Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
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Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans
(2016)
In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies.
Neuromelanin granules (NMGs) are organelle-like structures present in the human substantia nigra pars compacta. In addition to neuromelanin, NMGs contain proteins, lipids and metals. As NMG-containing dopaminergic neurons are preferentially lost in Parkinson’s disease and dementia with Lewy bodies (DLB), it is assumed that NMGs may play a role in neurodegenerative processes. Until now, this role is not completely understood and needs further investigation. We therefore set up an exploratory proteomic study to identify differences in the proteomic profile of NMGs from DLB patients (n = 5) compared to healthy controls (CTRL, n = 5). We applied a laser microdissection and mass-spectrometry-based approach, in which we used targeted mass spectrometric experiments for validation. In NMG-surrounding (SN\(_{Surr.}\)) tissue of DLB patients, we found evidence for ongoing oxidative damage and an impairment of protein degradation. As a potentially disease-related mechanism, we found α-synuclein and protein S100A9 to be enriched in NMGs of DLB cases, while the abundance of several ribosomal proteins was significantly decreased. As S100A9 is known to be able to enhance the formation of toxic α-synuclein fibrils, this finding points towards an involvement of NMGs in pathogenesis, however the exact role of NMGs as either neuroprotective or neurotoxic needs to be further investigated. Nevertheless, our study provides evidence for an impairment of protein degradation, ongoing oxidative damage and accumulation of potentially neurotoxic protein aggregates to be central mechanisms of neurodegeneration in DLB.
Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose–concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20–60 ng/ml) is applicable for minors. In the 64 patients (aged 11–18 years) included, a positive correlation between daily dose and the active moiety (RIS\(_{am}\)) concentration was found (r\(_s\) = 0.49, p = 0.001) with variation in dose explaining 24% (r\(_s\)\(^2\) = 0.240) of the variability in serum concentrations. While the RIS\(_{am}\) concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RIS\(_{am}\) concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RIS\(_{am}\) was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.
Trotz verbesserter Evidenzbasis bestehen in der kinder- und jugendpsychiatrischen Pharmakotherapie viele Unsicherheiten über die Wirkung und Verträglichkeit der häufig off-label oder in Kombinationstherapie verordneten Medikamente. Gerade auch vor dem Hintergrund der in vielen Fällen notwendigen mittel- bis langfristigen Einnahme sollen unerwünschte Arzneimittelwirkungen in dieser Altersstufe möglichst minimiert und eine auf die individuellen Charakteristika der Patientin oder des Patienten zugeschnittene, effektive Dosierung gefunden werden. Kinder und Jugendliche scheinen nicht nur besonders anfällig für bestimmte unerwünschte Arzneimittelwirkungen, sondern sind auch iatrogenen Risiken durch Dosierungs- oder Applikationsfehler ausgesetzt, die zu Unter- oder Überdosierungen führen können mit entsprechend negativen Auswirkungen auf den Therapieerfolg. Neben einer strengen Indikationsstellung sind daher eine präzise Dosisfindung sowie systematische Überwachung der Sicherheit der Psychopharmakotherapie unverzichtbar. In diesem Artikel wird Therapeutisches Drug Monitoring als hilfreiches klinisches Instrument vorgestellt und beschrieben, wie dessen richtige Anwendung sowohl die Wirksamkeit als auch die Sicherheit und Verträglichkeit einer Psychopharmakotherapie im Kindes- und Jugendalter zum unmittelbaren Nutzen für die Patientinnen und Patienten verbessern kann.
The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington’s and Alzheimer’s diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders.
Universal prevention for non-suicidal self-injury in adolescents is scarce - A systematic review
(2023)
Non-suicidal self-injury (NSSI) during adolescence is a high-risk marker for the development and persistence of mental health problems and has been recognized as a significant public health problem. Whereas targeted prevention has indeed shown to be effective in reducing NSSI and improve mental health problems, access to such programs is limited. By face validity, universal prevention of NSSI seems an ideal starting point for a stepped-care model to circumvent a lack of resources in the medical care system. However, it is yet unclear how effective such approaches are. Here, we provide a summary of existing work on universal prevention of NSSI in adolescents younger than 21 years based on a systematic literature search. We found that only seven studies are available. None of the programs evaluated was found to be effective in reducing the incidence or frequency of NSSI. After providing a comprehensive summary of the existing work, we evaluate the fact that existing work primarily focusses on selected/targeted prevention and on psychoeducational methods. We derive implications for future directions in the field of universal prevention of NSSI.