Spiroergometrie bei Patienten mit pulmonaler Hypertonie infolge einer Lungenfibrose, primärer pulmonaler Hypertonie, chronisch thromboembolischer pulmonaler Hypertonie und cystischer Fibrose

Die Spiroergometrie ist eine nichtinvasive Messmethode, die ein Verfahren bezeichnet, bei dem unter ergometrischer Belastung die Ventilation und der Gasaustausch gemessen wird. Mit dieser Untersuchungsmethode können die allgemeine körperliche Leistungsfähigkeit und die Zusammenhänge zwischen der Belastung und der Herzförderleistung, dem Sauerstoffverbrauch und der Ventilation der Lunge aufgezeigt werden. Wir haben 11 Patienten mit einer pulmonalen Hypertonie infolge einer Lungenfibrose (LF) mit 11 „gematchten“ gesunden Kontrollpersonen, 39 Patienten mit einer cystischen Fibrose (CF) mit 13 „gematchten“ gesunden Kontrollpersonen und 21 Patienten mit einer primären pulmonalen Hypertonie (PPH) mit 16 Patienten mit einer chronisch thromboembolischen pulmonalen Hypertonie (CTEPH) mittels Spiroergometrie und Blutgasanalyse untersucht und miteinander verglichen. So konnten wir die leistungslimitierenden Faktoren kardialer, ventilatorischer, metabolischer oder kardiorespiratorischer Art bei den untersuchten Gruppen vergleichen. Durch Korrelationsanalysen mit Lungenfunktions- bzw. Hämodynamikparametern wurde geprüft, welche Ruheparameter einen Vorhersagewert für die maximale Sauerstoffaufnahme (peak VO2) haben. Darüberhinaus wurden die komplexen Gasaustauschstörungen der Erkrankungen beschrieben und es wurden die Unterschiede zwischen Patienten mit primärer pulmonaler Hypertonie (PPH) und Patienten mit chronisch thromboembolischer pulmonaler Hypertonie (CTEPH) untersucht. Bei LF Patienten war die peak VO2 auf 46% der Norm signifikant gegenüber den Kontrollpersonen reduziert. Die Leistungslimitierung beruhte überwiegend auf ventilatorischen Faktoren, weiterhin aber auch auf zirkulatorische Faktoren, eingeschränkte Atmungseffektivität, erniedrigte Diffusionskapazität und Ventilations-Perfusions-Verteilungsstörungen Diese schweren Störungen im Gasaustausch führen zu enormer Totraumventilation einerseits und Hypoxämie andererseits, die beide zu der stark eingeschränkten peak VO2 beitragen. Bei unseren CF Patienten war die peak VO2 auf 73% der Norm signifikant gegenüber den Kontrollpersonen reduziert. Die Leistungslimitierung beruhte auf eingeschränkte Lungenfunktionsparameter (Einsekundenausatmungskapazität, Vitalkapazität und Resistance), erniedrigte Körpergröße und Körpergewicht und erniedrigter Diffusionskapazität. Weiterhin zeigten die Patienten eine erhöhte Totraumventilation und ein erhöhtes Atemäquivalent für CO2. CF Patienten weisen also erhebliche Gasaustauschstörungen auf, die zu gesteigerter Totraumventilation und zu Hypoxämie führen. Bei den PPH Patienten war die peak VO2 auf 55% der Norm und bei den CTEPH Patienten auf 43% der Norm reduziert. Die Patienten wiesen eine zirkulatorische Leistungslimitierung auf. Bei unseren PPH Patienten korrelierten der mittlere pulmonal-arterielle Druck, der zentral venöse Druck, die zentral venöse Sauerstoffsättigung, die arterielle Sauerstoffsättigung, und der Cardiac Index als hämodynamische Ruheparameter signifikant mit der peak VO2. Bei den CTEPH Patienten korrelierte dagegen keiner der hämodynamischen Ruheparameter signifikant mit der peak VO2. CTEPH Patienten wiesen eine signifikant höheres EQCO2 auf als PPH Patienten. Bei den PPH Patienten korrelierte dieser Parameter am besten mit der peak VO2. Dahingegen korrelierte dieser bei den CTEPH Patienten nicht mit der peak VO2. Als bester Parameter zur Unterscheidung zwischen PPH und CTEPH Patienten erwies sich die alveolo-arterielle CO2-Differenz (AaDCO2). PPH Patienten zeigten eine AaDCO2 von ca. 0,57% und CTEPH Patienten von 1,15% in Ruhe. Wenn eine AaDCO2 von >1% als Marker einer CTEPH zugrundegelegt wird, so erlaubt dieser die Abgrenzung von einer PPH mit einer Spezifität von 95% und einer Sensitivität von 75%. Bei maximaler Belastung betrug die AaDCO2 bei den PPH Patienten 0,52% und bei den CTEPH Patienten 1,31%. Wenn nun eine AaDCO2 ebenfalls von >1% als Marker einer CTEPH zugrundegelegt wird, so erlaubt dieser die Abgrenzung von einer PPH mit einer Spezifität von 90% und einer Sensitivität von 88%. So lassen sich PPH Patienten und CTEPH Patienten in Ruhe und unter maximaler Belastung mit relativ hoher Sensitivtät und Spezifität voneinander unterscheiden. Insgesamt erwies sich die Spiroergometrie bei Patienten mit schweren bronchialen, parenchymatösen und vaskulären Lungenkrankheiten als sichere und zuverlässige Methode zur Erfassung der maximalen Sauerstoffaufnahme und der leistungslimitierenden Faktoren

