Sex-specific pleiotropic changes in emotional behavior and alcohol consumption in human α-synuclein A53T transgenic mice during early adulthood.

Point mutations in the α-synuclein coding gene may lead to the development of Parkinson's disease (PD). PD is often accompanied by other psychiatric conditions, such as anxiety, depression, and drug use disorders, which typically emerge in adulthood. Some of these point mutations, such as SNCA and A30T, have been linked to behavioral effects that are not commonly associated with PD, especially regarding alcohol consumption patterns. In this study, we investigated whether the familial PD point mutation A53T is associated with changes in alcohol consumption behavior and emotional states at ages not yet characterized by α-synuclein accumulation. The affective and alcohol-drinking phenotypes remained unaltered in female PDGF-hA53T-synuclein-transgenic (A53T) mice during both early and late adulthood. Brain region-specific activation of ceramide-producing enzymes, acid sphingomyelinase (ASM), and neutral sphingomyelinase (NSM), known for their neuroprotective properties, was observed during early adulthood but not in late adulthood. In males, the A53T mutation was linked to a reduction in alcohol consumption in both early and late adulthood. However, male A53T mice displayed increased anxiety- and depression-like behaviors during both early and late adulthood. Enhanced ASM activity in the dorsal mesencephalon and ventral hippocampus may potentially contribute to these adverse behavioral effects of the mutation in males during late adulthood. In summary, the A53T gene mutation was associated with diverse changes in emotional states and alcohol consumption behavior long before the onset of PD, and these effects varied by sex. These alterations in behavior may be linked to changes in brain ceramide metabolism.

Self-management with alcohol over lifespan: psychological mechanisms, neurobiological underpinnings, and risk assessment.

Self-management includes all behavioural measures and cognitive activities aimed at coping with challenges arising throughout the lifespan. While virtually all of these challenges can be met without pharmacological means, alcohol consumption has long been instrumentalized as a supporting tool to help coping with problems arising selectively at adolescence, adulthood, and ageing. Here, we present, to our knowledge, the first systematic review of alcohol instrumentalization throughout lifespan. We searched MEDLINE, Google Scholar, PsycINFO and CINAHL (from Jan, 1990, to Dec, 2022) and analysed consumption patterns, goals and potential neurobiological mechanisms. Evidence shows a regular non-addictive use of alcohol to self-manage developmental issues during adolescence, adulthood, and ageing. Alcohol is selectively used to overcome problems arising from dysfunctional personality traits, which manifest in adolescence. A large range of psychiatric disorders gives rise to alcohol use for the self-management of distinct symptoms starting mainly in adulthood. We identify those neuropharmacological effects of alcohol that selectively serve self-management under specific conditions. Finally, we discuss the adverse effects and associated risks that arise from the use of alcohol for self-management. Even well-controlled alcohol use adversely impacts health. Based on these findings, we suggest the implementation of an entirely new view. Health policy action may actively embrace both sides of the phenomenon through a personalized informed use that allows for harm-controlled self-management with alcohol.

Masculine depression and its problem behaviors: use alcohol and drugs, work hard, and avoid psychiatry!

The gender role influences vulnerability to mental illness. Substance use, even critical in scale, is perceived as masculine, just like hard (over-)work, while not seeking help. With the ongoing separation between gender and sex, masculine norms become more relevant also to females' mental health. The male depression concept highlights the role of male symptoms in affective disorders. However, the empirical evidence is still limited. Here, we use the denomination 'masculine depression' to open the category for female patients and tested substance use patterns, health services' utilization, and working hours as predictors in a case-control study of 163 depressed in-patients (44% women; masculine vs. non-masculine depression according to a median split of the Male Depression Rating Scale-22) and 176 controls (51% women). We assessed higher depression severity in patients with masculine (vs. non-masculine) depression. Masculine depression (vs. non-masculine depression and vs. no depression) was predicted by more frequent and critical use of alcohol (including binge drinking), tobacco, and illicit drugs, and by longer working times. Moreover, fewer health services contacts due to mental complaints during the previous year were associated with masculine (vs. non-masculine) depression. Alarmingly, even critical substance misuse was not significantly associated with more frequent health services contacts; however, the higher the depression severity, the more contacts the patients reported. Here, we provide evidence that patients with masculine depression are highly burdened and undertreated, which applies equally to female and male patients. This study identified promising targets to establish specialized care offers.

