Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD): an in vitro study

<p>Abstract</p> <p>Background</p> <p>The catecholaminergic and serotonergic neurotransmitter systems are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The amino acid tyrosine is the precursor for synthesis of the catecholamines dopamine and norepinephrine, while tryptophan is the precursor of serotonin. A disturbed transport of tyrosine, as well as other amino acids, has been found in a number of other psychiatric disorders, such as schizophrenia, bipolar disorder and autism, when using the fibroblast cell model. Hence, the aim of this study was to explore whether children with ADHD may have disturbed amino acid transport.</p> <p>Methods</p> <p>Fibroblast cells were cultured from skin biopsies obtained from 14 boys diagnosed with ADHD and from 13 matching boys without a diagnosis of a developmental disorder. Transport of the amino acids tyrosine, tryptophan and alanine across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (<it>V_max</it>) and affinity constant (<it>K_m</it>) were determined. Any difference between the two groups was analyzed by Student's unpaired <it>t</it>-test or the Mann Whitney U test.</p> <p>Results</p> <p>The ADHD group had significantly decreased <it>V_max</it>(p = 0.039) and <it>K_m</it>(increased affinity) (p = 0.010) of tryptophan transport in comparison to controls. They also had a significantly higher <it>V_max</it>of alanine transport (p = 0.031), but the <it>Km </it>of alanine transport did not differ significantly. There were no significant differences in any of the kinetic parameters regarding tyrosine transport in fibroblasts for the ADHD group.</p> <p>Conclusions</p> <p>Tryptophan uses the same transport systems in both fibroblasts and at the blood brain barrier (BBB). Hence, a decreased transport capacity of tryptophan implies that less tryptophan is being transported across the BBB in the ADHD group. This could lead to deficient serotonin access in the brain that might cause disturbances in both the serotonergic and the catecholaminergic neurotransmitter systems, since these systems are highly interconnected. The physiological importance of an elevated transport capacity of alanine to the brain is not known to date.</p

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Peripheral Amino Acid Levels in Schizophrenia and Antipsychotic Treatment

Abnormal levels of amino acids have been reported in patients with schizophrenia and have also been investigated as a biomarker to monitor antipsychotic treatment, however results have been inconsistent. The purpose of the present review is to summarize the evidence in the literature of whether amino acid levels can be a biomarker and predict the treatment outcome in schizophrenia. The current review does not support amino acid concentration as a useful biomarker for monitoring antipsychotic response in patients with schizophrenia, although there is evidence that high levels of serum homocysteine and glutamate might be considered as a trait marker for schizophrenia. This review has also highlighted a considerable dearth of studies, specifically of studies evaluating antipsychotic side-effects

13C-phenylalanine breath test detects altered phenylalanine kinetics in schizophrenia patients

Phenylalanine is an essential amino acid required for the synthesis of catecholamines including dopamine. Altered levels of phenylalanine and its metabolites in blood and cerebrospinal fluid have been reported in schizophrenia patients. This study attempted to examine for the first time whether phenylalanine kinetics is altered in schizophrenia using L-[1-13C]phenylalanine breath test (13C-PBT). The subjects were 20 chronically medicated schizophrenia patients (DSM-IV) and the same number of age- and sex-matched controls. 13C-phenylalanine (99 atom% 13C; 100 mg) was administered orally and the breath 13CO2 /12CO2 ratio was monitored for 120 min. The possible effect of antipsychotic medication (risperidone (RPD) or haloperidol (HPD) treatment for 21 days) on 13C-PBT was examined in rats. Body weight (BW), age and diagnostic status were significant predictors of the area under the curve of the time course of Δ13CO2 (‰) and the cumulative recovery rate (CRR) at 120 min. A repeated measures analysis of covariance controlled for age and BW revealed that the patterns of CRR change over time differed between the patients and controls and that Δ13CO2 was lower in the patients than in the controls at all sampling time points during the 120 min test, with an overall significant difference between the two groups. Chronic administration of RPD or HPD had no significant effect on 13C-PBT indices in rats. Our results suggest that 13C-PBT is a novel laboratory test that can detect altered phenylalanine kinetics in chronic schizophrenia patients. Animal experiments suggest that the observed changes are unlikely to be attributable to antipsychotic medication

