A Bibliometric and Visual Analysis of Single Nucleotide Polymorphism Studies in Depression.

BACKGROUND: Genetic polymorphism has been proven to have an important association with depression, which can influence the risk of developing depression, the efficacy of medications, and adverse effects via metabolic and neurological pathways. Nonetheless, aspects of the association between single nucleotide polymorphisms and depression have not been systematically investigated by bibliometric analysis. OBJECTIVE: The aim of this study was to analyze the current status and trends of single nucleotide polymorphism research on depression through bibliometric and visual analysis. METHODS: The Web of Science Core Collection was used to retrieve 10,043 articles that were published between 1998 and 2021. CiteSpace (6.1 R4) was used to perform collaborative network analysis, co-citation analysis, co-occurrence analysis, and citation burst detection. RESULTS: The most productive and co-cited journals were the Journal of Affective Disorders and Biological Psychiatry, respectively, and an analysis of the references showed that the most recent research focused on the largest thematic cluster, "5-HT", reflecting the important research base in this area. "CYP2D6" has been in the spotlight since its emergence in 2009 and has become a research hotspot since its outbreak in 2019. However, "BDNF ", "COMT ", "older adults", "loci", and "DNA methylation" are also the new frontier of research, and some of them are currently in the process of exploration. CONCLUSION: These findings offer a useful perspective on existing research and potential future approaches in the study of the association between single nucleotide polymorphisms and depression, which may assist researchers in selecting appropriate collaborators or journals.

Factors influencing concentrations of risperidone and 9-hydroxyrisperidone in psychiatric outpatients taking immediate-release formulations of risperidone.

OBJECTIVES: To analyze the factors affecting the concentrations of the active moiety of risperidone (RIS) and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in psychiatric outpatients taking immediate-release formulations. METHODS: This is a retrospective study on the therapeutic drug monitoring (TDM) data regarding RIS and 9-OH-RIS in adult psychiatric outpatients. TDM data with simultaneous RIS and 9-OH-RIS monitoring from March 2018 to February 2020 and relevant medical records (including dosage, dosage form, sex, age, diagnosis, combined medication, and comorbid disease) from 399 adult psychiatric outpatients (223 males and 176 females) were included in this study. RESULTS: The daily dose of RIS was 5.56 ± 2.05 mg, the concentration of total active moiety was 42.35 ± 25.46 ng/mL, and the dose-adjusted plasma concentration (C/D) of active moiety was 7.83 ± 3.87 (ng/ml)/(mg/day). Dose, sex, and age were identified as important factors influencing concentrations of RIS and 9-OH-RIS in adult psychiatric outpatients. CONCLUSIONS: Individualized medication adjustments should be made according to the specific conditions of psychiatric outpatients. The findings strongly support the use of TDM to guide dosing decisions in psychiatric outpatients taking RIS.

Pluronic P85 decreases the delivery of phenytoin to the brain in drug-resistant rats with P-glycoprotein overexpressed chronic mesial temporal lobe epilepsy.

P-glycoprotein (Pgp) overexpressed in blood brain barrier (BBB) is hypothesized to lower brain drug concentrations and thus inhibit anticonvulsant effects in drug-resistant epilepsy. Pluronic P85 (P85) was proved to enhance the delivery of drugs into the brain by inhibition of Pgp. To determine whether the surfactant P85 [versus Pgp inhibitor tariquidar (TQD)] enhance phenytoin (PHT) into the brain in drug-resistant rats with chronic mesial temporal lobe epilepsy (MTLE) induced by lithium-pilocarpine, in brain of which Pgp were overexpressed, then direct verification of PHT transport via measurement of PHT concentration in brain using microdialysis. The drug-resistant model rats were randomly divided into three groups, which were treated with PHT, 1%P85 + PHT, or PHT+TQD, respectively. 1%P85 + PHT treatment displayed a lower ratio of the area under the curve (AUC) of the PHT concentration in the brain/plasma even than that of the PHT treatment in model rats (p < 0.05), while PHT+TQD showed the highest ratio of the AUC of all treatments. However, the ratio of the PHT concentration in the liver/plasma was similar in three model groups (p > 0.05). For the ratio of the kidney/plasma, PHT+TQD treatment model group had the highest ratio of the other treatments in model rats. Thus, P85 oppositely decreased PHT concentration in brain in drug-resistant model rats with Pgp overexpressed MTLE while TQD could increase PHT distribution in brain.

Development and validation of an LC-MS/MS method by one-step precipitation for cinacalcet in human plasma.