Alcohol does not influence trust in others or oxytocin, but increases positive affect and risk-taking: a randomized, controlled, within-subject trial.

BACKGROUND: Alcohol consumption to facilitate social interaction is an important drinking motive. Here, we tested whether alcohol influences trust in others via modulation of oxytocin and/or androgens. We also aimed at confirming previously shown alcohol effects on positive affect and risk-taking, because of their role in facilitating social interaction. METHODS: This randomized, controlled, within-subject, parallel group, alcohol-challenge experiment investigated the effects of alcohol (versus water, both mixed with orange juice) on perceived trustworthiness via salivary oxytocin (primary and secondary endpoint) as well as testosterone, dihydrotestosterone, positive affect, and risk-taking (additional endpoints). We compared 56 male participants in the alcohol condition (1.07 ± 0.18 per mille blood alcohol concentration) with 20 in the control condition. RESULTS: The group (alcohol versus control condition) × time (before [versus during] versus after drinking) interactions were not significantly associated with perceived trustworthiness (η2 < 0.001) or oxytocin (η2 = 0.003). Bayes factors provided also substantial evidence for the absence of these effects (BF01 = 3.65; BF01 = 7.53). The group × time interactions were related to dihydrotestosterone (η2 = 0.018 with an increase in the control condition) as well as positive affect and risk-taking (η2 = 0.027 and 0.007 with increases in the alcohol condition), but not significantly to testosterone. DISCUSSION: The results do not verify alcohol effects on perceived trustworthiness or oxytocin in male individuals. However, they indicate that alcohol (versus control) might inhibit an increase in dihydrotestosterone and confirm that alcohol amplifies positive affect and risk-taking. This provides novel mechanistic insight into social facilitation as an alcohol-drinking motive.

Effects of prenatal alcohol exposition on cognitive outcomes in childhood and youth: a longitudinal analysis based on meconium ethyl glucuronide.

BACKGROUND: Prenatal alcohol exposure (PAE) has been linked to severe, adverse child outcomes. However, little is known regarding subclinical outcomes of low/moderate PAE and its longitudinal consequences, especially regarding neurophysiological and neurocognitive development. A newborn biomarker of PAE, meconium ethyl glucuronide (EtG), has been shown to predict cognitive impairments in primary-school-aged children. The current study investigated the ongoing effects of subclinical PAE in adolescence. METHODS: A sample of n = 96 mother-child dyads of the FRAMES/FRANCES cohort were classified into PAE/no PAE using EtG with a 10 ng/g cutoff. Mothers were recruited during pregnancy and children were assessed during primary-school age (M = 7.57, SD = 0.65, range: 6.00-9.92 years) and adolescence (M = 13.26, SD = 0.31, range: 12.79-14.20 years) on three levels: clinical (ADHD rating), neuropsychological (IQ score and performance in a go/nogo task), and neurophysiological (analysis of P3 event-related potentials (ERP) during said go/nogo task). Developmental outcomes and courses following PAE were assessed using rmANCOVAs, controlling for relevant confounders (socioeconomic status (SES), birth weight, and maternal psychopathology). RESULTS: Neurophysiological impairments emerged for exposed children in the form of diminished attentional resource recruiting in childhood and adolescence (reduced go-P3 amplitudes) with no differences in performance. Neuropsychological testing showed a reduced IQ score for both time points with dose-dependent effects in childhood. Clinical ADHD symptoms were not significantly affected. CONCLUSION: Subclinical PAE, as determined by meconium EtG, has negative developmental consequences on cognitive function that persist from childhood to adolescence. These findings suggest that there is no safe limit for alcohol consumption during pregnancy and that more thorough screening of alcohol consumption during pregnancy is necessary for early identification and treatment of at-risk children.

