Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia

The atypical antipsychotic clozapine is one of the most potent drugs of its class, yet its precise mechanisms of action remain insufficiently understood. Recent evidence points toward the involvement of endogenous retinoic acid (RA) signaling in the pathophysiology of schizophrenia. Here we investigated whether clozapine may modulate RA-signaling. Effects of clozapine on the catabolism of all-trans RA (at-RA), the biologically most active metabolite of Vitamin A, were assessed in murine and human brain tissue and peripheral blood-derived mononuclear cells (PBMC). In patients with schizophrenia with and without clozapine treatment and matched healthy controls, at-RA serum levels and blood mRNA expression of retinoid-related genes in PBMCs were quantified. Clozapine and its metabolites potently inhibited RA catabolism at clinically relevant concentrations. In PBMC-derived microsomes, we found a large interindividual variability of the sensitivity toward the effects of clozapine. Furthermore, at-RA and retinol serum levels were significantly lower in patients with schizophrenia compared with matched healthy controls. Patients treated with clozapine exhibited significantly higher at-RA serum levels compared with patients treated with other antipsychotics, while retinol levels did not differ between treatment groups. Similarly, in patients without clozapine treatment, mRNA expression of RA-inducible targets CYP26A and STRA6, as well as at-RA/retinol ratio, were significantly reduced. In contrast, clozapine-treated patients did not differ from healthy controls in this regard. Our findings provide the first evidence for altered peripheral retinoid homeostasis in schizophrenia and suggest modulation of RA catabolism as a novel mechanism of action of clozapine, which may be useful in future antipsychotic drug development

