[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.

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.

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.

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 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.

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.

[Track treatment in psychiatry: the CIMH track model to overcome sector boundaries]. / Track-Behandlung in der Psychiatrie: das ZI-Track-Modell zur Überwindung von Sektorengrenzen.

The overall conditions for the treatment of patients with psychiatric disorders have changed and place new demands on therapy concepts and procedures. This concerns both the legal conditions of the treatment as well as the content and economic conditions for a patient-oriented diagnostic work-up and therapy. The Central Institute for Mental Health (CIMH) in Mannheim is currently implementing a track concept that takes these changes into account and aims to overcome sectoral boundaries in favor of treatment continuity.

[The CIMH track concept in the treatment of psychotic disorders]. / Das ZI-Track-Konzept in der Behandlung psychotischer Störungen.

The treatment of psychotic disorders and illnesses is a challenge for therapists and institutions due to the heterogeneity of the cause and course, refractory symptoms, lack of therapy adherence and high rates of relapse. These circumstances can be effectively counteracted by the flexibility of therapeutic approaches and settings. A useful but rarely used concept is the treatment of psychoses within the so-called track unit. A track unit is defined as a syndrome-oriented, decentralized, modular unit, adjusted to the patient's individual stage-specific needs across both inpatient and outpatient sectors. The track concept offers a fully integrated sector-spanning model of treatment at all stages of psychotic illnesses as well as a continuity of treatment. Another important goal is the early availability of timely treatment for as many psychotic patients as possible so that the symptoms can be alleviated as soon as possible and the quality of life can be sustainably improved or preserved. The track concept not only improves the current situation of treatment for acutely or chronically psychotic patients but also represents a necessary investment in the future. This treatment model aims to ensure that the good but complex and costly treatment options are available to patients even if inpatient treatment is not favored by the patient.

[The CIMH Track Concept in Psychiatry: Syndrome-specific Treatment across Modalities - Part 2 - Practical implementation]. / Das ZI-Track-Konzept in der modernen Psychiatrie: Eine syndromspezifische sektorenübergreifende Behandlung.

Modern psychiatry needs to implement novel mental health care systems in order to address recent developments in diagnostics and treatment of psychiatric patients. In this context, it is necessary to take into account recent ethical and certain legal aspects which explicitly seek to reduce coercive treatment. The so-called "track-unit" is a promising strategy in order to achieve these goals. The "track-unit" seeks to enhance and improve patients' autonomy, setting-overlapping team continuity, compliance and adherence to treatment as well as to reduce time of patients in hospital as inpatients by more flexible intervention. Although there are many interfaces between normal wards and the "track-unit", implementation into daily routine should be done gradually. The first part of this paper will focus on required changes taking as an example the Department of Psychiatry and Psychotherapy at the Central Institute of Mental Health in Mannheim. In the second part, we will describe corresponding helpful constructional measures. In part three, we will discuss the socio-economic aspects and benefits of "track-units". In conclusion, the implementation of "track-units" in a German psychiatric department is a personnel and economic endeavor to improve the link and coordination between diagnostics and treatment throughout all stages of mental illness.

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.

[First Aid for Mental Health in Germany].

Early recognition of mental disorders and psychological crisis is essential for successful therapy and good outcome of affected persons. Relatives and affected persons need health knowledge in order to identify early symptoms and psychological crisis and to guide patients to the health care system. Mental Health First Aid is a lay-based program of health education, which is evidence-based and wide-spread in English-speaking countries. In a 12-hour "Standard Course" lay persons learn basic knowledge of mental disorders and of the health care system in order to be able to access persons with beginning mental disorders or in crisis, to provide First Aid and to give advice about professional help. Currently, Mental Health First Aid is introduced in Switzerland and Germany.

Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation.

BACKGROUND: Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels. METHODS: Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females. RESULTS: Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns. CONCLUSION: The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight.

Serum brain-derived neurotrophic factor (BDNF) in sleep-disordered patients: relation to sleep stage N3 and rapid eye movement (REM) sleep across diagnostic entities.

Experimental and clinical evidence suggests an association between neuroplasticity, brain-derived neurotrophic factor and sleep. We aimed at testing the hypotheses that brain-derived neurotrophic factor is associated with specific aspects of sleep architecture or sleep stages in patients with sleep disorders. We included 35 patients with primary insomnia, 31 patients with restless legs syndrome, 17 patients with idiopathic hypersomnia, 10 patients with narcolepsy and 37 healthy controls. Morning serum brain-derived neurotrophic factor concentrations were measured in patients and controls. In patients, blood sampling was followed by polysomnographic sleep investigation. Low brain-derived neurotrophic factor levels were associated with a low percentage of sleep stage N3 and rapid eye movement sleep across diagnostic entities. However, there was no difference in brain-derived neurotrophic factor levels between diagnostic groups. Our data indicate that serum levels of brain-derived neurotrophic factor, independent of a specific sleep disorder, are related to the proportion of sleep stage N3 and REM sleep. This preliminary observation is in accordance with the assumption that sleep stage N3 is involved in the regulation of neuroplasticity.

Cortisol, cortisone, and BDNF in amniotic fluid in the second trimester of pregnancy: Effect of early life and current maternal stress and socioeconomic status.

The prenatal environment shapes the offspring's phenotype; moreover, transgenerational stress and stress during pregnancy may play a role. Brain-derived neurotrophic factor (BDNF) and glucocorticoids influence neurodevelopment during pregnancy, and there is evidence that BDNF in amniotic fluid is mainly of fetal origin, while the source of glucocorticoids is maternal. We tested the hypothesis that maternal early life stress, psychiatric diagnoses, anxiety, perceived stress, and socioeconomic status influence BDNF and glucocorticoid concentrations in amniotic fluid in the second trimester. We studied 79 pregnant women who underwent amniocentesis in the early second trimester and analyzed BDNF, cortisol, and cortisone concentrations in amniotic fluid. The endocrine data were related to maternal early life adversities (Childhood Trauma Questionaire), perceived stress (Perceived Stress Scale), anxiety, socioeconomic status (family income), and the presence of psychiatric diseases. We found BDNF in amniotic fluid to be positively related to maternal early adversity (Childhood Trauma Questionaire). Low family income (socioeconomic status) was related to high amniotic fluid glucocorticoid concentrations. Neither glucocorticoid concentrations nor hydroxy steroid dehydrogenase (HSD2) activity could be related to BDNF concentrations in amniotic fluid. Early maternal adverse events may be reflected in the fetal BDNF regulation, and it should be tested whether this relates to differences in neurodevelopment.

Impact of prenatal stress on the dyadic behavior of mothers and their 6-month-old infants during a play situation: role of different dimensions of stress.

Prenatal stress (PS) is an established risk factor in the etiology of mental disorders. Although mother-child interaction is the infant's first important training in dealing with stress, little is yet known about the impact of PS on mother-infant dyadic behavior. The current study aimed to elucidate the prospective influence of psychological and physiological stresses during pregnancy on mother-infant dyadic behavior. Mother-infant interactions were videotaped at 6-month postpartum and coded into three dyadic patterns: (1) both positive; (2) infant protesting-mother positive; and (3) infant protesting-mother negative, using the infant and caregiver engagement phases. Exposure to PS was assessed during pregnancy using psychological (i.e., psychopathological, perceived, and psychosocial PS; n = 164) and physiological stress measures (i.e., maternal cortisol; n = 134). Group comparisons showed that psychosocial PS was predictive of mother-infant behavior at 6-month postpartum, indicating that dyads of prenatally high-stressed mothers exhibited significantly more positive interaction patterns (i.e., infant positive-mother positive) as compared to the prenatally low-stressed group. Physiological PS was unrelated to mother-infant behavior. These results suggest that mild psychosocial PS may be advantageous for positive mother-infant dyadic behavior, which is in accordance with the stress-inoculation model that assumes a beneficial effect of PS.

Hypothalamic-Pituitary-Adrenocortical Dysfunction in Elderly, Male Marathon Runners: Feedback Sensitivity, Stress Response, and Effects on Verbal Memory.

Animal studies suggest that repeated episodes of elevated glucocorticoids lead to a dysregulation of the hypothalamic-pituitary-adrenal (HPA) system at a suprapituitary level, and to impaired mnemonic function. We compared cognitive tests, as well as feedback integrity and stress responsivity of the HPA system, between 11 elderly, male marathon runners - a model of repeated HPA system activation - and 10 sedentary controls. The marathon runners had significantly increased baseline, stress, and post-stress ACTH - but not cortisol - concentrations. Also, suppression of ACTH by 3 mg dexamethasone was impaired in the athletes compared to the control subjects, while the ACTH and cortisol response to additional CRH did not differ between the 2 groups. Finally, long-term verbal memory was impaired in the athletes compared to the controls. Regarding the HPA system, these findings are in accordance with an acquired suprapituitary feedback disturbance in marathon runners; however, the similar glucocorticoid concentrations in the 2 groups may be due to reduced adrenal sensitivity to ACTH. Together with impaired verbal memory, these data support the assumption that repeated episodes of HPA system activity may exert negative effects at the level of the hippocampus.

City living and urban upbringing affect neural social stress processing in humans.

More than half of the world's population now lives in cities, making the creation of a healthy urban environment a major policy priority. Cities have both health risks and benefits, but mental health is negatively affected: mood and anxiety disorders are more prevalent in city dwellers and the incidence of schizophrenia is strongly increased in people born and raised in cities. Although these findings have been widely attributed to the urban social environment, the neural processes that could mediate such associations are unknown. Here we show, using functional magnetic resonance imaging in three independent experiments, that urban upbringing and city living have dissociable impacts on social evaluative stress processing in humans. Current city living was associated with increased amygdala activity, whereas urban upbringing affected the perigenual anterior cingulate cortex, a key region for regulation of amygdala activity, negative affect and stress. These findings were regionally and behaviourally specific, as no other brain structures were affected and no urbanicity effect was seen during control experiments invoking cognitive processing without stress. Our results identify distinct neural mechanisms for an established environmental risk factor, link the urban environment for the first time to social stress processing, suggest that brain regions differ in vulnerability to this risk factor across the lifespan, and indicate that experimental interrogation of epidemiological associations is a promising strategy in social neuroscience.

Fast sleep spindle reduction in schizophrenia and healthy first-degree relatives: association with impaired cognitive function and potential intermediate phenotype.

Several studies in patients with schizophrenia reported a marked reduction in sleep spindle activity. To investigate whether the reduction may be linked to genetic risk of the illness, we analysed sleep spindle activity in healthy volunteers, patients with schizophrenia and first-degree relatives, who share an enriched set of schizophrenia susceptibility genes. We further investigated the correlation of spindle activity with cognitive function in first-degree relatives and whether spindle abnormalities affect both fast (12-15 Hz) and slow (9-12 Hz) sleep spindles. We investigated fast and slow sleep spindle activity during non-rapid eye movement sleep in a total of 47 subjects comprising 17 patients with schizophrenia, 13 healthy first-degree relatives and 17 healthy volunteers. Groups were balanced for age, gender, years of education and estimated verbal IQ. A subsample of relatives received additional testing for memory performance. Compared to healthy volunteers, fast spindle density was reduced in patients with schizophrenia and healthy first-degree relatives following a pattern consistent with an assumed genetic load for schizophrenia. The deficit in spindle density was specific to fast spindles and was associated with decreased memory performance. Our findings indicate familial occurrence of this phenotype and thus support the hypothesis that deficient spindle activity relates to genetic liability for schizophrenia. Furthermore, spindle reductions predict impaired cognitive function and are specific to fast spindles. This physiological marker should be further investigated as an intermediate phenotype of schizophrenia. It could also constitute a target for drug development, especially with regard to cognitive dysfunction.

Electroconvulsive Therapy Induces Transient Sensitivity for a Serotonin Syndrome: A Case Report.

Introduction: Serotonin syndrome is a potentially life-threatening condition with delirium, vegetative and neuromuscular symptoms as well as neural hyperexcitability. The main causes are combinations of serotonergic drugs, excessive dosages of serotonergic agents or the recreational use of certain drugs. Methods and Results: We report a case of a patient who started developing serotonin syndrome after a cumulative dose of only 900 mg lithium carbonate given in temporal association with electroconvulsive therapy (ECT). The patient tolerated the serotonergic combination of escitalopram and lithium well a few weeks after ECT. Discussion: Generally, hypersensitivity to psychotropic medications during a course of ECT is rare and hypothetically attributed to a possible and reversible alteration of the blood brain barrier. Consecutively, drugs with assumed central nervous side effects should be started at low dosages and slow titration within the first two days after ECT because even low plasma concentrations may not be tolerated. Importantly and as in other cases, the liability appeared to be of transient nature. In cases of non-tolerance immediately after ECT, a re-exposure after several weeks seems justified.

Hypercortisolemic Depressed Women: Lean but Viscerally Obese?

BACKGROUND: Activation of the hypothalamic-pituitary-adrenal (HPA) system in depressed patients has been related to visceral adiposity. In contrast, low HPA system activity is associated with increased body fat in the general population. Our study intended to clarify whether HPA system activity is related to body weight and composition in depressed inpatients. METHODS: In a cohort of 51 female and 20 male depressed inpatients, we measured saliva cortisol (HPA system activity), body mass index (BMI), waist circumference as well as body composition as reflected by bioimpedance. RESULTS: In female patients, cortisol in saliva was negatively associated with fat-to-muscle ratio and BMI. CONCLUSION: In depressed inpatients, especially women, there is evidence that activation of the HPA system is related to relatively low body weight and low body fat content.