A Systematic Review of Clozapine Concentration–Dose Ratio from Therapeutic Drug Monitoring Studies in Children and Adolescents Treated with Clozapine for Mental Disorders

Background: Therapeutic drug monitoring of clozapine in children and adolescents has received insufficient attention. Calculation of concentration-to-dose (C/D) ratios from trough steady-state concentrations estimate drug clearance. Methods: A systematic electronic literature search was conducted in 3 article databases from inception until January 10, 2023, and articles reporting clozapine concentrations in children and adolescents were retrieved. The pharmacokinetic quality of the studies was assessed, and clozapine C/D ratios were calculated using the sample mean clozapine dose and concentration. Results: Of the 37 articles of potential interest, only 7 reported clozapine trough and steady-state concentrations. After excluding case reports and a study confounded by fluvoxamine, 4 studies on psychosis from Europe and the United States were included. The clozapine C/D ratios were similar to published adult values and ranged from 0.82 to 1.24 with a weighted mean of 1.08 ng/mL per mg/d. The weighted means were 334 mg/d for the dose and 380 ng/mL for the concentration. The stratified analysis of the weighted mean clozapine C/D ratios from 2 studies showed lower values in 52 male (1.05 ng/mL per mg/d) than in 46 female (1.46 ng/mL per mg/d) children and adolescents, with values similar to those reported for European adult nonsmokers. Two female adolescents had high clozapine C/D ratios (2.54 ng/mL per mg/d), an Asian American patient with borderline obesity and a patient with intellectual disability with low dosage (mean = 102 mg/d) and concentration (mean = 55 ng/mL). Conclusions: Reports on clozapine therapeutic drug monitoring in children and adolescents are limited in number and quality. Future studies should focus on basic pharmacokinetic issues, such as stratification by sex, smoking, and relevant comedications with inductive or inhibitory properties

Weight gain and increase of body mass index among children and adolescents treated with antipsychotics: a critical review

We performed an updated review of the available literature on weight gain and increase of body mass index (BMI) among children and adolescents treated with antipsychotic medications. A PubMed search was conducted specifying the following MeSH terms: (antipsychotic agents) hedged with (weight gain) or (body mass index). We selected 127 reports, including 71 intervention trials, 42 observational studies and 14 literature reviews. Second-generation antipsychotics (SGAs), in comparison with first-generation antipsychotics, are associated with a greater risk for antipsychotic-induced weight gain although this oversimplification should be clarified by distinguishing across different antipsychotic drugs. Among SGAs, olanzapine appears to cause the most significant weight gain, while ziprasidone seems to cause the least. Antipsychotic-induced BMI increase appears to remain regardless of the specific psychotropic co-treatment. Children and adolescents seem to be at a greater risk than adults for antipsychotic-induced weight gain; and the younger the child, the higher the risk. Genetic or environmental factors related to antipsychotic-induced weight gain among children and adolescents are mostly unknown, although certain genetic factors related to serotonin receptors or hormones such as leptin, adiponectin or melanocortin may be involved. Strategies to reduce this antipsychotic side effect include switching to another antipsychotic drug, lowering the dosage or initiating treatment with metformin or topiramate, as well as non-pharmacological interventions. Future research should avoid some methodological limitations such as not accounting for age- and sex-adjusted BMI (zBMI), small sample size, short period of treatment, great heterogeneity of diagnoses and confounding by indication

Oxidative stress parameters and antioxidants in patients with bipolar disorder: Results from a meta-analysis comparing patients, including stratification by polarity and euthymic status, with healthy controls

Abstract Objective: To investigate oxidative stress markers and antioxidants in bipolar disorder (BD). Methods: Electronic MEDLINE/PubMed/Cochrane-Library/Scopus/TripDatabase search until 06/30/2019 for studies comparing antioxidant or oxidative stress markers between BD and healthy controls (HCs). Standardized mean differences (SMD) and 95% confidence intervals (CIs) were calculated for ≥3 studies. Results: Forty-four studies (n = 3,767: BD = 1,979; HCs = 1,788) reported on oxidative stress markers malondialdehyde (MDA), thiobarbituric acid reactive substances (TBARS), and total nitrites; antioxidants glutathione (GSH), uric acid, and zinc; or antioxidantenhancing enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and GSH-transferase (GST). Compared with HCs, BD was associated with higher GST (P = .01), CAT (P = .02), nitrites (P < .0001), TBARS (P < .0001), MDA (P = .01), uric acid (P < .0001), and lower GSH (P = .006), without differences in SOD, GPX, and zinc. Compared to HCs, levels were higher in BD-mania for TBARS (P < .0001) and uric acid (P < .0001); in BD-depression for TBARS (P = .02); and BD-euthymia for uric acid (P = .03). Uric acid levels were higher in BD-mania vs BD-depression (P = .002), but not vs BD euthymia. TBARS did not differ between BD-mania and BD-depression. Medication-free BD-mania patients had higher SOD (P = .02) and lower GPX (P < .0001) than HCs. After treatment, BD did not differ from HCs regarding SOD and GPX. Conclusions: Beyond a single biomarker of oxidative stress, the combination of several parameters appears to be more informative for BD in general and taking into account illness polarity. BD is associated with an imbalance in oxidative stress with some phase-specificity for uric acid and TBARS and possible treatment benefits for SOD and GPX. Future studies should take into account confounding factors that can modify oxidative stress status and simultaneously measure oxidative stress markers and antioxidants including different blood sources

Features Associated With Depressive Predominant Polarity and Early Illness Onset in Patients With Bipolar Disorder

Objective: The aim of this study is to determine the prevalence of three possible diagnostic specifiers, namely predominant polarity (PP) throughout illness, polarity of the first episode and early age at onset, in a sample of bipolar disorder (BD) patients and their association with important socio-demographic, clinical and course-of-illness variables. Methods: A retrospective and naturalistic study on 108 BD outpatients, who were classified according to the PP, polarity of the first episode and early age at onset ( 20 years) [vs. late (>20 years)] and were characterized by their demographics, clinical data, functionality and social support, among others features. After bivariate analyses, those variables showing certain association (P value < 0.25) with the three dependent variables were entered in logistic regression backward selection procedures to identify the variables independently associated with the PP, polarity of the first episode and early age at onset. Results: The sample consisted of 75 women ad 33 men, 74% with type I BD and 26% with type II. Around 70% had depressive PP, onset with a depressive episode and onset after age 20. Depressive PP was independently associated with depressive onset, higher score on the CGI severity scale and work disability. Onset with depressive episode was associated with type II BD, longer diagnostic delay and higher score on family disability. Early age at onset ( 20 years) was associate with younger age, longer diagnostic delay, presence of ever psychotic symptoms, current use of antipsychotic drugs and higher social support score. Conclusions: The results of this study show that BD patients with depressive PP, onset with depression and early age at onset may represent greater severity, because they are frequently associated with variables that worsen the prognosis. Our findings match up with the conclusions of two systematic reviews and we also include a disability factor (at family and work) that has not been previously reported. This work contributes to the use of polarity and age at onset in BD patients, as it can become a useful instrument in the prognostic and therapeutic applications

Human Coronavirus Virulence Motifs and Virulence

Trabajo presentado en el XIV International Nidovirus Symposium (Nido2017), celebrado en Kansas City, Missouri (Estados Unidos), del 4 al 9 de junio de 2017We have shown that SARS-CoV E protein is a virulence factor that includes at least two virulence motifs: its ion channel (IC) activity encoded within the transmembrane domain and a PDZ binding motif (PBM) located at its carboxy-terminus. We showed that E protein pathogenicity was caused by the activation of different host signaling pathways. One of them was the activation of inflammasome, a process mediated by the conductance of Ca++ byEprotein IC activity, leading to an increased expression of IL-1beta, TNF-alpha and IL-6 levels. Another signaling pathway implied the activation of a proinflammatory response mediated by NF-kB activation. This activation was a consequence of E protein-syntenin binding mediated by PBM-PDZ interactions. This binding caused an increase of p38MAPK phosphorylation promoting the induction of acute respiratory distress syndrome (ARDS), edema and death of mice infected with a mouse adapted SARS-CoV. The relevance of p38 MAPK activation after infection with the mouse adapted SARS-CoV was confirmed by the protection of mice in the presence of an inhibitor of p38 MAPK, but not in its absence. These results illustrated the identification of an efficient coronavirus (CoV) antiviral. The presence of a virulence factor such as the PBM motif in E protein allows the virus to interact with more than 400 cell proteins containing PDZ motifs, conferring the virus the potential to control a high number of cell-signaling pathways increasing its replication and virulence. In fact, we are analyzing the proteome of the viral PBM-cellular PDZ interactions using system biology approaches. Frequently, the ARDS caused by lung infection with mild respiratory viruses is resolved before it evolves to serious edema. In contrast, after SARS-CoV infection frequently this resolution does not take place. We have shown the binding of E protein to a main mediator of edema resolution, the Na+ /K+ ATPase, and proposed that this may be one of the procedures by which edema recovery is prevented after SARS-CoV infection, either by inhibition of Na+ /K+ ATPase activity or by relocating this enzyme to another subcellular compartment. Deadly human CoVs as SARS- and MERS-CoVs have at least two viral proteins with IC activity and PBM motifs. Studies on the relevance of E and 3a SARS-CoV proteins in replication and virulence, and the interdependence among them have shown that the presence in the virus of at least E or 3a proteins was needed for virus viability. In fact, we have shown that the complementation between E and 3a proteins is mediated by the PBM motifs located at the carboxy-terminus of these proteins. Our studies on the interaction of SARS-CoV and MERS-CoV with the host, and the engineering of reverse genetics systems for each of these viruses, led us to the development of genetically stable vaccine candidates that provided full-protection against the challenge with the homologous virulent virus using mice models

Clones y vectores infectivos derivados de coronavirus y sus aplicaciones

Referencia OEPM: P9902673.-- Fecha de solicitud: 03/12/1999.-- Titular: Consejo Superior de Investigaciones Científicas (CSIC).Clones y vectores infectivos derivados de coronavirus y sus aplicaciones. El clon infectivo derivado de un coronavirus comprende un cDNA que codifica el gRMA de un coronavirus clonado bajo una secuencia promotora de la transcripción. El vector viral recombinante comprende un clon infectivo modificado para contener un ácido nucleico heterólogo insertado en dicho clon infectivo bajo condiciones que permiten la expresión de dicho ácido nucleico heterólogo. Los clones y vectores infectivos son útiles tanto en investigación básica como aplicada, en el desarrollo de sistemas de expresión eficientes de productos de interés (proteínas, enzimas, anticuerpos, etc.), vectores vacunales y terapia génica.Peer reviewe

Diagnostic accuracy of the Eurotest for dementia: a naturalistic, multicenter phase II study

Abstract Background Available screening tests for dementia are of limited usefulness because they are influenced by the patient's culture and educational level. The Eurotest, an instrument based on the knowledge and handling of money, was designed to overcome these limitations. The objective of this study was to evaluate the diagnostic accuracy of the Eurotest in identifying dementia in customary clinical practice. Methods A cross-sectional, multi-center, naturalistic phase II study was conducted. The Eurotest was administered to consecutive patients, older than 60 years, in general neurology clinics. The patients' condition was classified as dementia or no dementia according to DSM-IV diagnostic criteria. We calculated sensitivity (Sn), specificity (Sp) and area under the ROC curves (aROC) with 95% confidence intervals. The influence of social and educational factors on scores was evaluated with multiple linear regression analysis, and the influence of these factors on diagnostic accuracy was evaluated with logistic regression. Results Sixteen neurologists recruited a total of 516 participants: 101 with dementia, 380 without dementia, and 35 who were excluded. Of the 481 participants who took the Eurotest, 38.7% were totally or functionally illiterate and 45.5% had received no formal education. Mean time needed to administer the test was 8.2+/-2.0 minutes. The best cut-off point was 20/21, with Sn = 0.91 (0.84–0.96), Sp = 0.82 (0.77–0.85), and aROC = 0.93 (0.91–0.95). Neither the scores on the Eurotest nor its diagnostic accuracy were influenced by social or educational factors. Conclusion This naturalistic and pragmatic study shows that the Eurotest is a rapid, simple and useful screening instrument, which is free from educational influences, and has appropriate internal and external validity.</p