Overconfidence in incorrect perceptual judgments in patients with schizophrenia

Background: Patients with schizophrenia show overconfidence in memory and social cognition errors. The present investigation examined whether this cognitive distortion also manifests in perceptual tasks. Methods: A total of 55 individuals with schizophrenia, 58 with obsessive–compulsive disorder (OCD) as well as 45 non-clinical controls were presented 24 blurry black and white pictures, half of which contained a hidden object; the other half contained (“snowy”) visual noise. Participants had to judge whether the pictures depicted an object or not and how confident they were in this judgment. Results: Participants with schizophrenia showed overconfidence in errors and an enhanced knowledge corruption index (i.e. rate of high-confident errors on all high-confident responses) relative to both control groups. In contrast, accuracy scores did not differ between clinical groups. Metacognitive parameters were correlated with self-rated levels of current paranoia. Discussion: To the best of our knowledge, this is the first study to demonstrate overconfidence in errors among individuals with psychosis using a visual perception task. Speaking to the specificity of this abnormality for schizophrenia and its pathogenetic relevance, overconfidence in errors and knowledge corruption were elevated in patients with schizophrenia relative to both control groups and were correlated with paranoia

Bias against disconfirmatory evidence in the 'at-risk mental state' and during psychosis

Prior studies have confirmed a bias against disconfirmatory evidence (BADE) in schizophrenia which has been associated with delusions. However, its role in the pathogenesis of psychosis is yet unclear. The objective was to investigate BADE for the first time in subjects with an at-risk-mental-state for psychosis (ARMS), patients with a first episode of psychosis without antipsychotic treatment (FEP) and healthy controls (HC). A standard BADE test presenting written scenarios was employed. In addition, psychometric rating scales and a neuropsychological test battery were applied. A three-staged image was revealed. FEP-patients showed a significant BADE compared to the other groups. The performance of ARMS-patients lay in between HC and FEP-patients. A trend towards significance became evident for a bias against confirmatory evidence (BACE) in FEP-patients. Results were not attributable to antipsychotic or other medication or depressive symptoms. Correlations with delusions reached medium effect sizes but failed significance after Bonferroni-corrections. These results provide evidence for aberrations in evidence integration in the pathogenesis of psychosis and contribute to our knowledge of metacognitive functioning which can be used for (meta-)cognitive intervention in psychosis

A randomized double-blind controlled trial to assess the benefits of amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill schizophrenia patients (COMBINE): methods and design

This report presents the rationale and design of a multi-center clinical trial that examines the efficacy and safety of antipsychotic combination treatment in acutely ill schizophrenia patients compared to antipsychotic monotherapy. Antipsychotic combination treatment is common in clinical practice worldwide, despite clinical guidelines generally not recommending such practice due to lacking evidence for its efficacy and safety. Olanzapine has a related chemical structure and comparable receptor-binding profile as clozapine, which demonstrated superior efficacy in combination studies, but has a more unfavorable side-effect profile compared to olanzapine. Amisulpride and olanzapine have shown promising therapeutic efficacy in meta-analyses in monotherapy for people with schizophrenia. Combining amisulpride and olanzapine, complementary receptor-binding properties may enhance efficacy and possibly reduce (or at least not augment) side effects due to the different receptor profiles and metabolization pathways. Accordingly, we hypothesize that patients treated with amisulpride plus olanzapine show greater improvement on the Positive and Negative Syndrome Scale total score after 8 weeks versus either monotherapy. A randomized, double-blind controlled trial is performed at 16 German centers comparing flexibly dosed monotherapy of oral amisulpride (400-800 mg/day), and olanzapine (10-20 mg/day) and amisulpride-olanzapine co-treatment. Sample size was calculated to be n = 101 per treatment arm, assuming an effect size of 0.500 and a two-sided alpha = 0.025 and beta = 0.90. Recruitment for this trial started in June 2012. Until December 2018, 328 patients have been randomized. Trial conduct has been extended to reach the projected sample size. Publication of the study results is expected in 2019 informing an evidence-based recommendation regarding specific antipsychotic combination treatment

Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial

Background Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy. Methods A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20. Findings Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40.2 years (SD 11.7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29.6 [SD 14.5]) than in the olanzapine plus placebo group (-24.1 [13.4], p=0.049, Cohen's d=0.396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25.2 [SD 15 .9], p=0.095, Cohen's d=0.29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment). Interpretation The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered. Copyright (C) 2022 Elsevier Ltd. All rights reserved