Portable polygraphic device (Somnocheck micro CARDIO®) provides accurate diagnostic information in psychiatric patients at risk for obstructive sleep apnoea: an observational cohort study.

BACKGROUND: Symptoms of obstructive sleep apnoea (OSA) overlap significantly with those of psychiatric disorders, making accurate diagnosis of OSA challenging within psychiatric settings. Diagnosing OSA in psychiatric patients is crucial because untreated OSA can exacerbate psychiatric symptoms, reduce treatment efficacy, and impair overall quality of life. This study aimed to determine the diagnostic accuracy of a readily accessible procedure for psychiatric patients in a real-world clinical setting by comparing the Somnocheck micro CARDIO® (SCm) portable cardiorespiratory polygraphy device with the gold standard polysomnography (PSG). METHODS: This observational cohort study included consecutive psychiatric patients at intermediate to high risk for OSA based on screening with the STOP-Bang questionnaire, admitted to a single tertiary care centre between June 1, 2016 and December 31, 2022. The Apnoea-Hypopnoea-Index (AHI), Apnoea-Index (AI), Oxygen-Desaturation-Index (ODI), and minimum oxygen saturation were measured sequentially by SCm and PSG. RESULTS: A total of 57 patients were analysed (median age 62.0 [Interquartile Range (IQR), 51.5-72.5] years; 34 [59.6%] men). Regarding AHI, no significant differences (AHI measured by PSG, median, 16.6 [IQR, 6.2-26.7] vs. AHI measured by SCm, median, 14.9 [IQR, 10.0-22.8]; p = 0.812; r = 0.71) were found between SCm and PSG. AI, ODI and minimum oxygen saturation differed significantly between SCm and PSG. Using optimised cut-off values (any OSA: AHISCm ≥ 9.25), SCm showed high sensitivity (0.894) and high specificity (0.800) for the diagnosis of OSA, with an area under the receiver operating characteristic curve of 0.877. CONCLUSIONS: This study found that the SCm portable device was accurate in identifying psychiatric patients with OSA. AHI measurement by SCm provided reliable diagnostic performance in comparison with the gold standard polysomnography. These findings support the integration of polygraphic measurements into the routine sleep assessment of psychiatric patients. Early and accurate diagnosis of OSA in this population can significantly improve the management of both sleep disorders and psychiatric conditions, potentially enhancing overall treatment outcomes and quality of life for these patients.

Promoting motivation and reducing stress in medical students by utilizing self-determination theory - a randomized controlled trial in practical psychiatry courses.

BACKGROUND: Medical students experience high levels of stress and related mental health problems. Students' autonomous and controlled motivation and their mental well-being are interconnected. This study aimed to investigate whether an innovative teaching concept based on self-determination theory (SDT) could improve students' motivation and thereby reduce their stress levels, ultimately providing a healthier framework for learning. METHODS: In a week-long practical psychiatry course for medical students, a new didactic concept was implemented in half the groups (n = 73) and compared with the preexisting concept (n = 75) as a randomized controlled trial (RCT). To promote the SDT-target factors of perceived autonomy, competence, and relatedness, the methods used included team building, exclusively positive feedback, group discussions, and choice in task distribution. Significant group differences in motivation, stress, performance, and their relationships were analyzed through t-tests, multiple linear regression analyses, mediation analyses, and hierarchical linear modeling (HLM) using questionnaires collected before (t0) and after (t1) the course, and students' exam results (t2). RESULTS: In the innovation group (n = 53), intrinsic motivation/interest (d = 0.41; p = .019) and perceived choice/autonomy (d = 0.33; p = .048) were greater than in the control group (n = 52). While autonomous regulation remained stable, the innovation group showed reduced controlled regulation (d = -0.36; p = .033) and reported significantly lower stress (d = -0.55; p = .003). The observed changes in motivation collectively mediated the stress reduction. However, students in the innovation group achieved lower exam scores, which seemed to result from the absence of critical feedback, but not from the observed differences in motivation or stress. CONCLUSIONS: This study demonstrated that enhancing intrinsic motivation through SDT-based teaching can effectively reduce stress in medical students. Exclusively strengths-based positive feedback may have hindered exam performance, but optimizing educational concepts to promote motivation and reduce stress will be a valuable step toward improving medical students' mental well-being.