A sensitive, convenient, rapid and economic liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to determine cinacalcet concentration in human plasma. A stable isotope cinacalcet (cinacalcet-D3) was selected as internal standard and the analytes were extracted from plasma samples by a one-step precipitation procedure. Chromatography separation was conducted on an Eclipse Plus C18 column by gradient elution with mobile phase of methanol-water-ammonium formate system at a constant flow rate of 0.6 mL/min. Mass spectrometric detection was conducted by multiple reaction monitoring using positive electrospray ionization. Cinacalcet concentrations in human plasma were determined over the concentration range of 0.1-50 ng/mL. The accuracies of lower limit of quantification (LLOQ) and quality control samples were all within the range of 85-115%, and the inter- and intra-batch precisions (CV%) were all within 15%. The average extraction recovery rates were 95.67-102.88%, and the quantification was not interfered by the matrix components. The validated method was successfully applied to determined cinacalcet concentrations in human plasma from secondary hyperparathyroidism patients.

Comprehensive Approach to Assessment of Liver Viability During Normothermic Machine Perfusion.

Liver transplantation is the most effective treatment of advanced liver disease, and the use of extended criteria donor organs has broadened the source of available livers. Although normothermic machine perfusion (NMP) has become a useful tool in liver transplantation, there are no consistent criteria that can be used to evaluate the viability of livers during NMP. This review summarizes the criteria, indicators, and methods used to evaluate liver viability during NMP. The shape, appearance, and hemodynamics of the liver can be analyzed at a macroscopic level, while markers of liver injury, indicators of liver and bile duct function, and other relevant indicators can be evaluated by biochemical analysis. The liver can also be assessed by tissue biopsy at the microscopic level. Novel methods for assessment of liver viability are introduced. The limitations of evaluating liver viability during NMP are discussed and suggestions for future clinical practice are provided.

Deleterious effect in endothelin receptor-mediated coronary artery smooth muscle contractility in high-salt diet rats.

BACKGROUND AND AIMS: High-salt diet has been suggested to increase the risk of heart disease. However, the mechanisms underlying coronary artery tension dysfunction caused by high-salt diet are unclear. Previous studies have shown that coronary artery spasm is often induced by endothelin-1 (ET-1) and thromboxane, leading to myocardial ischemia, while the store-operated Ca2+ entry (SOCE) function of coronary smooth muscle is very important in this process. METHODS AND RESULTS: Tension measurements of endothelium-denuded coronary artery ring segments showed that vasocontraction induced by U46619, ET-1, orSTIM1/Orai1-mediated SOCE was significantly lower in 4% high-salt diet rats than in control rats fed a regular diet. The results of western blotting and immunohistochemistry assays showed lower expression levels of endothelial receptors ETA and ETB, STIM1 and Orai1 in coronary artery of high-salt intake rats compared with control rats. Fibrosis was observed by using Masson's trichrome staining and picrosirius red staining. The plasma ET-1 concentration in high-salt diet rats was significantly higher than that of controls. The interventricular septum and posterior wall of high-salt diet rats were significantly thickened. CONCLUSION: Our findings indicated that coronary artery tension was significantly decreased in 4% high-salt diet rats and that this decrease may be due to the change of endothelin receptor and its downstream pathway SOCE related protein expression in coronary artery. Coronary fibrosis was observed in rats fed with high-salt diet. This study provides potential mechanistic insights into high-salt intake-induced heart disease.

Increasing audiovisual speech integration in autism through enhanced attention to mouth.

Autistic children (AC) show less audiovisual speech integration in the McGurk task, which correlates with their reduced mouth-looking time. The present study examined whether AC's less audiovisual speech integration in the McGurk task could be increased by increasing their mouth-looking time. We recruited 4- to 8-year-old AC and nonautistic children (NAC). In two experiments, we manipulated children's mouth-looking time, measured their audiovisual speech integration by employing the McGurk effect paradigm, and tracked their eye movements. In Experiment 1, we blurred the eyes in McGurk stimuli and compared children's performances in blurred-eyes and clear-eyes conditions. In Experiment 2, we cued children's attention to either the mouth or eyes of McGurk stimuli or asked them to view the McGurk stimuli freely. We found that both blurring the speaker's eyes and cuing to the speaker's mouth increased mouth-looking time and increased audiovisual speech integration in the McGurk task in AC. In addition, we found that blurring the speaker's eyes and cuing to the speaker's mouth also increased mouth-looking time in NAC, but neither blurring the speaker's eyes nor cuing to the speaker's mouth increased their audiovisual speech integration in the McGurk task. Our findings suggest that audiovisual speech integration in the McGurk task in AC could be increased by increasing their attention to the mouth. Our findings contribute to a deeper understanding of relations between face attention and audiovisual speech integration, and provide insights for the development of professional supports to increase audiovisual speech integration in AC. HIGHLIGHTS: The present study examined whether audiovisual speech integration in the McGurk task in AC could be increased by increasing their attention to the speaker's mouth. Blurring the speaker's eyes increased mouth-looking time and audiovisual speech integration in the McGurk task in AC. Cuing to the speaker's mouth also increased mouth-looking time and audiovisual speech integration in the McGurk task in AC. Audiovisual speech integration in the McGurk task in AC could be increased by increasing their attention to the speaker's mouth.