Gene expression biomarkers of response to citalopram treatment in major depressive disorder

There is significant variability in antidepressant treatment outcome, with ∼30–40% of patients with major depressive disorder (MDD) not presenting with adequate response even following several trials. To identify potential biomarkers of response, we investigated peripheral gene expression patterns of response to antidepressant treatment in MDD. We did this using Affymetrix HG-U133 Plus2 microarrays in blood samples, from untreated individuals with MDD (N=63) ascertained at a community outpatient clinic, pre and post 8-week treatment with citalopram, and used a regression model to assess the impact of gene expression differences on antidepressant response. We carried out technical validation of significant probesets by quantitative reverse transcriptase PCR and conducted central nervous system follow-up of the most significant result in post-mortem brain samples from 15 subjects who died during a current MDD episode and 11 sudden-death controls. A total of 32 probesets were differentially expressed according to response to citalopram treatment following false discovery rate correction. Interferon regulatory factor 7 (IRF7) was the most significant differentially expressed gene and its expression was upregulated by citalopram treatment in individuals who responded to treatment. We found these results to be concordant with our observation of decreased expression of IRF7 in the prefrontal cortex of MDDs with negative toxicological evidence for antidepressant treatment at the time of death. These findings point to IRF7 as a gene of interest in studies investigating genomic factors associated with antidepressant response

The Human Serum Metabolome

Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca

Working according to the ACT model : Specialist nurse experience of her skills in the team

Bakgrund: ACT- modellen växte fram under 70 och 80-talet i samband med att många psykiatriska kliniker stängdes i USA. Den ursprungliga ACT- modellen kan ses som en fullservicemodell men har sedan modifierats och anpassats efter samhällets och sjukvårdens rådande förhållanden. Som det ser ut idag så har flera modeller utvecklats med utgångspunkt från ACT-modellen men kan särskiljas av vilka komponenter som ingår. Modellen har visat positiva resultat avseende patienters delaktighet och återhämtning. Sjuksköterskan har en bred yrkesbakgrund och anses ha en viktig roll i teamet. Med sin kompetens har de grundläggande kunskaper för att utföra medicinsk och psykiatrisk omvårdnad men flera studier har visat att det finns ett behov av specialistutbildade sjuksköterskor då många av patienterna är svårt sjuka. Syfte: Syftet var att beskriva psykiatriska specialistsjuksköterskors erfarenheter av sin kompetens och roll i team som arbetar enligt ACT-modellen Metod: En kvalitativ design har valts. Datainsamling skedde med semi-strukturerade intervjuer. En kvalitativ innehållsanalys med induktiv ansats användes för att bearbeta materialet. Resultat: Innehållsanalysen resulterade i två huvudkategorier, Kompetensen med in i teamet samt Den mångsidiga sjuksköterskan, med tillhörande sex underkategorier. Diskussion: Resultatet diskuterades utifrån de två huvudkategorierna Kompetensen med in i teamet och Den mångsidiga sjuksköterskan. Som stöd i diskussionen användes till ämnet relevanta artiklar och litteratur samt Phil Barkers tio förpliktelser som utgångspunkt.Background: The ACT model developed in the 70's and 80's when many psychiatric clinics were closed in the United States. The original ACT model can be seen as a full service model but has since been modified and adapted to the current conditions of society and health care. As it appears today, several models have been developed based on the ACT model but can be distinguished by which components are included. The model has shown positive results regarding patient participation and recovery. The nurse has a wide professional background and is considered to be an important part of the team. With their skills, they have the basic knowledge to perform medical and psychiatric care, but several studies have shown that there is a need for specialist educated nurses, as many of the patients are severely ill. Aim: The aim of this study was to describe the psychiatric specialist nurse's experience of their competence and role in teams working under the ACT model. Method: A qualitative design has been selected. Data collection was done with semi-structured interviews. A qualitative content analysis with inductive approach was used to process the material. Results: The content analysis resulted in two main categories, skills in the team and the versatile nurse, with six associated subcategories. Discussions: The result was discussed based on the two main categories, skills in the team and the versatile nurse. In support of the discussion, relevant topics and literature were used as well as Phil Barker's ten obligations as a starting point