Neurofilaments and progranulin are related to atrophy in frontotemporal lobar degeneration - A transdiagnostic study cross-validating atrophy and fluid biomarkers.

INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. METHODS: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. RESULTS: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. DISCUSSION: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. HIGHLIGHTS: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.

Brain Region-Specific Expression Levels of Synuclein Genes in an Acid Sphingomyelinase Knockout Mouse Model: Correlation with Depression-/Anxiety-Like Behavior and Locomotor Activity in the Absence of Genotypic Variation.

Accumulating evidence suggests an involvement of sphingolipids, vital components of cell membranes and regulators of cellular processes, in the pathophysiology of both Parkinson's disease and major depressive disorder, indicating a potential common pathway in these neuropsychiatric conditions. Based on this interaction of sphingolipids and synuclein proteins, we explored the gene expression patterns of α-, ß-, and γ-synuclein in a knockout mouse model deficient for acid sphingomyelinase (ASM), an enzyme catalyzing the hydrolysis of sphingomyelin to ceramide, and studied associations with behavioral parameters. Normalized Snca, Sncb, and Sncg gene expression was determined by quantitative PCR in twelve brain regions of sex-mixed homozygous (ASM-/-, n = 7) and heterozygous (ASM+/-, n = 7) ASM-deficient mice, along with wild-type controls (ASM+/+, n = 5). The expression of all three synuclein genes was brain region-specific but independent of ASM genotype, with ß-synuclein showing overall higher levels and the least variation. Moreover, we discovered correlations of gene expression levels between brain regions and depression- and anxiety-like behavior and locomotor activity, such as a positive association between Snca mRNA levels and locomotion. Our results suggest that the analysis of synuclein genes could be valuable in identifying biomarkers and comprehending the common pathological mechanisms underlying various neuropsychiatric disorders.

Peripheral Upregulation of Parkinson's Disease-Associated Genes Encoding α-Synuclein, ß-Glucocerebrosidase, and Ceramide Glucosyltransferase in Major Depression.

Due to the high comorbidity of Parkinson's disease (PD) with major depressive disorder (MDD) and the involvement of sphingolipids in both conditions, we investigated the peripheral expression levels of three primarily PD-associated genes: α-synuclein (SNCA), lysosomal enzyme ß-glucocerebrosidase (GBA1), and UDP-glucose ceramide glucosyltransferase (UGCG) in a sex-balanced MDD cohort. Normalized gene expression was determined by quantitative PCR in patients suffering from MDD (unmedicated n = 63, medicated n = 66) and controls (remitted MDD n = 39, healthy subjects n = 61). We observed that expression levels of SNCA (p = 0.036), GBA1 (p = 0.014), and UGCG (p = 0.0002) were higher in currently depressed patients compared to controls and remitted patients, and expression of GBA1 and UGCG decreased in medicated patients during three weeks of therapy. Additionally, in subgroups, expression was positively correlated with the severity of depression and anxiety. Furthermore, we identified correlations between the gene expression levels and PD-related laboratory parameters. Our findings suggest that SNCA, GBA1, and UGCG analysis could be instrumental in the search for biomarkers of MDD and in understanding the overlapping pathological mechanisms underlying neuro-psychiatric diseases.

Clinical significance of plasma candidate biomarkers of Alzheimer's Disease.

The number of patients with Alzheimer's Disease (AD) has increased rapidly in recent decades. AD is a complex progressive neurodegenerative disease affecting c.14 million patients in Europe and the United States. The hallmarks of this disease are neurotic plaques composed of the amyloid-ß (Aß) peptide and neurofibrillary tangles formed of hyperphosphorylated tau protein (pTau). To date, four CSF biomarkers: amyloid beta 42 (Aß42), Aß42/40 ratio, Tau protein, and Tau phosphorylated at threonine 181 (pTau181) have been validated as core neurochemical AD biomarkers. Imaging biomarkers are valuable for AD diagnosis, although they suffer from limitations in their cost and accessibility, while CSF biomarkers require lumbar puncture. Thus, there is an urgent need for alternative, less invasive and more cost-effective biomarkers capable of diagnosing and monitoring AD progression in a clinical context, as well as expediting the development of new therapeutic strategies. This review assesses the potential clinical significance of plasma candidate biomarkers in AD diagnosis. We conclude that these proteins might hold great promise in identifying the pathological features of AD. However, the future implementation process, and validation of the assays' accuracy using predefined cut-offs across more diverse patient populations, are crucial in establishing their utility in daily practice.

Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice.

Major depressive disorder (MDD) is a severe disease of unknown pathogenesis that will affect ∼10% of people during their lifetime. Therapy for MDD requires prolonged treatment and often fails, predicating a need for novel treatment strategies. Here, we report increased ceramide levels in the blood plasma of MDD patients and in murine stress-induced models of MDD. These blood plasma ceramide levels correlated with the severity of MDD in human patients and were independent of age, sex, or body mass index. In addition, intravenous injection of anti-ceramide antibodies or neutral ceramidase rapidly abrogated stress-induced MDD, and intravenous injection of blood plasma from mice with MDD induced depression-like behavior in untreated mice, which was abrogated by ex vivo preincubation of the plasma with anti-ceramide antibodies or ceramidase. Mechanistically, we demonstrate that ceramide accumulated in endothelial cells of the hippocampus of stressed mice, evidenced by the quantitative measurement of ceramide in purified hippocampus endothelial cells. We found ceramide inhibited the activity of phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus. Finally, we show intravenous injection of PLD or phosphatidic acid abrogated MDD, indicating the significance of this pathway in MDD pathogenesis. Our data indicate that ceramide controls PLD activity and phosphatidic acid formation in hippocampal endothelial cells and thereby mediates MDD. We propose that neutralization of plasma ceramide could represent a rapid-acting targeted treatment for MDD.

The acid sphingomyelinase/ceramide system in COVID-19.

Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of "old" drugs against COVID-19.

Amyloid-ß levels and cognitive trajectories in non-demented pTau181-positive subjects without amyloidopathy.

Phosphorylated Tau181 (pTau181) in CSF and recently in plasma has been associated with Alzheimer's disease. In the absence of amyloidopathy, individuals with increased total Tau levels and/or temporal lobe atrophy experience no or only mild cognitive decline compared with biomarker-negative controls, leading to the proposal to categorize this constellation as suspected non-Alzheimer's disease pathophysiology (SNAP). We investigated whether the characteristics of SNAP also applied to individuals with increased CSF-pTau181 without amyloidopathy. In this long-term observational study, 285 non-demented individuals, including 76 individuals with subjective cognitive impairment and 209 individuals with mild cognitive impairment, were classified based on their CSF levels of pTau181 (T), total Tau (N), amyloid-ß42 (Aß42) and Aß42/Aß40 ratio (A) into A+T+N±, A+T-N±, A-T+N±, and A-T-N-. The longitudinal analysis included 154 subjects with a follow-up of more than 12 months who were followed to a median of 4.6 years (interquartile range = 4.3 years). We employed linear mixed models on psychometric tests and region of interest analysis of structural MRI data. Cognitive decline and hippocampal atrophy rate were significantly higher in A+T+N± compared to A-T+N±, whereas there was no difference between A-T+N± and A-T-N-. Furthermore, there was no significant difference between A-T+N± and controls in dementia risk [hazard ratio 0.3, 95% confidence interval (0.1, 1.9)]. However, A-T+N± and A-T-N- could be distinguished based on their Aß42 and Aß40 levels. Both Aß40 and Aß42 levels were significantly increased in A-T+N± compared to controls. Long term follow-up of A-T+N± individuals revealed no evidence that this biomarker constellation was associated with dementia or more severe hippocampal atrophy rates compared to controls. However, because of the positive association of pTau181 with Aß in the A-T+N± group, a link to the pathophysiology of Alzheimer's disease cannot be excluded in this case. We propose to refer to these individuals in the SNAP group as 'pTau and Aß surge with subtle deterioration' (PASSED). The investigation of the circumstances of simultaneous elevation of pTau and Aß might provide a deeper insight into the process under which Aß becomes pathological.

