Association between benzodiazepine receptor agonist use and mortality in patients hospitalised for COVID-19: a multicentre observational study.

AIMS: To examine the association between benzodiazepine receptor agonist (BZRA) use and mortality in patients hospitalised for coronavirus disease 2019 (COVID-19). METHODS: A multicentre observational study was performed at Greater Paris University hospitals. The sample involved 14 381 patients hospitalised for COVID-19. A total of 686 (4.8%) inpatients received a BZRA at hospital admission at a mean daily diazepam-equivalent dose of 19.7 mg (standard deviation (s.d.) = 25.4). The study baseline was the date of admission, and the primary endpoint was death. We compared this endpoint between patients who received BZRAs and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, medical comorbidities and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW). RESULTS: Over a mean follow-up of 14.5 days (s.d. = 18.1), the primary endpoint occurred in 186 patients (27.1%) who received BZRAs and in 1134 patients (8.3%) who did not. There was a significant association between BZRA use and increased mortality both in the crude analysis (hazard ratio (HR) = 3.20; 95% confidence interval (CI) = 2.74-3.74; p < 0.01) and in the IPW analysis (HR = 1.61; 95% CI = 1.31-1.98, p < 0.01), with a significant dose-dependent relationship (HR = 1.55; 95% CI = 1.08-2.22; p = 0.02). This association remained significant in sensitivity analyses. Exploratory analyses indicate that most BZRAs may be associated with an increased mortality among patients hospitalised for COVID-19, except for diazepam, which may be associated with a reduced mortality compared with any other BZRA treatment. CONCLUSIONS: BZRA use may be associated with an increased mortality among patients hospitalised for COVID-19, suggesting the potential benefit of decreasing dose or tapering off gradually these medications when possible.

Individual differences in inflammatory and oxidative mechanisms of stress-related mood disorders.

Emotional stress leads to the development of peripheral disorders and is recognized as a modifiable risk factor for psychiatric disorders, particularly depression and anxiety. However, not all individuals develop the negative consequences of emotional stress due to different stress coping strategies and resilience to stressful stimuli. In this review, we discuss individual differences in coping styles and the potential mechanisms that contribute to individual vulnerability to stress, such as parameters of the immune system and oxidative state. Initial differences in inflammatory and oxidative processes determine resistance to stress and stress-related disorders via the alteration of neurotransmitter content in the brain and biological fluids. Differences in coping styles may serve as possible predictors of resistance to stress and stress-related disorders, even before stressful conditions. The investigation of natural variabilities in stress resilience may allow the development of new methods for preventive medicine and the personalized treatment of stress-related conditions.

Correlation of CSF- and MRI-Biomarkers and Progression of Cognitive Decline in an Open Label MCI Trial.

BACKGROUND: In several randomized controlled trials (RCT) acetylcholinesterase-inhibitors (AChE-I) were tested in patients with mild cognitive impairment (MCI) but were ineffective in delaying disease progression as determined by neuropsychological testing only. Here we present data from an open label observational extension of a multicenter RCT in order to assess if biomarkers are providing useful additional information about a drug's efficacy. We followed 83 amnestic MCI patients and performed correlational analyses of Aß 1-42 and total-Tau in the cerebrospinal fluid (CSF), hippocampal and amygdala volume at baseline, the total duration of blinded and open label AChE-I treatment and the outcome 24 months after inclusion into the RCT. Twelve out of 83 amnestic MCI (14%) had progressed to Alzheimer's disease (AD). Overall, worsening and disease progression as measured by the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) and Clinical Dementia Rating (CDR) did not correlate with the duration of AChE-I treatment. However, a specific multidimensional biomarker profile at baseline indicated more reliably than cognitive testing alone progression to AD. We conclude that pharmacological RCTs testing symptomatic treatment effects in MCI should include biomarker assessment.

Epigenetic control of epilepsy target genes contributes to a cellular memory of epileptogenesis in cultured rat hippocampal neurons.