Transgenic mice secreting coronavirus neutralizing antibodies into the milk

Ten lines of transgenic mice secreting transmissible gastroenteritis coronavirus (TGEV) neutralizing recombinant monoclonal antibodies (rMAbs) into the milk were generated. The rMAb light- and heavy-chain genes were assembled by fusing the genes encoding the variable modules of the murine MAb 6A. C3, which binds an interspecies conserved coronavirus epitope essential for virus infectivity, and a constant module from a porcine myeloma with the immunoglobulin A (IgA) isotype. The chimeric antibody led to dimer formation in the presence of J chain. The neutralization specific activity of the recombinant antibody produced in transiently or stably transformed cells was 50-fold higher than that of a monomeric rMAb with the IgG1 isotype and an identical binding site. This rMAb had titers of up to 104 by radioimmunoassay (RIA) and neutralized virus infectivity up to 104- fold. Of 23 transgenic mice, 17 integrated both light and heavy chains, and at least 10 of them transmitted both genes to the progeny, leading to 100% of animals secreting functional TGEV neutralizing antibody during lactation. Selected mice produced milk with TGEV-specific antibody titers higher than 106 as determined by A, neutralized virus infectivity by 10-fold, and produced up to 6 mg of antibody per ml. Antibody expression levels were transgene copy number independent and integration site dependent. Comicroinjection of the genomic β-lactoglobulin gene with rMAb light and heavy-chain genes led to the generation of transgenic mice carrying the three transgenes. The highest antibody titers were produced by transgenic mice that had integrated the antibody and β-lactoglobulin genes, although the number of transgenic animals generated does not allow a definitive conclusion on the enhancing effect of β-lactoglobulin cointegration. This approach may lead to the generation of transgenic animals providing lactogenic immunity to their progeny against enteric pathogens.This work has been supported by grants from the Consejo Superior de Investigaciones Científicas, the Comisión Interministerial de Ciencia y Tecnología (CICYT), The Instituto Nacional de Investigación y Tecnología Agraria y Alimentación project SC-GAN94-119, La Consejería de Educación y Cultura de la Comunidad de Madrid, and Laboratorios Fort Dodge from Spain and the European Communities (Projects Science and Biotech). I.S., J.C., and J.M.S.-M. received fellowships from the Consejo Superior de Investigaciones Científicas, the Department of Education, University and Research of the Gobierno Vasco, and the Colegio Oficial de Veterinarios de la Comunidad de Madrid (Spain), respectively. C.B.A.W. and A.J.C. are supported by the BBSRC

Caffeine consumption in a long-term psychiatric hospital:Tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use

This study further explores the association between schizophrenia and caffeine use by combining two prior published Spanish samples (250 schizophrenia outpatients and 290 controls from the general population) with two Spanish long-term inpatient samples from the same hospital (145 with schizophrenia and 64 with other severe mental illnesses). The specific aims were to establish whether or not, after controlling for confounders including tobacco smoking, the association between schizophrenia and caffeine is consistent across schizophrenia samples and across different definitions of caffeine use. The frequency of caffeine use in schizophrenia inpatients was not significantly higher than that in non-schizophrenia inpatients (77%, 111/145 vs. 75%, 48/64) or controls but was significantly higher than in schizophrenia outpatients. The frequency of high caffeine users among caffeine users in schizophrenia inpatients was not significantly higher than in non-schizophrenia inpatients (45%, 50/111 vs. 52%, 25/48) or controls, but was significantly lower than in schizophrenia outpatients. Smoking was significantly associated with caffeine use across all samples and definitions. Between 2 and 3% of schizophrenia inpatients, schizophrenia outpatients and non-schizophrenia inpatients showed caffeinism (\u3e 700 mg/day in smokers). Several of these smoking patients with caffeinism were also taking other inducers, particularly omeprazole. The lack of consistent association between schizophrenia and caffeine use is surprising when compared with the very consistent association between tobacco smoking and caffeine use across all of our analyses (use and high use in users) and all our samples. The confounding effects of tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use