Association between Pupillary Unrest Index (PUI) and waking EEG activity

Hintergrund: Die Aufzeichnung und Analyse des spontanen Pupillenverhaltens im Dunkeln (Langzeitpupillographie) im Rahmen des pupillographischen Schläfrigkeitstests (PST) hat sich im Verlauf der letzten Jahre als eine vielversprechende, zeitlich und personell ökonomische Methode zur Bestimmung des zentralnervösen Aktivierungsniveaus herausgestellt. Ziel der vorliegenden Studie war eine weitergehende Prüfung der Validität der Langzeitpupillographie zur Erfassung des zentralnervösen Aktivierungsniveaus anhand der Untersuchung der Assoziation zwischen pupillographischen Parametern, subjektiven Schläfrigkeitsmaßen und spezifischen Korrelaten des zentralnervösen Aktivierungsniveaus im Wach-EEG. Methode: Bei 24 jungen gesunden Probanden erfolgte in einem von 21:00-23:00 Uhr des nachfolgenden Tages andauernden Experiment im Verlauf einer insgesamt 40-stündigen Schlafdeprivation zeitgleich zu einer kontinuierlichen Aufzeichnung des Wach-EEG zu definierten Messzeitpunkten eine Erhebung des subjektiven Schläfrigkeitsgrades mittels der Stanford Sleepiness Scale (SSS) und der Visuellen Analogskala zu Wachheit und Leistungsfähigkeit (VAS) sowie des zentralnervösen Aktivierungsniveaus mittels Langzeitpupillographie. Als pupillographisches Maß des zentralnervösen Aktivierungsniveaus wurde der Pupillen-Unruhe-Index (PUI, mm/min) gewählt. 5-s -EEG-Epochen, die simultan zur Langzeitpupillographie abgeleitet worden waren, wurden einer Spektralanalyse unterzogen; für die statistische Datenanalyse wurden Amplitudenspektralwerte als artefaktfrei gewerteter 5-s-EEG-Epochen der Ableitung C4-(A1+A2)/2 ausgewählt. Die Ergebnisse von 6 Probanden wurden aufgrund einer zu hohen Anzahl fehlender Werte von einer weiteren Analyse ausgeschlossen. Ergebnisse: Die nichtparametrische Varianzanalyse mit Messwiederholung ergab signifikante Änderungen des PUI, des subjektiven Schläfrigkeitsgrades anhand der SSS und VAS sowie der Aktivität im Delta- (1,5-5,5 Hz), Theta- (5,5-8,5 Hz), Alpha1- (8,5-10 Hz), Beta1- (12-18 Hz) sowie Beta3- (21-30 Hz) Frequenzbereich im Zeitverlauf. Für den PUI ließ sich aufgrund des im Vergleich zu vorangegangenen Studien längeren Beobachtungszeitraums neben einem deutlichen Anstieg mit zunehmender Dauer der Wachzeit erstmals eine trotz ausgeprägten homöostatischen Schlafdrucks vorliegende circadiane Modulation mit lokalem Minimum in den Abendstunden aufzeigen. Zu Zeitpunkten des niedrigsten im Vergleich zu Zeitpunkten des höchsten zentralnervösen Aktivierungsniveaus definiert anhand des PUI fanden sich signifikant höhere subjektive Schläfrigkeitswerte anhand der SSS und VAS sowie signifikante Zunahmen der Aktivität im Delta-, Theta-, Alpha1- sowie Beta1-Frequenzbereich. Die Berechnung intraindividueller Korrelationen nach Spearman ergab eine mit einem mittleren Korrelationskoeffizienten von ρ=0,523±0,280 bzw. ρ=0,502±0,318 signifikant positive Assoziation zwischen PUI und SSS- bzw. VAS-Werten sowie eine signifikant positive Assoziation zwischen PUI und der Aktivität im Delta- (ρ=0,589±0,227), Theta- (ρ=0,616±0,198) sowie Alpha1- (ρ=0,527±0,304) Frequenzbereich. Schlussfolgerungen: Die in der vorliegenden Studie erstmals für gesunde Probanden nachgewiesene enge Assoziation pupillographischer Parameter des zentralnervösen Aktivierungsniveaus mit spezifischen Korrelaten des zentralnervösen Aktivierungsniveaus im Wach-EEG erweitert die bisher vorliegenden Untersuchungen testtheoretischer Gütekriterien des PST und untermauert die Validität der Langzeitpupillographie als objektives Verfahren zur Erfassung des zentralnervösen Aktivierungsniveaus.Introduction: In recent years there has been growing interest in the use of pupillography as an objective and time-saving method to measure daytime sleepiness. The aim of the present study was to further elucidate the validity of pupillography as a measure of sleepiness by investigating the association of pupillometric variables with subjective sleepiness and waking EEG activity. Methods: 24 young healthy adults participated in the study. In an experiment lasting from 9 p.m. to 11 p.m. the following day a test battery including the assessment of subjective sleepiness and pupillography was performed at regular time intervals during 40 h of sustained wakefulness. Subjective sleepiness was assessed using the Stanford Sleepiness Scale (SSS) and a Visual Analogue Scale (VAS). Spontaneous pupillary oscillations were recorded by means of infrared video pupillography and Pupillary Unrest Index (PUI; mm/min) was calculated. Waking EEG activity was recorded continuously at different electrode positions using a Vitaport system. 5-s epochs recorded during pupillography were visually inspected for artifacts and subjected to spectral analysis; the results presented refer to epochs selected from the C4-(A1+A2)/2 derivation. The recordings of 6 subjects had to be excluded from further analysis due to missing data. Results: Nonparametric analysis of variance for repeated measurements revealed significant variations over time in PUI, SSS, VAS, and power in the delta (1.5-5.5 Hz), theta (5.5-8.5 Hz), alpha1 (8.5-10 Hz), beta1 (12-18 Hz), and beta3 (21-30 Hz) frequency range. Due to the longer period of sleep deprivation as compared to previous studies for the first time a prominent circadian modulation of PUI under high homeostatic sleep pressure was shown. At time points of maximum PUI indicating a high level of sleepiness significant increases were found in subjective sleepiness as well as in delta, theta, alpha1, and beta1 power. Relating in individual subjects changes in PUI to changes in subjective sleepiness and waking EEG activity revealed a significant positive intra-individual correlation between PUI and subjective sleepiness (SSS: ρ=0.523±0.280; VAS: ρ=0.502±0.318) as well as between PUI and power in the delta (ρ=0.589±0.227), theta (ρ=0.616±0.198) and alpha1 (ρ=0.527±0.304) frequency band. Conclusions: The novel finding of a close association between pupillometric variables and distinct changes in waking EEG activity further supports the validity of pupillography as an objective method to assess the level of sleepiness