Hypersynchronous neuronal excitation manifests clinically as seizure (ictogenesis), and may recur spontaneously and repetitively after a variable latency period (epileptogenesis). Despite tremendous research efforts to describe molecular pathways and signatures of epileptogenesis, molecular pathomechanisms leading to chronic epilepsy remain to be clarified. We hypothesized that epigenetic modifications may form the basis for a cellular memory of epileptogenesis, and used a primary neuronal cell culture model of the rat hippocampus to study the translation of massive neuronal excitation into persisting changes of epigenetic signatures and pro-epileptogenic target gene expression. Increased spontaneous activation of cultured neurons was detected 3 and 7 days after stimulation with 10 µM glutamate when compared to sham-treated time-matched controls using calcium-imaging in vitro. Chromatin-immunoprecipitation experiments revealed short-term (3 h, 7 h, and 24 h) and long-term (3 d and 2 weeks) changes in histone modifications, which were directly linked to decreased expression of two selected epilepsy target genes, e.g. excitatory glutamate receptor genes Gria2 and Grin2a. Increased promoter methylation observed 4 weeks after glutamate stimulation at respective genes suggested long-term repression of Gria2 and Grin2a genes. Inhibition of glutamatergic activation or blocking the propagation of action potentials in cultured neurons rescued altered gene expression and regulatory epigenetic modifications. Our data support the concept of a cellular memory of epileptogenesis and persisting epigenetic modifications of epilepsy target genes, which are able to turn normal into pro-epileptic neurons and circuits.

Prenatal and adult androgen activities in alcohol dependence.

OBJECTIVE: Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. METHOD: We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). RESULTS: The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P < 0.001) and alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P < 0.005). Moreover, stress levels (P = 0.002), alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). CONCLUSION: Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence.

Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment.

Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ɛ4 (apolipoprotein E-ɛ4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.

Association of Common Polymorphisms in the Nicotinic Acetylcholine Receptor Alpha4 Subunit Gene with an Electrophysiological Endophenotype in a Large Population-Based Sample.

Variation in genes coding for nicotinic acetylcholine receptor (nAChR) subunits affect cognitive processes and may contribute to the genetic architecture of neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in the CHRNA4 gene that codes for the alpha4 subunit of alpha4/beta2-containing receptors have previously been implicated in aspects of (mostly visual) attention and smoking-related behavioral measures. Here we investigated the effects of six synonymous but functional CHRNA4 exon 5 SNPs on the N100 event-related potential (ERP), an electrophysiological endophenotype elicited by a standard auditory oddball. A total of N = 1,705 subjects randomly selected from the general population were studied with electroencephalography (EEG) as part of the German Multicenter Study on nicotine addiction. Two of the six variants, rs1044396 and neighboring rs1044397, were significantly associated with N100 amplitude. This effect was pronounced in females where we also observed an effect on reaction time. Sequencing of the complete exon 5 region in the population sample excluded the existence of additional/functional variants that may be responsible for the observed effects. This is the first large-scale population-based study investigation the effects of CHRNA4 SNPs on brain activity measures related to stimulus processing and attention. Our results provide further evidence that common synonymous CHRNA4 exon 5 SNPs affect cognitive processes and suggest that they also play a role in the auditory system. As N100 amplitude reduction is considered a schizophrenia-related endophenotype the SNPs studied here may also be associated with schizophrenia outcome measures.

[Remember, Avert, Prevent: Franz Ludwig Berthold Kihn--A Typology of "Euthanasia"]. / Erinnern, Verhindern, Vorbeugen: Zur Typologie des Umgangs mit "Euthanasie" am Beispiel des T4-Gutachters Franz Ludwig Berthold Kihn.

BACKGROUND: The current debate on assisted suicide provides the occasion for calling to mind the role of Berthold Kihn as a psychiatrist under National Socialism. With a historical presentation of a typology of euthanasia, the Academic Psychiatry of Erlangen together with the Medical Ethics would like to sensitize discussions on assisted suicide by drawing attention to the start and end of Kihn's scientific career. METHOD: Relevant archive material, primary and secondary literature were analyzed and evaluated. RESULTS: As Assistant and Senior Physician at the Psychiatric and Neurological Hospital of the University of Erlangen, Kihn lectured on "the elimination of the inferiors". As Director of the Psychiatric and Neurological Hospital of Jena University, Kihn selected psychiatric patients to be murdered under the "T4 action". Kihn participated in drafting a "Euthanasia Law". Despite his involvement in the murder of mentally ill, Kihn returned to Erlangen as a "Soviet Zone refugee", where a Denazification Court considered him a "hanger-on". Kihn was reintegrated in the academic faculty of the Friedrich-Alexander-University and headed a private clinic. On 21.01.1963, the State's Attorney Nuremberg-Fuerth dropped the criminal procedure against Kihn--officially due to a lack of proof of punishable guilt. DISCUSSION: An appropriate medical historical contextualization can represent an important condition for an adequate medical ethical debate on physician-assisted suicide and the involvement of psychiatrists. FINAL COMMENT: The analysis of Kihn's patterns of thought and argumentation can help sensitize those involved in debates on physician-assisted suicide and highlights the critical role of psychiatry as a discipline in this context.

[Evidence-based health services research--a short review and implications]. / Versorgungsforschung--evidenzbasiert Ein Kurzüberblick und Implikationen.

BACKGROUND: Health services research aims to generate knowledge about care processes of people with illnesses who access health-care services. In addition, the consequences of those processes in the care routine concerning the involved persons and the health system are analyzed. CONCEPT OF THE THEORETICAL WORK: In the first part of the manuscript, an overview concerning the current definitions and subsumptions of the concept of health services research is given. The second part of the manuscript focuses on demonstrating how evidence-based health services research can be used to enable optimization of the care system. The concept is called the "circle of care optimization". In the first step the current care situation concerning its deficits and their reasons is analyzed. In the second step a relevant care goal is defined. In the third step an improvement of an existing care process is developed to achieve the defined care goal. In the fourth step, a comparative empirical study with a high-quality study design is carried out, to assess whether the improved care process is superior to the current care as usual. A health economic evaluation will be performed if applicable. If the results show no or only small advantages, the "circle" starts again with step 3. However, if the results show a significant effect in favour of the new care process and are relevant for the delivery of care and efficient in the context of health economics, a fifth step will be performed which involves developing and testing strategies for implementation. Where relevant, the consequences of implementation are investigated in a sixth step. A "best-practice" practical example is demonstrated to illustrate the "circle of care optimization". CONCLUSIONS: conclusions are derived by illustrating future challenges for health services research.

αCaMKII controls the establishment of cocaine's reinforcing effects in mice and humans.

Although addiction develops in a considerable number of regular cocaine users, molecular risk factors for cocaine dependence are still unknown. It was proposed that establishing drug use and memory formation might share molecular and anatomical pathways. Alpha-Ca(2+)/calmodulin-dependent protein kinase-II (αCaMKII) is a key mediator of learning and memory also involved in drug-related plasticity. The autophosphorylation of αCaMKII was shown to accelerate learning. Thus, we investigated the role of αCaMKII autophosphorylation in the time course of establishing cocaine use-related behavior in mice. We found that αCaMKII autophosphorylation-deficient αCaMKII(T286A) mice show delayed establishment of conditioned place preference, but no changes in acute behavioral activation, sensitization or conditioned hyperlocomotion to cocaine (20 mg kg(-1), intraperitoneal). In vivo microdialysis revealed that αCaMKII(T286A) mice have blunted dopamine (DA) and blocked serotonin (5-HT) responses in the nucleus accumbens (NAcc) and prefrontal cortex after acute cocaine administration (20 mg kg(-1), intraperitoneal), whereas noradrenaline responses were preserved. Under cocaine, the attenuated DA and 5-HT activation in αCaMKII(T286A) mice was followed by impaired c-Fos activation in the NAcc. To translate the rodent findings to human conditions, several CAMK2A gene polymorphisms were tested regarding their risk for a fast establishment of cocaine dependence in two independent samples of regular cocaine users from Brazil (n=688) and Switzerland (n=141). A meta-analysis across both samples confirmed that CAMK2A rs3776823 TT-allele carriers display a faster transition to severe cocaine use than C-allele carriers. Together, these data suggest that αCaMKII controls the speed for the establishment of cocaine's reinforcing effects.

[The "Erlangen System" of open care: a tribute to Gustav Kolb (1870-1938)]. / Das "Erlanger System" der offenen Fürsorge: Eine Würdigung Gustav Kolbs (1870-1938).

BACKGROUND: This year marks the 80th anniversary of the forced retirement (1st March 1934) of Gustav Kolb (1870 - 1938). He is considered the founder of the "Erlangen System" of open care. The following article pays tribute to Gustav Kolb's "life's work", by delineating the formation, active period and the fall of his "Erlangen system" in its historical context. METHOD: Relevant archive materials and secondary literature were assessed. RESULTS: Beginning in 1914, Gustav Kolb, as Director of the Mental Asylum in Erlangen (1911 - 1934) introduced the care of the emotionally ill in their own families. In 1930, 4200 of the 770 000 residents in a catchment area covering about 3200 square kilometers were being treated in open care. The "Erlangen system" was the largest organisation of its kind in Germany. Although Gustav Kolb was inspired by eugenic ideas, he opposed the national-socialist health politics. Kolb withdrew professionally in 1933 and died five years later. DISCUSSION: The situation in the tense area of open care between helping institutions for and controlling bodies over emotionally ill people was relatively balanced in the Weimar Republic. Later, Gustav Kolb's organisational thoroughness, with its creation of a central register of people under open care in the Erlangen system, provided considerable biogenetic information. Tragically, this was abused as an important source in carrying out the national-socialist law for prevention of genetically-impaired offspring (14.7.1933). Several aspects contributed to the misfortune that Kolb's liberal system could be distorted to a recording instrument by the National Socialists. Final Comment: Individual efforts to reestablish open care facilities after 1945 were not implemented. It was not until during the socio-psychiatric movement of the 1960 s that Kolb's concept could achieve a renaissance, although it was unnamed and unrecognised at the time.

[Adolf Abraham Gustav Bingel (1901-1982): pioneer of electroconvulsive treatment in Germany]. / Adolf Abraham Gustav Bingel (1901-1982): Pionier der Elektrokonvulsionsbehandlung in Deutschland.

INTRODUCTION: Adolf Bingel, internal medicine specialist, neurologist and psychiatrist, was a pioneer in the establishment of electroconvulsive treatment (ECT) in Germany. Thanks to his dedication, the psychiatric department of the University of Erlangen was Germany's first clinic to offer ECT. METHODS: We have analysed relevant archival material and the secondary literature. RESULTS: As a consequence of denazification, Adolf Bingel was classified as a hanger-on by the Tribunal in Heidelberg. In 1946 the accredited German scientist moved to Houston as a "Paperclip-Boy". DISCUSSION: The ECT-pioneer Bingel has repeatedly been mistaken for the co-inventor of pneumo-encephalograpy, whose name was also Adolf Bingel. This confusion in names has to be corrected. CONCLUSION: In 1957 Bingel was awarded the title Associate Professor Emeritus by the University of Erlangen. In 1959 he became Associate Professor of Neurology/Baylor University College in Houston/Texas.

Long-term use of flupirtine leads to withdrawal symptoms and is associated with dependency.

This is the case of a 44-year-old woman, who was treated as an inpatient because of withdrawal symptoms like sweating, tremors, sleeping disorders and irritability after long-term use of flupirtine. She recovered by symptom-based application of pipamperone within 72 h after flupirtine cessation.

Sphingolipids in psychiatric disorders and pain syndromes.

Despite the high prevalence and devastating impact of psychiatric disorders, little is known about their etiopathology. In this review, we provide an overview on the participation of sphingolipids and enzymes responsible for their metabolism in mechanisms underlying psychiatric disorders. We focus on the pathway from sphingomyelin to proapoptotic ceramide and the subsequent metabolism of ceramide to sphingosine, which is in turn phosphorylated to yield anti-apoptotic sphingosine-1-phosphate (S1P).The sphingomyelinase/ceramide system has been linked to effects of reactive oxygen species and proinflammatory cytokines in the central nervous system as well as to synaptic transmission. Compared to ubiquitously expressed acid sphingomyelinase, acid and neutral ceramidase and neutral sphingomyelinase are highly active in brain regions. Depressed patients show elevated plasma ceramide levels and increased activities of acid sphingomyelinase which is functionally inhibited by many anti-depressive drugs. Exposure to alcohol is associated with an activation of acid and neutral sphingomyelinase observed in cell culture, mouse models and in alcohol-dependent patients and with increased concentrations of ceramide in various organs.Levels of sphingomyelin and ceramide are altered in erythrocytes and post-mortem brain tissues of schizophrenic patients in addition to changes in expression patterns for serine palmitoyltransferase and acid ceramidase leading to impaired myelination. After induction of anxiety-like behavior in animal models, higher serum levels of S1P were reported to lead to neurodegeneration. Correspondingly, S1P infusion appeared to increase anxiety-like behavior. Significantly upregulated levels of the endogenous ceramide catabolite N,N-dimethylsphingosine were observed in rat models of allodynia. Conversely, rats injected intrathecally with N,N-dimethylsphingosine developed mechanical allodynia. Moreover, S1P has been implicated in spinal nociceptive processing.The increasing interest in lipidomics and improved analytical methods led to growing insight into the connection between psychiatric and neurological disorders and sphingolipid metabolism and may once provide new targets and strategies for therapeutic intervention.

[Germany's unique panoptical asylum--an appreciation of the first Bavarian mental home in Erlangen]. / Die einzige "panoptische" Anstalt Deutschlands: Eine Würdigung der "Kreis-Irrenanstalt Erlangen"

INTRODUCTION: There are only two edifices left that represent one of the most impressive cultural monuments of mental homes in Middle Europe. Government and institutions are removing these historical buildings to establish a modern "Translational Research Centre". Our objective is to illustrate the significance of the asylum in the history of psychiatric architecture. METHODS: In the context of the history of psychiatry we analysed and interpreted relevant primary sources, secondary literature and selected illustrations. RESULTS: Several panoptical asylums were built in Great Britain. In France, Italy and Germany, a unique example was realised. The entire ward could be checked from a central room. This ensured the optimal surveillance of the patients and enabled the minimisation of staff. In contrast to the vicinal emergent industrial cities Erlangen disposed of enough building ground. There, Johann Michael Leupoldt (1794-1874) gave lectures dealing only with psychiatry. Thanks to his advice, the first Bavarian mental home was completed within only 12 years. The cruciform floor plan was supplemented by cross buildings. This constituted a relevant modification of the panoptical system. DISCUSSION: Although the "H-design" has been evaluated as more adequate, the obsolete architectural "concept of rays" was chosen for the asylum in Erlangen. Did financial distress play a decisive role? Neither the files nor Leupoldt's autobiography take a firm stand on this point. CONCLUSION: As the TRC-project may serve as a document for future medical progress, it is important to remember the "Kreis-Irrenanstalt Erlangen" as a milestone in the evolution of psychiatric architecture.