Matrix metalloproteinase 10 is linked to the risk of progression to dementia of the Alzheimer's type.

Alzheimer's disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer's disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer's type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer's type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 (MMP-10) showed a higher probability of progressing to dementia of the Alzheimer's type and a faster cognitive decline. CSF MMP-10 increased the prediction accuracy of CSF amyloid-ß 42 (Aß42), phospho-tau 181 (P-tau181) and total tau (T-tau) for conversion to dementia of the Alzheimer's type. Including MMP-10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aß42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aß42, P-tau181 and T-tau. MMP-10 was correlated with age in subjects with normal Aß42, P-tau181 and T-tau levels. Our findings support the use of CSF MMP-10 as a prognostic marker for dementia of the Alzheimer's type and its inclusion in the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of MMP-10 may reflect ageing and neuroinflammation.

Sex-specific association between prenatal androgenization (second-to-fourth digit length ratio) and frontal brain volumes in adolescents.

Prenatal androgenization associates sex-dependently with behavior and mental health in adolescence and adulthood, including risk-taking, emotionality, substance use, and depression. However, still little is known on how it affects underlying neural correlates, like frontal brain control regions. Thus, we tested whether prenatal androgen load is sex-dependently related to frontal cortex volumes in a sex-balanced adolescent sample. In a cross-sectional magnetic resonance imaging study, we examined 61 adolescents (28 males, 33 females; aged 14 or 16 years) and analyzed associations of frontal brain region volumes with the second-to-fourth digit length ratio (2D:4D), an established marker for prenatal androgenization, using voxel-based morphometry in a region-of-interest approach. Lower 2D:4D (indicative of higher prenatal androgen load) correlated significantly with smaller volumes of the right anterior cingulate cortex (r-ACC; ß = 0.45) in male adolescents and with larger volumes of the left inferior frontal gyrus orbital part (l-IFGorb; ß = - 0.38) in female adolescents. The regression slopes of 2D:4D on the r-ACC also differed significantly between males and females. The study provides novel evidence that prenatal androgenization may influence the development of the frontal brain in a sex- and frontal brain region-specific manner. These effects might contribute to the well-known sex differences in risk-taking, emotionality, substance use, and depression. Future research is needed to elucidate the role of prenatal androgenization within the biopsychosocial model.

Prevalence of COVID-19 and Psychotropic Drug Treatment in Psychiatric In-patients in Germany in 2020: Results from a Nationwide Pilot Survey.

INTRODUCTION: In patients with a pre-existing mental disorder, an increased risk for a first manifestation of a psychiatric disorder in COVID-19 patients, a more severe course of COVID-19 and an increased mortality have been described. Conversely, observations of lower COVID-19 incidences in psychiatric in-patients suggested protective effects of psychiatric treatment and/or psychotropic drugs against COVID-19. METHODS: A retrospective multi-center study was conducted in 24 German psychiatric university hospitals. Between April and December 2020 (the first and partly second wave of COVID-19), the effects of COVID-19 were assessed on psychiatric in-patient care, the incidence and course of a SARS-CoV-2 infection, and treatment with psychotropic drugs. RESULTS: Patients (n=36,322) were admitted to the hospitals. Mandatory SARS-CoV-2 tests before/during admission were reported by 23 hospitals (95.8%), while 18 (75%) conducted regular testing during the hospital stay. Two hundred thirty-two (0.6%) patients were tested SARS-CoV-2-positive. Thirty-seven (16%) patients were receiving medical treatment for COVID-19 at the psychiatric hospital, ten (4.3%) were transferred to an intermediate/intensive care unit, and three (1.3%) died. The most common prescription for SARS-CoV-2-positive patients was for second-generation antipsychotics (n=79, 28.2%) and antidepressants (SSRIs (n=38, 13.5%), mirtazapine (n=36, 12.9%) and SNRIs (n=29, 10.4%)). DISCUSSION: Contrary to previous studies, our results showed a low number of infections and mortality in SARS-CoV-2-positive psychiatric patients. Several preventive measures seem effective to protect this vulnerable group. Our observations are compatible with the hypothesis of a protective effect of psychotropic drugs against COVID-19 as the overall mortality and need for specific medical treatment was low.

