACEs and age at trauma as predictors and three cortisol outcomes (AUCG (area under the curve with respect to the ground), decline (morning to night) and CAR (cortisol awakening response)) was performed. For AUCG, we found a negative association of individual experience of violence only in lACE participants. For decline, a positive association with neglect was observed for the whole study sample. The overall model for CAR was not statistically significant. Our findings support the hypothesis that type as well as timing of ACEs might influence diurnal HPA axis functioning into old age. These findings may contribute to a better understanding of the lifelong influence of ACEs.

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.

Fat compartments in patients with depression: A meta-analysis.

INTRODUCTION: Depressive disorders are a common illness worldwide. Major depression is known as a significant predictor of the metabolic syndrome. However, the effects of depression on adipose tissue compartments are controversial. This meta-analysis aimed to evaluate the state of research on the relationship between patients with depression and adipose tissue compartments as compared to nondepressed individuals. METHODS: The PubMed database was searched for human studies that measured adipose tissue compartments such as visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and/or organ-specific adipose tissue measurements using dual-energy X-ray absorptiometry, magnetic resonance imaging or computed tomography scan and reported the means and a measure of variance separately for depressed individuals and healthy controls. Twelve articles were identified, including a total of 1,141 depressed and 2,545 nondepressed individuals. RESULTS: Major depressive disorder and self-reported depressive symptoms were associated with elevated visceral adipose tissue and elevated subcutaneous adipose tissue. Subanalyses for gender, age, method of adipose tissue measurement, and method of depression assessment showed elevated visceral adipose in depressed individuals. The results could be replicated when focussing on studies controlling for body mass index (BMI). Regarding other adipose tissue compartments, meta-analysis could not be carried out due to lack of studies. CONCLUSIONS: Depression is associated with enlarged visceral and subcutaneous adipose tissue. Further, especially longitudinal, research is needed to identify the mechanism through which depressive disorders contribute to visceral adiposity.

Enhanced Vigilance Stability during Daytime in Insomnia Disorder.

Central nervous hyperarousal is as a key component of current pathophysiological concepts of chronic insomnia disorder. However, there are still open questions regarding its exact nature and the mechanisms linking hyperarousal to sleep disturbance. Here, we aimed at studying waking state hyperarousal in insomnia by the perspective of resting-state vigilance dynamics. The VIGALL (Vigilance Algorithm Leipzig) algorithm has been developed to investigate resting-state vigilance dynamics, and it revealed, for example, enhanced vigilance stability in depressive patients. We hypothesized that patients with insomnia also show a more stable vigilance regulation. Thirty-four unmedicated patients with chronic insomnia and 25 healthy controls participated in a twenty-minute resting-state electroencephalography (EEG) measurement following a night of polysomnography. Insomnia patients showed enhanced EEG vigilance stability as compared to controls. The pattern of vigilance hyperstability differed from that reported previously in depressive patients. Vigilance hyperstability was also present in insomnia patients showing only mildly reduced sleep efficiency. In this subgroup, vigilance hyperstability correlated with measures of disturbed sleep continuity and arousal. Our data indicate that insomnia disorder is characterized by hyperarousal at night as well as during daytime.