A simple approach to optimum pool size for pooled SARS-CoV-2 testing

Systematic, large-scale testing of asymptomatic subjects is an important strategy in the management of the SARS-CoV-2 pandemic. In order to increase the capacity of laboratory-based molecular SARS-CoV-2 testing, it has been suggested to combine several samples and jointly measure them in a sample pool. While saving cost and labour at first sight, pooling efficiency depends on the pool size and the presently experienced prevalence of positive samples. Here we address the question of the optimum pool size at a given prevalence. We demonstrate the relation between analytical effort and pool size and delineate the effects of the target prevalence on the optimum pool size. Finally, we derive a simple-to-use formula and table that allow laboratories performing sample pooling to assess the optimum pool size at the currently experienced target prevalence rate

Anti-inflammatory effects of minocycline are mediated by retinoid signaling

Abstract Background Minocycline is a lipophilic tetracycline of increasing appeal in neuroscience as it inhibits microglial activation, a mechanism involved in numerous neuropsychiatric disorders. Own data point towards retinoid-mediated effects of minocycline in murine brain and skin, and towards a vicious cycle of neuroinflammation which is driven by microglial activation-induced breakdown of local retinoids such as retinoic acid (RA). We therefore sought to study minocycline’s anti-inflammatory effects on human microglial-like monocyte-derived cells in the context of retinoid signaling. Results As hypothesized, minocycline exposure resulted in a substantial increase of RA levels in the human monocytic cell line THP-1. While pro-inflammatory stimulation with lipopolysaccharides resulted in increased tryptophane-degrading indoleamine-2,3-dioxygenase IDO-expression and TNF-α levels in primary human monocyte-derived microglial-like cells, this effect was attenuated by minocycline only in the presence of retinoids. The anti-inflammatory effects of minocycline on TNF-α expression were completely abolished by a pharmacological blockage of retinoic acid receptors (RARs) using BMS-493 and unaffected by selectively blocking retinoid-X-receptors using UVI-3003. Conclusions Our data indicate for the first time a RA-dependent, anti-inflammatory effect for minocycline in human microglial-like cells via inhibition of local RA turnover. The RA-dependent mode of action for minocycline appears to be predominantly mediated through RAR-signaling

Effect of environmental extremely low-frequency electromagnetic fields exposure on inflammatory mediators and serotonin metabolism in a human neuroblastoma cell line

Exposure to environmental extremely low-frequency electromagnetic fields (ELF-EMF) in everyday life is increasing and it is a matter of great debate whether exposure to ELF-EMF can be harmful to human health. The neuropathology and symptoms of neurodegenerative disease depends on factors involving other than genetic predispositions, such as environmental exposure to disease-related risk factors. Research focusing on a possible contribution of ELF-EMF to cell injury and to the development of neurodegenerative disorders is characterized by conflicting data from epidemiological and animal studies. Due to lack of a direct link between neurodegenerative processes and ELF-EMF exposure, our goal was to investigate if ELF-EMF exposure may represent a possible risk factor. In the present study, using neuronal-like SH-SY5Y neuroblastoma cells, we show that the balance between generation and elimination of reactive oxygen species, as well as the balance between pro- and anti-inflammatory cytokines linked to oxidative stress, was maintained ensuring that cells respond properly to ELF-EMF (50Hz /1mT). In SH-SY5Y-exposed cells we observed increased intracellular 5-hydroxyindoleacetic acid/5-hydroxytryptamine ratio reflecting the rate of transmitter synthesis, catabolism and release, while matrix metalloproteinase that play critical roles in neuronal cell death were not significantly altered. The results presented here indicate that changes caused by short (1h-3h) and sub-chronic (48 h) exposure to 50Hz/1mT ELF-EMF in SH-SY5Y cells are minor in comparison to the neuronal cell damage expected to underlie neurodegeneration or cognitive impairment. Thus, these results are in accord with epidemiological studies that have provided little support for a link between ELF-EMFs and neurodegeneration

QUETIAPINE AS COMBINATION TREATMENT WITH CITALOPRAM IN UNIPOLAR DEPRESSION WITH PROMINENT SOMATIC SYMPTOMS: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED PILOT STUDY