Association of the P441L KCNQ1 variant with severity of long QT syndrome and risk of cardiac events.

Dysfunction of potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is a primary cause of long QT syndrome type 1 (LQT1). Here, we report a missense mutation P441L in KCNQ1 C-terminus of a 37-year-old woman with severe LQT1 phenotype. Variant P441L transporting to the plasma membrane and interacting with KCNE1 were both markedly decreased, leading to potassium efflux disorder and eventually LQT1. Mutations between the C-terminal helix A and helix B of KCNQ1 have linked with low cardiac event risk, however, we firstly find variant P441L causing a severe LQT1 phenotype with a high risk of cardiac events.

Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients: Based on the impact of sex and concomitant valproate on clearance.

WHAT IS KNOWN AND OBJECTIVE: Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated. METHODS: Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters. RESULTS: The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h-1 , 15.4 L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F = 15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10 mg may be sufficient to achieve the therapeutic range of olanzapine. WHAT IS NEW AND CONCLUSION: Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.

Pharmacokinetics of immediate and sustained-release formulations of paroxetine: Population pharmacokinetic approach to guide paroxetine personalized therapy in chinese psychotic patients.

Paroxetine is one of the most potent selective serotonin reuptake inhibitors (SSRIs) approved for treating depression, panic disorder, and obsessive-compulsive disorder. There is evidence linking genetic polymorphisms and nonlinear metabolism to the Paroxetine's pharmacokinetic (PK) variability. The purpose of the present study was to develop a population PK (PPK) model of paroxetine in Chinese patients, which was used to define the paroxetine's PK parameters and quantify the effect of clinical and baseline demographic factors on these PK characteristics. The study included 184 inpatients with psychosis (103 females and 81 males), with a total of 372 serum concentrations of paroxetine for PPK analyses. The total daily dosage ranged from 20 to 75 mg. One compartment model could fit the PKs characterize of paroxetine. Covariate analysis revealed that dose, formulation, and sex had a significant effect on the PK parameters of paroxetine; however, there was no evident genetic influence of CYP2D6 enzymes on paroxetine concentrations in Chinese patients. The study determined that the population's apparent distribution volume (V/F) and apparent clearance (CL/F), respectively, were 8850 and 21.2 L/h. The CL/F decreased 1-2-fold for each 10 mg dose increase, whereas the different formulations caused a decrease in V/F of 66.6%. Sex was found to affect bioavailability (F), which decreased F by 47.5%. Females had higher F values than males. This PPK model described data from patients with psychosis who received paroxetine immediate-release tablets (IR-T) and/or sustained-release tablets (SR-T). Paroxetine trough concentrations and relative bioavailability were different between formulations and sex. The altered serum concentrations of paroxetine resulting from individual variants and additive effects need to be considered, to optimize the dosage regimen for individual patients.

Population pharmacokinetics model for escitalopram in Chinese psychiatric patients: effect of CYP2C19 and age.