Psychometric properties of the German Penn Alcohol Craving Scale.

Craving for alcohol is an important diagnostic criterion in alcohol use disorder (AUD) and an established predictor of future relapse. The 5-item Penn Alcohol Craving Scale (PACS) is one of the most widely used questionnaires to quantify craving and has been translated into different languages. It is assumed that the PACS constitutes one factor, although theoretical considerations suggest an additional second factor. We conducted stability and factor analyses (principal component and confirmatory factor analyses) of the German PACS (PACS-G) in samples of patients with AUD from the following three German study sites: Erlangen, N = 188 (mean age: 47.1 years, 43.5% female); Mannheim, N = 440 (45.5 years, 28.6% female); Hannover, N = 107 (48.1 years, 48.6% female). In our samples, the 2-factor solution of the PACS-G version is more stable than the internationally assumed 1-factor solution. The resulting two PACS-G subscores 'difficulty to resist' (items 4 and 5) and 'thoughts about alcohol' (items 1, 2, and 3) have an internal consistency (Cronbach's alpha) of 0.80 ≤ α ≤ 0.90, m = 0.86 and 0.86 ≤ α ≤ 0.91, m = 0.89 with an overlap of R2 = 62%. We found good convergent validity assessed via the Craving Automatized Scale-Alcohol and the Obsessive-Compulsive Drinking Scale, but also correlations with depression and anxiety assessed via the Beck's Depression and Anxiety Inventories. This study is the first to provide evidence for a 2-factor solution ('difficulty to resist' and 'thoughts about alcohol') underlying the PACS-G version.

Genetic variants in the genes of the sex steroid hormone metabolism and depressive symptoms during and after pregnancy.

PURPOSE: The aim of this study was to conduct an association analysis of depressive symptoms and polymorphisms in the ESR1, PGR, CYP19A1, and COMT genes in pregnant and postpartum women. METHODS: The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for assessment of maternal and fetal health. The German version of the 10-item Edinburgh Postnatal Depression Scale (EPDS) was completed at three time points in this prospective cohort study. Visit 1 was at study entry in the third trimester of pregnancy, visit 2 was shortly after birth, and visit 3 was 6-8 months after birth. Germline DNA and depression measurements from 361 pregnant women were available for analysis. Six single nucleotide polymorphisms (SNPs) in the above-mentioned genes were genotyped. After reconstruction of haplotypes for PGR (rs1042838 and rs10895068) and CYP19A1 (rs10046 and rs4646), a multifactorial linear mixed model was applied to the data to describe the association between haplotypes and depression values. The single SNPs for ESR1 (rs488133) and COMT (rs4680) were analyzed separately using linear mixed models analogously. RESULTS: The mean antepartum EPDS measurement was 5.1, the mean postpartal measurement after 48-72 h was 3.5, and the mean value 6-8 months postpartum was 4.2. The SNPs in PGR were reconstructed into three haplotypes. The most common haplotype was GG, with 63.43% of patients carrying two copies and 33.52% carrying one copy. For haplotype GA, the group of carriers of two copies (0.28%) was combined with the carriers of one copy (9.70%). Haplotype reconstruction using CYP19A1 SNPs resulted in three haplotypes. The most common haplotype was TC, with 25.48% of patients carrying two copies and 51.52% one copy. None of the haplotype blocks and neither of the two single SNPs showed any significant associations with EPDS values. CONCLUSIONS: The candidate haplotypes analyzed in PGR and CYP19A1 and single SNPs in ESR1 and COMT did not show any association with depression scores as assessed by EPDS in this cohort of healthy unselected pregnant women.

Relationship of serum beta-synuclein with blood biomarkers and brain atrophy.

BACKGROUND: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). METHODS: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores. RESULTS: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy. DISCUSSION: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations. HIGHLIGHTS: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL).