The risk of acute infections in new users of antidepressants: An observational cohort study.

BACKGROUND: Preclinical studies suggested that drugs that functionally inhibit acid sphingomyelinase (FIASMA)may enhance immune cell longevity and potentially offer protection against infections. Many antidepressants have shown FIASMA activity. METHODS: We conducted a cohort study using primary-care data from the UK-based Clinical Practice Research Datalink (2000-2021). We assessed the association of composite diagnosed acute infections in new users of fluoxetine, sertraline, paroxetine, or venlafaxine aged 18-80 years compared to citalopram. We compared SARS-CoV-2 infections between groups in a secondary analysis. We estimated incidence rates (IR) and IR ratios (IRR) of acute infections in four pairwise comparisons using negative binomial regression. We applied propensity score (PS) fine stratification to control for confounding. RESULTS: In the PS-weighted cohorts, we included 353,138 fluoxetine, 222,463 sertraline, 69,963 paroxetine, 32,608 venlafaxine, and between 515,996 and 516,583 new citalopram users. PS-weighted IRs ranged between 76.8 acute infections /1000 person-years (py) (sertraline) and 98.9 infections/1000 py (citalopram). We observed PS-weighted IRRs around unity for paroxetine (0.97, 95 % CI, 0.95-1.00), fluoxetine (0.94, 95 % CI, 0.92-0.95), and venlafaxine (0.90, 95 % CI, 0.87-0.94) vs citalopram. Reduced IRR for sertraline vs citalopram (0.84, 95 % CI, 0.82-0.85), became null within subgroups by cohort entry date. In the analysis of SARS-CoV-2 infection, no statistically relevant risk reduction was seen. LIMITATIONS: Analysis not limited to patients with diagnosed depression, possible underestimation of infection incidence, and unclear FIASMA activity of citalopram. CONCLUSIONS: Fluoxetine, sertraline, paroxetine, and venlafaxine were not associated with a reduced risk of acute infection when compared with the presumably weak FIASMA citalopram.

The dynamic relationship between sleep and psychotic experiences across the early stages of the psychosis continuum.

BACKGROUND: Psychotic disorders develop gradually along a continuum of severity. Understanding factors associated with psychosis development, such as sleep, could aid in identification of individuals at elevated risk. This study aimed to assess (1) the dynamic relationship between psychotic experiences (PEs) and sleep quality and quantity, and (2) whether this relationship differed between different clinical stages along the psychosis continuum. METHODS: We used daily diary data (90 days) of individuals (N = 96) at early stages (i.e. before a first diagnosis of psychosis) along the psychosis continuum. Multilevel models were constructed with sleep quality and sleep quantity as predictors of PEs and vice versa. Post-hoc, we constructed a multilevel model with both sleep quality and quantity as predictors of PEs. In addition, we tested whether associations differed between clinical stages. RESULTS: Within persons, poorer sleep predicted next day PEs (B = -0.02, p = 0.01), but not vice versa. Between persons, shorter sleep over the 90-day period predicted more PEs (B = -0.04, p = 0.002). Experiencing more PEs over 90-days predicted poorer (B = -0.02, p = 0.02) and shorter (B = -1.06, p = 0.008) sleep. We did not find any significant moderation effects for clinical stage. CONCLUSIONS: We found a bidirectional relationship between sleep and PEs with daily fluctuations in sleep predicting next day PEs and general patterns of more PEs predicting poorer and shorter sleep. Our results highlight the importance of assessing sleep as a risk marker in the early clinical stages for psychosis.

Attentional salience and the neural substrates of response inhibition in borderline personality disorder.

BACKGROUND: Impulsivity is a central symptom of borderline personality disorder (BPD) and its neural basis may be instantiated in a frontoparietal network involved in response inhibition. However, research has yet to determine whether neural activation differences in BPD associated with response inhibition are attributed to attentional saliency, which is subserved by a partially overlapping network of brain regions. METHODS: Patients with BPD (n = 45) and 29 healthy controls (HCs; n = 29) underwent functional magnetic resonance imaging while completing a novel go/no-go task with infrequent odd-ball trials to control for attentional saliency. Contrasts reflecting a combination of response inhibition and attentional saliency (no-go > go), saliency processing alone (oddball > go), and response inhibition controlling for attentional saliency (no-go > oddball) were compared between BPD and HC. RESULTS: Compared to HC, BPD showed less activation in the combined no-go > go contrast in the right posterior inferior and middle-frontal gyri, and less activation for oddball > go in left-hemispheric inferior frontal junction, frontal pole, superior parietal lobe, and supramarginal gyri. Crucially, BPD and HC showed no activation differences for the no-go > oddball contrast. In BPD, higher vlPFC activation for no-go > go was correlated with greater self-rated BPD symptoms, whereas lower vlPFC activation for oddball > go was associated with greater self-rated attentional impulsivity. CONCLUSIONS: Patients with BPD show frontoparietal disruptions related to the combination of response inhibition and attentional saliency or saliency alone, but no specific response inhibition neural activation difference when attentional saliency is controlled. The findings suggest a neural dysfunction in BPD underlying attention to salient or infrequent stimuli, which is supported by a negative correlation with self-rated impulsiveness.

Temporal changes of the endothelin system in human cytotrophoblasts during the first trimester of pregnancy.

The first trimester of pregnancy is characterized by continuous proliferation, invasion and differentiation of cytotrophoblasts. These processes are precisely controlled both, in space and time by molecules such as endothelin-1 (ET-1). ET-1 is expressed in human first trimester trophoblast and is known to stimulate cytotrophoblast proliferation through endothelin A and B receptor subtypes (ET(A) and ET(B)), and cytotrophoblast invasion through ET(B). However, temporal changes of the ET system during the first trimester of pregnancy have not been previously studied. This study tested the hypothesis that ET-1 release, ET(A) and ET(B) expression are increased towards the end of the first trimester of pregnancy (weeks 10-12 vs. weeks 6-9), resulting in increased cytotrophoblast proliferation and invasion. Tissue samples were obtained from 17 surgical pregnancy interruptions (week 6-9: n=9; week 10-12: n=8). After cytotrophoblast isolation, the invasive and proliferative phenotypes were immune-separated by an alpha(6)-integrin antibody. Both proliferative and invasive cytotrophoblasts were cultured separately on plastic or Matrigel for 24 h. ET-1 release into the culture medium of both cytotrophoblast subtypes was measured by radioimmunoassay. ET(A) and ET(B) mRNA expression was measured by RT-PCR, and the ET-1 effect on cytotrophoblast proliferation and invasion was determined using proliferation and invasion assays, respectively. ET-1 release increased from early to late first trimester of pregnancy in both proliferative (1.8-4.5 fold) and invasive cytotrophoblasts (9.3-28 fold), especially when cultured on Matrigel. This was paralleled by less ET(B) mRNA on invasive cytotrophoblasts independent of the time period in first trimester, whereas ET(A) expression was similar on proliferative an invasive cytotrophoblasts. Proliferation and invasion of cytotrophoblasts under control conditions decreased from early to late first trimester. ET-1 stimulated both processes at both periods with the most pronounced effect (7-fold) on invasion in late first trimester. The ET-1/ET-receptor system changes between weeks 6-9 and 10-12 in pregnancy. Our data suggest an autocrine and endocrine ET-1 effect, which is stronger in late than in early first trimester of pregnancy paralleled by different stimulatory effects on trophoblast invasion and proliferation. In general, this suggests time as an additional effector of the critical processes governing placental development in the first trimester of human pregnancy.

Long-term reduction of seclusion and forced medication on a hospital-wide level: Implementation of an open-door policy over 6 years.

BACKGROUND: Psychiatric inpatient treatment is increasingly performed in settings with locked doors. However, locked wards have well-known disadvantages and are ethically problematic. In addition, recent data challenges the hypothesis that locked wards provide improved safety over open-door settings regarding suicide, absconding and aggression. Furthermore, there is evidence that the introduction of an open-door policy may lead to short-term reductions in involuntary measures. The aim of this study was to assess if the introduction of an open-door policy is associated with a long-term reduction of the frequency of seclusion and forced medication. METHOD: In this 6-year, hospital-wide, longitudinal, observational study, we examined the frequency of seclusion and forced medication in 17,359 inpatient cases admitted to the Department of Adult Psychiatry, Universitäre Psychiatrische Kliniken (UPK) Basel, University of Basel, Switzerland. In an approach to enable a less restrictive policy, six previously closed psychiatric wards were permanently opened beginning from August 2011. During this process, a systematic change towards a more patient-centered and recovery-oriented care was applied. Statistical analysis consisted of generalized estimating equations (GEE) models. RESULTS: In multivariate analyses controlling for potential confounders, the implementation of an open-door policy was associated with a continuous reduction of seclusion (from 8.2 to 3.5%; ηp2=0.82; odds ratio: 0.88) and forced medication (from 2.4 to 1.2%; ηp2=0.70; odds ratio: 0.90). CONCLUSION: This underlines the potential of the introduction of an open-door policy to attain a long-term reduction in involuntary measures.

Acute LSD effects on response inhibition neural networks.

BACKGROUND: Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations. METHODS: In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire. RESULTS: Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery. CONCLUSION: Our findings show that 5-HT2AR activation by LSD leads to a hippocampal-prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.

Do time of birth, unit volume, and staff seniority affect neonatal outcome in deliveries at ≥34+0 weeks of gestation?

OBJECTIVE: We investigated whether time of birth, unit volume, and staff seniority affect neonatal outcome in neonates born at ≥34+0 weeks of gestation. DESIGN: Population-based prospective cohort study. SETTING: Ten public hospitals in the Austrian province of Styria. SAMPLE: A total of 87 065 neonates delivered in the period 2004-2015. METHODS: Based on short-term outcome data, generalised linear mixed models were used to calculate the risk for adverse and severely adverse neonatal outcomes according to time of birth, unit volume, and staff seniority. MAIN OUTCOME MEASURES: Neonatal composite adverse and severely adverse outcome measures. RESULTS: The odds ratio for severely adverse events during the night-time (22:01-07:29 hours) compared with the daytime (07:30-15:00 hours) was 1.35 (95% confidence interval, 95% CI 1.13-1.61). There were no significant differences in neonatal outcome comparing weekdays and weekends, and comparing office hours and shifts. Units with 500-1000 deliveries per year had the lowest risk for adverse events. Adverse and severely adverse neonatal outcomes were least common for midwife-guided deliveries, and became more frequent with the level of experience of the doctors attending the delivery. With increasing pregnancy risks, senior staff attending delivery and delivering in a tertiary centre reduce the odds ratio for adverse events. CONCLUSIONS: Different times of delivery were associated with increased adverse neonatal outcomes. The management of uncomplicated deliveries by less experienced staff showed no negative impact on perinatal outcome. In contrast, riskier pregnancies delivered by senior staff in a tertiary centre favour a better outcome. Achieving a better balance in the total number of labour ward staff during the day and the night appears to be a greater priority than increasing the continuous presence of senior obstetrical staff on the labour ward during the out-of-hours period. TWEETABLE ABSTRACT: Deliveries during night time lead to a greater number of neonates experiencing severely adverse events.

Increased thalamic resting-state connectivity as a core driver of LSD-induced hallucinations.

OBJECTIVE: It has been proposed that the thalamocortical system is an important site of action of hallucinogenic drugs and an essential component of the neural correlates of consciousness. Hallucinogenic drugs such as LSD can be used to induce profoundly altered states of consciousness, and it is thus of interest to test the effects of these drugs on this system. METHOD: 100 µg LSD was administrated orally to 20 healthy participants prior to fMRI assessment. Whole brain thalamic functional connectivity was measured using ROI-to-ROI and ROI-to-voxel approaches. Correlation analyses were used to explore relationships between thalamic connectivity to regions involved in auditory and visual hallucinations and subjective ratings on auditory and visual drug effects. RESULTS: LSD caused significant alterations in all dimensions of the 5D-ASC scale and significantly increased thalamic functional connectivity to various cortical regions. Furthermore, LSD-induced functional connectivity measures between the thalamus and the right fusiform gyrus and insula correlated significantly with subjective auditory and visual drug effects. CONCLUSION: Hallucinogenic drug effects might be provoked by facilitations of cortical excitability via thalamocortical interactions. Our findings have implications for the understanding of the mechanism of action of hallucinogenic drugs and provide further insight into the role of the 5-HT2A -receptor in altered states of consciousness.

Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects.

Lysergic acid diethylamide (LSD) induces profound changes in various mental domains, including perception, self-awareness and emotions. We used functional magnetic resonance imaging (fMRI) to investigate the acute effects of LSD on the neural substrate of emotional processing in humans. Using a double-blind, randomised, cross-over study design, placebo or 100 µg LSD were orally administered to 20 healthy subjects before the fMRI scan, taking into account the subjective and pharmacological peak effects of LSD. The plasma levels of LSD were determined immediately before and after the scan. The study (including the a priori-defined study end point) was registered at ClinicalTrials.gov before study start (NCT02308969). The administration of LSD reduced reactivity of the left amygdala and the right medial prefrontal cortex relative to placebo during the presentation of fearful faces (P<0.05, family-wise error). Notably, there was a significant negative correlation between LSD-induced amygdala response to fearful stimuli and the LSD-induced subjective drug effects (P<0.05). These data suggest that acute administration of LSD modulates the engagement of brain regions that mediate emotional processing.

Maternal obesity modulates intracellular lipid turnover in the human term placenta.

BACKGROUND: Obesity before pregnancy is associated with impaired metabolic status of the mother and the offspring later in life. These adverse effects have been attributed to epigenetic changes in utero, but little is known about the role of placental metabolism and its contribution to fetal development. OBJECTIVES: We examined the impact of maternal pre-pregnancy obesity on the expression of genes involved in placental lipid metabolism in lean and obese women. SUBJECTS/METHODS: Seventy-three lean and obese women with healthy pregnancy were recruited at term elective cesarean delivery. Metabolic parameters were measured on maternal venous blood samples. Expression of 88 genes involved in lipid metabolism was measured in whole placenta tissue. Proteins of genes differently expressed in response to maternal obesity were quantified, correlated with maternal parameters and immunolocalized in placenta sections. Isolated primary trophoblasts were used for in vitro assays. RESULTS: Triglyceride (TG) content was increased in placental tissue of obese (1.10, CI 1.04-1.24 mg g-1, P<0.05) vs lean (0.84, CI 0.72-1.02 mg g-1) women. Among target genes examined, six showed positive correlation (P<0.05) with maternal pre-pregnancy BMI, namely ATGL (PNPLA2), FATP1 (SLC27A1), FATP3 (SLC27A3), PLIN2, PPARG and CGI-58 (ABHD5). CGI-58 protein abundance was twofold higher (P<0.001) in placentas of obese vs lean women. CGI-58 protein levels correlated positively with maternal insulin levels and pre-pregnancy body mass index (R=0.63, P<0.001 and R=0.64, P<0.001, respectively). CGI-58 and PLIN2 were primarily located in the syncytiotrophoblast and, were upregulated (1.38- and 500-fold, respectively) upon oleic acid and insulin treatment of cultured trophoblast cells. CONCLUSION: Pre-gravid obesity significantly modifies the expression of placental genes related to transport and storage of neutral lipids. We propose that the upregulation of CGI-58, a master regulator of TG hydrolysis, contributes to the turnover of intracellular lipids in placenta of obese women, and is tightly regulated by metabolic factors of the mother.

Labour and Childbirth After Previous Caesarean Section: Recommendations of the Austrian Society of Obstetrics and Gynaecology (OEGGG).

The new expert recommendation from the Austrian Society of Obstetrics and Gynaecology (OEGGG) comprises an interpretation and summary of guidelines from the leading specialist organisations worldwide (RCOG, ACOG, SOGC, CNGOF, WHO, NIH, NICE, UpToDate). In essence it outlines alternatives to the direct pathway to elective repeat caesarean section (ERCS). In so doing it aligns with international trends, according to which a differentiated, individualised clinical approach is recommended that considers benefits and risks to both mother and child, provides detailed counselling and takes the patient's wishes into account. In view of good success rates (60-85 %) for vaginal birth after caesarean section (VBAC) the consideration of predictive factors during antenatal birth planning has become increasingly important. This publication provides a compact management recommendation for the majority of standard clinical situations. However it cannot and does not claim to cover all possible scenarios. The consideration of all relevant factors in each individual case, and thus the ultimate decision on mode of delivery, remains the discretion and responsibility of the treating obstetrician.

Shall we really say goodbye to first rank symptoms?

BACKGROUND: First rank symptoms (FRS) of schizophrenia have been used for decades for diagnostic purposes. In the new version of the DSM-5, the American Psychiatric Association (APA) has abolished any further reference to FRS of schizophrenia and treats them like any other "criterion A" symptom (e.g. any kind of hallucination or delusion) with regard to their diagnostic implication. The ICD-10 is currently under revision and may follow suit. In this review, we discuss central points of criticism that are directed against the continuous use of first rank symptoms (FRS) to diagnose schizophrenia. METHODS: We describe the specific circumstances in which Schneider articulated his approach to schizophrenia diagnosis and discuss the relevance of his approach today. Further, we discuss anthropological and phenomenological aspects of FRS and highlight the importance of self-disorder (as part of FRS) for the diagnosis of schizophrenia. Finally, we will conclude by suggesting that the theory and rationale behind the definition of FRS is still important for psychopathological as well as neurobiological approaches today. RESULTS: Results of a pivotal meta-analysis and other studies show relatively poor sensitivity, yet relatively high specificity for FRS as diagnostic marker for schizophrenia. Several methodological issues impede a systematic assessment of the usefulness of FRS in the diagnosis of schizophrenia. However, there is good evidence that FRS may still be useful to differentiate schizophrenia from somatic causes of psychotic states. This may be particularly important in countries or situations with little access to other diagnostic tests. FRS may thus still represent a useful aid for clinicians in the diagnostic process. CONCLUSION: In conclusion, we suggest to continue a tradition of careful clinical observation and fine-grained psychopathological assessment, including a focus on symptoms regarding self-disorders, which reflects a key aspect of psychosis. We suggest that the importance of FRS may indeed be scaled down to a degree that the occurrence of a single FRS alone should not suffice to diagnose schizophrenia, but, on the other hand, absence of FRS should be regarded as a warning sign that the diagnosis of schizophrenia or schizoaffective disorder is not warranted and requires specific care to rule out other causes, particularly neurological and other somatic disorders. With respect to the current stage of the development of ICD-11, we appreciate the fact that self-disorders are explicitly mentioned (and distinguished from delusions) in the list of mandatory symptoms but still feel that delusional perceptions and complex hallucinations as defined by Schneider should be distinguished from delusions or hallucinations of "any kind". Finally, we encourage future research to explore the psychopathological context and the neurobiological correlates of self-disorders as a potential phenotypic trait marker of schizophrenia.

Does knowledge of fetal outcome influence the interpretation of intrapartum cardiotocography and subsequent clinical management? A multicentre European study.

OBJECTIVE: To investigate whether knowledge of fetal outcome influences retrospective interpretation of cardiotocographic tracings and subsequent management recommendations. DESIGN: Prospective online study. SETTING: Seven university hospitals in five European countries. POPULATION: Forty-two intrapartum tracings from women with singleton pregnancies and uneventful antepartum courses. METHODS: Using an online questionnaire, 123 healthcare professionals interpreted 42 tracings without any knowledge of fetal outcome and provided management recommendations according to the National Institute of Clinical Excellence guidelines (intrapartum care). Two months later, 93 of the 123 participants re-interpreted the same re-ordered tracings, this time with information on the newborn's umbilical artery pH. OUTCOME MEASURES: Comparison of the evaluation of tracing features, overall tracing classification, and management recommendations between the initial analysis and re-interpretation. RESULTS: In newborns with umbilical artery pH ≤ 7.05, knowledge of the pH value led to significant changes in the evaluation of all basic tracing features. In this group, classification of tracings as 'normal' decreased 76% (8.8-2.1%, P < 0.001), whereas classification as 'pathologic' increased 51% (44.7-67.5%, P < 0.001). In newborns with pH 7.06-7.19, classification of tracings as 'normal' decreased 36% (22.4-14.4%, P < 0.001), and in those with pH ≥ 7.20, classification of tracings as 'pathologic' decreased 40% (23.4-14.1%, P < 0.001). In the group of newborns with umbilical artery pH ≤ 7.05, the recommendations 'no attention needed' decreased 75% (10.2-2.6%, P < 0.001), and the number of recommendations 'rapid reversal of hypoxic cause or immediate delivery' increased 70.3% (42.1-71.7%, P < 0.001). CONCLUSIONS: When provided with information on adverse fetal outcome, healthcare professionals provide a more pessimistic evaluation of basic tracing features, overall classification, and clinical management recommendations. TWEETABLE ABSTRACT: Knowledge of adverse fetal outcome leads to more pessimistic CTG evaluation and management recommendations.

Neuroimaging in moderate MDMA use: A systematic review.

MDMA ("ecstasy") is widely used as a recreational drug, although there has been some debate about its neurotoxic effects in humans. However, most studies have investigated subjects with heavy use patterns, and the effects of transient MDMA use are unclear. In this review, we therefore focus on subjects with moderate use patterns, in order to assess the evidence for harmful effects. We searched for studies applying neuroimaging techniques in man. Studies were included if they provided at least one group with an average of <50 lifetime episodes of ecstasy use or an average lifetime consumption of <100 ecstasy tablets. All studies published before July 2015 were included. Of the 250 studies identified in the database search, 19 were included. There is no convincing evidence that moderate MDMA use is associated with structural or functional brain alterations in neuroimaging measures. The lack of significant results was associated with high methodological heterogeneity in terms of dosages and co-consumption of other drugs, low quality of studies and small sample sizes.

[A Systematic Review of Personality Disorders and Addiction: Epidemiology, Course and Treatment]. / Persönlichkeitsstörungen und Sucht: Systematische Literaturübersicht zu Epidemiologie, Verlauf und Behandlung.

AIM: This paper provides a systematic overview of the comorbidity of personality and addictive disorders including behavioural addictions. METHOD: Systematic review. RESULTS: Personality disorders and substance-related addictions show high comorbidity rates. This is equally true of behavioural addictions. Most empirical research is on comorbidity with borderline personality disorder. For treatment of individuals with dual diagnoses, three psychotherapies have been demonstrated to be effective. Pharmacotherapeutic approaches have hardly been investigated. CONCLUSION: METHODologically integrative treatment represents therapy of choice for patients with dual diagnoses. Comorbidity of personality disorders and behavioural addictions needs further investigation.