Objective: To establish a population pharmacokinetic model in Chinese psychiatric patients to characterize escitalopram pharmacokinetic profile to identify factors influencing drug exposure, and through simulation to compare the results with the established therapeutic reference range. Methods: Demographic information, dosing regimen, CYP2C19 genotype, concomitant medications, and liver and kidney function indicators were retrospectively collected for inpatients taking escitalopram with therapeutic drug monitoring from 2018 to 2021. Nonlinear mixed-effects modeling was used to model the pharmacokinetic characteristics of escitalopram. Goodness-of-fit plots, bootstrapping, and normalized prediction distribution errors were used to evaluate the model. Simulation for different dosing regimens was based on the final estimations. Results: The study comprised 106 patients and 337 measurements of serum sample. A structural model with one compartment with first-order absorption and elimination described the data adequately. The population-estimated apparent volume of distribution and apparent clearance were 815 and 16.3 L/h, respectively. Age and CYP2C19 phenotype had a significant effect on the apparent clearance (CL/F). CL/F of escitalopram decreased with increased age, and CL/F of poor metabolizer patients was significantly lower than in extensive and immediate metabolizer patients. The final model-based simulation showed that the daily dose of adolescents with poor metabolizer might be as high as 15 mg or 20 mg and referring to the therapeutic range for adults may result in overdose and a high risk of adverse effects in older patients. Conclusion: A population pharmacokinetics model of escitalopram was successfully created for the Chinese population. Depending on the age of the patients, CYP2C19 genotype and serum drug concentrations throughout treatment are required for adequate individualization of dosing regimens. When developing a regimen for older patients, especially those who are poor metabolizers, vigilance is required.

A Simple and Sensitive HPLC-MS/MS Assay for the Quantitation of Blonanserin and N-Desethyl Blonanserin in Rat Plasma and Its Application to Pharmacokinetic Study.

A high-performance liquid chromatographic method coupled with triple quadrupole mass spectrometry (LC-MS/MS) for the analysis of blonanserin and its active metabolite, N-desethyl blonanserin, in rat plasma has been developed and validated. The biological samples were treated by simple direct protein precipitation before separation on an Agilent Eclipse Plus C18 column (4.6 × 100 mm, 3.5 µm) with a column temperature of 35°C at a flow rate of 0.5 mL/min. The mobile phase A is a mixture of methanol and water (75 : 25, v/v, 5 mM ammonium formate), and the mobile phase B is acetonitrile containing 0.1% formic acid. The ratio of mobile phase A to mobile phase B is 15 : 85. Electrospray ionization (ESI) multiple reaction monitoring modes are used for detection, which are m/z 368.10 ⟶ 296.90 (blonanserin), m/z 340.15 ⟶ 297.05(N-desethyl blonanserin), and m/z 348.15⟶ 302.05 (N-desethyl blonanserin-d8). The linear response range was 0.1-100.0 ng/mL for blonanserin and N-desethyl blonanserin. The lower limit of quantification (LLOQ), calibration curves, carryover, and matrix effects were sufficiently accurate and precise according to the National Medical Products Administration (NMPA) guidelines for bioanalytical method validation. This analytical method was successfully applied in a blonanserin-poloxamer thermosensitive gel pharmacokinetic study in rats.

Britanin relieves ferroptosis-mediated myocardial ischaemia/reperfusion damage by upregulating GPX4 through activation of AMPK/GSK3ß/Nrf2 signalling.

CONTEXT: Ferroptosis was described as an important contributor to the myocardial ischaemia/reperfusion (MIR) injury, and britanin (Bri) was reported to exert antitumor and anti-inflammatory activities. OBJECTIVE: Our study explores the effect and mechanism of Bri on MIR damage. MATERIALS AND METHODS: The rat model of MIR was established by ligation of the left anterior descending coronary artery. Male Sprague-Dawley (SD) rats were divided into three groups: sham group (n = 6), MIR group (n = 6) and MIR + Bri group (n = 6; 50 mg/kg). Rats were intragastrically pre-treated with Bri or normal saline once daily for 3 days. To further verify the role and mechanism of Bri, H9C2 cells were subjected to hypoxia plus reoxygenation (H/R) to induce the in vitro model of MIR. RESULTS: Compared with MIR rats, Bri significantly decreased infarct area (22.50% vs. 38.67%), myocardial apoptosis (23.00% vs. 41.5%), creatine phosphokinase (0.57 U/mL vs. 0.76 U/mL), and lactate dehydrogenase levels (3.18 U/mL vs. 5.17 U/mL), concomitant with alleviation of ferroptosis. Mechanistically, Bri treatment induced the activation of the adenosine monophosphate activated protein kinase (AMPK)/glycogen synthase kinase 3ß (GSK3ß)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in vivo. In addition, the AMPK/GSK3ß/Nrf2 pathway participated in the regulation of glutathione peroxidase 4 (GPX4) expression, and silencing of Nrf2 attenuated the effect of Bri on H/R-induced cell injury. DISCUSSION AND CONCLUSIONS: Bri protected against ferroptosis-mediated MIR damage by upregulating GPX4 through activation of the AMPK/GSK3ß/Nrf2 signalling, suggesting that Bri might become a novel therapeutic agent for MIR.