Background: Patients with major depressive disorder (MDD) accompanied by physical symptoms may be less responsive to antidepressant treatment. Quetiapine has been evaluated in the treatment of bipolar depression and has been recently approved as an add-on therapy for unipolar depression. Less is known about the efficacy of combination therapies in patients suffering from MDD with somatic symptoms. The aim of the present study was to evaluate the efficacy of quetiapine as adjunctive therapy to the SSRI citalopram in patients with MDD and somatic complaints. Subjects and methods: 41 inpatients with nonpsychotic DSM-IV MDD experiencing significant symptoms of somatic distress as defined by a baseline score on the SCL-90-R somatization subscale greater one standard deviation above adult nonpatient norms were randomly assigned to receive either citalopram 40 mg/day plus placebo (n=20) or citalopram 40 mg/day plus quetiapine, 300 to 600 mg/day (n=21) for 6 weeks. The primary outcome measure was the Hamilton Depression Rating Scale (HDRS) score. Results: Mean changes in HDRS scores from baseline to week 6 using last-observation-carried-forward methods were -12.3±6.2 and -10.7±5.1 in the citalopram-quetiapine and citalopram-placebo group, respectively. Remission rates were significant higher in the citalopram-quetiapine-group (41.1%) than in the citalopram-placebo-group (26.3%), respectively. Conclusions: Although quetiapine as add-on to citalopram did not separate statistically from placebo on the HDRS score in improving depressive symptoms and somatic symptoms in patients with MDD and prominent somatic complaints, higher remission rates and other second outcome parameters showed advantages for quetiapine. Larger, double-blind, placebo-controlled trials of quetiapine as augmentation therapy in MDD with somatic symptoms are warranted

Using routine MRI data of depressed patients to predict individual responses to electroconvulsive therapy

Electroconvulsive therapy (ECT) is one of the most effective treatments in cases of severe and treatment resistant major depression. 60–80% of patients respond to ECT, but the procedure is demanding and robust prediction of ECT responses would be of great clinical value. Predictions based on neuroimaging data have recently come into focus, but still face methodological and practical limitations that are hampering the translation into clinical practice. In this retrospective study, we investigated the feasibility of ECT response prediction using structural magnetic resonance imaging (sMRI) data that was collected during ECT routine examinations. We applied machine learning techniques to predict individual treatment outcomes in a cohort of N = 71 ECT patients, N = 39 of which responded to the treatment. SMRI-based classification of ECT responders and non-responders reached an accuracy of 69% (sensitivity: 67%; specificity: 72%). Classification on additionally investigated clinical variables had no predictive power. Since dichotomisation of patients into ECT responders and non-responders is debatable due to many patients only showing a partial response, we additionally performed a post-hoc regression-based prediction analysis on continuous symptom improvements. This analysis yielded a significant relationship between true and predicted treatment outcomes and might be a promising alternative to dichotomization of patients. Based on our results, we argue that the prediction of individual ECT responses based on routine sMRI holds promise to overcome important limitations that are currently hampering the translation of such treatment biomarkers into everyday clinical practice. Finally, we discuss how the results of such predictive data analysis could best support the clinician's decision on whether a patient should be treated with ECT.ISSN:0014-4886ISSN:1090-243

Anxiety during ketamine infusions is associated with negative treatment responses in major depressive disorder

About 20 to 30 percent of patients with Major Depressive Disorder (MDD) do not respond to standard treatment and are considered treatment-resistant. The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in treatment-resistant MDD, but it is unknown whether its acute psychological effects are related to the later antidepressant effect. Therefore, we investigated the association between antidepressant responses to ketamine and the quality of ketamine-induced psychological experiences in MDD. A total of 31 patients (M = 49.5 ± 11.2 years, 16 women) were treated with three ketamine infusions per week (0.5 mg/ kg over 40 min) administered for two consecutive weeks. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, after four and 24 h and at end of treatment. The 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) was applied four hours after the first infusion to assess the subjective quality of acute psychological effects. Patients with a ≥ 50% MADRS reduction from baseline to end of treatment were considered as responders. After six infusions, 17 of 31 patients (55%) showed a response to ketamine treatment, while 14 patients (45%) had no response. Anxiety-related experiences induced by ketamine were significantly higher in non-responders. Percentage MADRS reduction after four hours and individual levels of ketamine-induced anxiety were predictive of a response at end of treatment. The study demonstrated the considerable impact of ketamine-induced anxiety on the antidepressant efficacy of ketamine. It underpins the importance of considering patients' subjective experiences and underlines the possibility of a phenotypic response predictor