Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis

Rationale: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. Objectives: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. Methods: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. Results: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. Conclusions: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy

IntroductionA titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11–21 ng/ml) that are expected under the approved dose range (10–20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy.MethodsFollowing our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram.ResultsOf 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C).ConclusionBased on our findings, we propose a target range of 20–40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram’s reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873]

The cross-sectional GRAS sample: A comprehensive phenotypical data collection of schizophrenic patients

<p>Abstract</p> <p>Background</p> <p>Schizophrenia is the collective term for an exclusively clinically diagnosed, heterogeneous group of mental disorders with still obscure biological roots. Based on the assumption that valuable information about relevant genetic and environmental disease mechanisms can be obtained by association studies on patient cohorts of ≥ 1000 patients, if performed on detailed clinical datasets and quantifiable biological readouts, we generated a new schizophrenia data base, the GRAS (Göttingen Research Association for Schizophrenia) data collection. GRAS is the necessary ground to study genetic causes of the schizophrenic phenotype in a 'phenotype-based genetic association study' (PGAS). This approach is different from and complementary to the genome-wide association studies (GWAS) on schizophrenia.</p> <p>Methods</p> <p>For this purpose, 1085 patients were recruited between 2005 and 2010 by an invariable team of traveling investigators in a cross-sectional field study that comprised 23 German psychiatric hospitals. Additionally, chart records and discharge letters of all patients were collected.</p> <p>Results</p> <p>The corresponding dataset extracted and presented in form of an overview here, comprises biographic information, disease history, medication including side effects, and results of comprehensive cross-sectional psychopathological, neuropsychological, and neurological examinations. With >3000 data points per schizophrenic subject, this data base of living patients, who are also accessible for follow-up studies, provides a wide-ranging and standardized phenotype characterization of as yet unprecedented detail.</p> <p>Conclusions</p> <p>The GRAS data base will serve as prerequisite for PGAS, a novel approach to better understanding 'the schizophrenias' through exploring the contribution of genetic variation to the schizophrenic phenotypes.</p

V2me - Virtuelles Coaching für Senioren

Eine Herausforderung von alternden Gesellschaften ist die zunehmende Vereinsamung älterer Personen. Als Folge von Todesfällen im sozialen Umkreis, zunehmend mobilen Familien, oder den Wechsel in eine betreute Wohneinrichtung ändern sich die Möglichkeiten zur sozialen Interaktion - die empfundene Einsamkeit nimmt zu. Dies kann sowohl Psyche als auch Physis deutlich belasten. Im Rahmen des Projekts V2me wurde eine Trainingsplattform entwickelt, die über verschiedene technische Geräte in der Lage ist, immersive, virtuelle Trainingslektionen wiederzugeben, die auf verschiedene Webdienste zugreifen können. In einem ersten Schritt wurde diese Plattform speziell darauf zugeschnitten, eine individuelle und digitale Variante des Friendship Enrichment Programs bereitzustellen. Dieses Interventionsprogramm für Senioren vermittelt in Gruppensitzungen Fähigkeiten, die den Teilnehmern ermöglichen neue soziale Kontakte zu gewinnen und bestehende Kontakte besser zu pflegen. In diesem Beitrag stellen wir die technische Infrastruktur vor, und beschreiben im Detail wie diese zu den vorgestellten Zielen beiträgt. One challenge of ageing societies is an increased feeling of loneliness in the older population. Death in the social circles, an increased mobility of family members or moving into assisted living facilities are all potential reasons that may affect the social interaction, and in turn the perceived loneliness. This can negatively affect both psychological and physical well-being. The project V2me has developed a training platform that uses different technical devices to provide immersive, virtual training lessons that can be connected to different web services. As a first step V2me is focused on showcasing a personalized and digital variety of the Friendship Enrichment Program. This intervention program is aimed at seniors and imparts the skills required to create new social contacts and strengthen the relationship to the existing social circle. In this contribution we present the technical infrastructure of V2me and how it is used to tackle the presented challenges

V2me - Virtuelles Coaching für Senioren

Eine Herausforderung von alternden Gesellschaften ist die zunehmende Vereinsamung älterer Personen. Als Folge von Todesfällen im sozialen Umkreis, zunehmend mobilen Familien, oder den Wechsel in eine betreute Wohneinrichtung ändern sich die Möglichkeiten zur sozialen Interaktion - die empfundene Einsamkeit nimmt zu. Dies kann sowohl Psyche als auch Physis deutlich belasten. Im Rahmen des Projekts V2me wurde eine Trainingsplattform entwickelt, die über verschiedene technische Geräte in der Lage ist, immersive, virtuelle Trainingslektionen wiederzugeben, die auf verschiedene Webdienste zugreifen können. In einem ersten Schritt wurde diese Plattform speziell darauf zugeschnitten, eine individuelle und digitale Variante des Friendship Enrichment Programs bereitzustellen. Dieses Interventionsprogramm für Senioren vermittelt in Gruppensitzungen Fähigkeiten, die den Teilnehmern ermöglichen neue soziale Kontakte zu gewinnen und bestehende Kontakte besser zu pflegen. In diesem Beitrag stellen wir die technische Infrastruktur vor, und beschreiben im Detail wie diese zu den vorgestellten Zielen beiträgt. One challenge of ageing societies is an increased feeling of loneliness in the older population. Death in the social circles, an increased mobility of family members or moving into assisted living facilities are all potential reasons that may affect the social interaction, and in turn the perceived loneliness. This can negatively affect both psychological and physical well-being. The project V2me has developed a training platform that uses different technical devices to provide immersive, virtual training lessons that can be connected to different web services. As a first step V2me is focused on showcasing a personalized and digital variety of the Friendship Enrichment Program. This intervention program is aimed at seniors and imparts the skills required to create new social contacts and strengthen the relationship to the existing social circle. In this contribution we present the technical infrastructure of V2me and how it is used to tackle the presented challenges

Personalization of virtual coaching applications using procedural modeling

Virtual coaching is an application area that allows individuals to improve existing skills or learn new ones; it ranges from simple textual tutoring tools to fully immersive 3D learning situations. The latter aim at improving the learning experience with realistic 3D environments. In highly individual training scenarios it can be beneficial to provide some level of personalization of the environment. This can be supported using procedural modeling that allows to easily modify shape, look and contents of an environment. We present the application of personalization using procedural modeling in learning applications in the project V2me. This project combines virtual and social networks to help senior citizens maintain and create meaningful relationships. We present a system that uses a procedurally generated ambient virtual coaching environment that can be adjusted by training subjects themselves or in collaboration. A small user experience study has been executed that gives first insight to the acceptance of such an approach