Early development of social attention in toddlers at high familial risk for autism spectrum disorder.

The present study explored the early development of social attention of toddlers at high familial risk (HR) for autism spectrum disorder (ASD). Eighteen HR toddlers and twenty-two toddlers at low familial risk for ASD (LR) between 11 and 24 months were asked to watch paired social and non-social videos. We found that: (1) the initial social preference in HR group decreased with age, but not in LR group; (2) both groups showed significant social habituation across trials, but HR group habituated slightly slower as age increased. These findings suggest that atypical social attention could be an early characteristic of toddlers at high familial risk for ASD.

Investigating intra-individual variability of face scanning in autistic children.

LAY ABSTRACT: Atypical face scanning is suggested to be related to social interactions and communicative deficits in autistic children. We systematically examined whether autistic and non-autistic children used consistent scanning patterns when performing different tasks and scanning different types of faces. We found that autistic children scanned faces more variably than non-autistic children: While non-autistic children used more consistent scanning patterns, autistic children's scanning patterns changed frequently when watching different faces. Autistic children's variable face scanning patterns might delay and impair face processing, resulting in a social interaction deficit. What's more, variable scanning patterns may create an unstable and unpredictable perception of the environment for autistic children. Developing in such an unstable environment might motivate autistic children to retract from the environment, avoid social interaction, and focus instead on the performance of repetitive behavior. Therefore, studying face scanning variability might represent a new avenue for understanding core symptoms in autistic people.

Vigilance or avoidance: How do autistic traits and social anxiety modulate attention to the eyes?

Introduction: Social anxiety disorder (SAD) and autism spectrum disorder (ASD) are highly overlapping in symptoms and have a high rate of comorbidity, posing challenges in diagnosis and intervention for both disorders. Both disorders are linked to abnormal attention to the eyes, yet how they interactively modulate the attentional process to the eyes remains unclear. Methods: In this study, we explored how autistic traits and social anxiety in college students separately and together affected different temporal stages of attention to the eyes. Participants were instructed to view virtual faces for 10 s and make an emotional judgment, while their eye movements were recorded. Results: We found that social anxiety and autistic traits affected different temporal stages of eye-looking. Social anxiety only affected the first fixation duration on the eyes, while autistic traits were associated with eye avoidance at several time points in the later stage. More importantly, we found an interactive effect of autistic traits and social anxiety on the initial attention to the eyes: Among people scoring high on autistic traits, social anxiety was related to an early avoidance of the eyes as well as attention maintenance once fixated on the eyes. Discussion: Our study suggests the separate and interactive roles of social anxiety and autistic traits in attention to the eyes. It contributes to a deeper understanding of the mechanisms of social attention in both SAD and ASD and highlights the application of psychiatric diagnoses using eye-tracking techniques.

Proteomics and weighted gene correlated network analysis reveal glutamatergic synapse signaling in diazepam treatment of alcohol withdrawal.

Background: Alcohol use disorder (AUD) is characterized by chronic excessive alcohol consumption, often alternating with periods of abstinence known as alcohol withdrawal syndrome (AWS). Diazepam is the preferred benzodiazepine for treatment of alcohol withdrawal syndrome under most circumstances, but the specific mechanism underlying the treatment needs further research. Methods: We constructed an animal model of two-bottle choices and chronic intermittent ethanol exposure. LC-MS/MS proteomic analysis based on the label-free and intensity-based quantification approach was used to detect the protein profile of the whole brain. Weighted gene correlated network analysis was applied for scale-free network topology analysis. We established a protein-protein interaction network based on the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software and identified hub proteins by CytoHubba and MCODE plugins of Cytoscape. The online tool Targetscan identified miRNA-mRNA pair interactions. Results: Seven hub proteins (Dlg3, Dlg4, Shank3, Grin2b, Camk2b, Camk2a and Syngap1) were implicated in alcohol withdrawal syndrome or diazepam treatment. In enrichment analysis, glutamatergic synapses were considered the most important pathway related to alcohol use disorder. Decreased glutamatergic synapses were observed in the late stage of withdrawal, as a protective mechanism that attenuated withdrawal-induced excitotoxicity. Diazepam treatment during withdrawal increased glutamatergic synapses, alleviating withdrawal-induced synapse inhibition. Conclusion: Glutamatergic synapses are considered the most important pathway related to alcohol use disorder that may be a potential molecular target for new interventional strategies.

Dual-emission 3D supramolecular framework hydrogel beads: highly selective detection of antibiotics and mechanism research.

Ratiometric fluorescent probes based on coordination polymers (CPs) have been widely applied in optical applications. Therefore, it is very important to develop a dual-emitting gel material based on coordination polymers for specific recognition of molecules. Cu-atda (H2atda = 3,3'-(4-amino-1,2,4-triazol-3,5-diyl) dibenzoic acid) is synthesized with a porous structure and a large number of amino sites exposed on the surface, which can be regarded as a carrier for fluorescent molecules and well disperse in the SA hydrogel network. A dual-emission Eu3+ functionalized CP hydrogel bead (9A/Cu-atda@Eu3+/SA, 9A = 9-anthraldehyde and SA = sodium alginate) is successfully prepared, which presents ratiometric fluorescence detection of flumequine with a low detection limit (48 nM) and high selectivity. Furthermore, it also displays an excellent fluorescence quenching effect on nitrofuran antibiotics, exhibiting a dual functional performance. In addition, the fluorescence response mechanisms of flumequine and nitrofuran antibiotics are discussed in depth. As a portable material, visualization 9A/Cu-atda@Eu3+/SA beads provide an extensive and convenient application prospect for real-time monitoring of antibiotics in the water environment.

Modeling and Simulation for Individualized Therapy of Amisulpride in Chinese Patients with Schizophrenia: Focus on Interindividual Variability, Therapeutic Reference Range and the Laboratory Alert Level.

PURPOSE: To explain the high inter-individual variability (IIV) and the frequency of exceeding the therapeutic reference range and the laboratory alert level of amisulpride, a population pharmacokinetic (PPK) model in Chinese patients with schizophrenia was built based on therapeutic drug monitoring (TDM) data to guide individualized therapy. PATIENTS AND METHODS: Plasma concentration data (330 measurements from 121 patients) were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach with first-order conditional estimation with interaction (FOCE I). The concentrations of amisulpride were detected by HPLC-MS/MS. Age, weight, sex, combination medication history and renal function status were evaluated as main covariates. The model was internally validated using goodness-of-fit, bootstrap and normalized prediction distribution error (NPDE). Recommended dosage regimens for patients with key covariates were estimated on the basis of Monte Carlo simulations and the established model. RESULTS: A one-compartment model with first-order absorption and elimination was found to adequately characterize amisulpride concentration in Chinese patients with schizophrenia. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. Age significantly affected the clearance of amisulpride and the final model was as follows: CL/F=1.04×(AGE/32)-0.624 (L/h). To avoid exceeding the laboratory alert level (640 ng/mL), the model-based simulation results showed that the recommended dose of amisulpride was no more than 600 mg/d for patients aged 60 years, 800 mg/d for those aged 40 years and 1200 mg/d for those aged 20 years, respectively. CONCLUSION: Dosage optimization of amisulpride can be carried out according to age to reduce the risk of adverse reactions. The model can be used as a suitable tool for designing individualized therapy for Chinese patients with schizophrenia.

Face-viewing patterns predict audiovisual speech integration in autistic children.

Autistic children show audiovisual speech integration deficits, though the underlying mechanisms remain unclear. The present study examined how audiovisual speech integration deficits in autistic children could be affected by their looking patterns. We measured audiovisual speech integration in 26 autistic children and 26 typically developing (TD) children (4- to 7-year-old) employing the McGurk task (a videotaped speaker uttering phonemes with her eyes open or closed) and tracked their eye movements. We found that, compared with TD children, autistic children showed weaker audiovisual speech integration (i.e., the McGurk effect) in the open-eyes condition and similar audiovisual speech integration in the closed-eyes condition. Autistic children viewed the speaker's mouth less in non-McGurk trials than in McGurk trials in both conditions. Importantly, autistic children's weaker audiovisual speech integration could be predicted by their reduced mouth-looking time. The present study indicated that atypical face-viewing patterns could serve as one of the cognitive mechanisms of audiovisual speech integration deficits in autistic children. LAY SUMMARY: McGurk effect occurs when the visual part of a phoneme (e.g., "ga") and the auditory part of another phoneme (e.g., "ba") uttered by a speaker were integrated into a fused perception (e.g., "da"). The present study examined how McGurk effect in autistic children could be affected by their looking patterns for the speaker's face. We found that less looking time for the speaker's mouth in autistic children could predict weaker McGurk effect. As McGurk effect manifests audiovisual speech integration, our findings imply that we could improve audiovisual speech integration in autistic children by directing them to look at the speaker's mouth in future intervention.