Pharmacogenetic markers to predict safety of antipsychotics in adolescents experiencing acute psychotic episodes
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ABSTRACT: Introduction
SUBMITTER: Ivashchenko D
PROVIDER: S-EPMC9565971 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Project description:Inflammation is implicated in depression and psychosis, including association of childhood inflammatory markers on the subsequent risk of developing symptoms. However, it is unknown whether early-life inflammatory markers are associated with the number of depressive and psychotic symptoms from childhood to adulthood. Using the prospective Avon Longitudinal Study of Children and Parents birth cohort (N = up-to 6401), we have examined longitudinal associations of early-life inflammation [exposures: interleukin-6 (IL-6), C-reactive protein (CRP) levels at age 9y; IL-6 and CRP DNA-methylation (DNAm) scores at birth and age 7y; and IL-6 and CRP polygenic risk scores (PRSs)] with the number of depressive episodes and psychotic experiences (PEs) between ages 10-28 years. Psychiatric outcomes were assessed using the Short Mood and Feelings Questionnaire and Psychotic Like Symptoms Questionnaires, respectively. Exposure-outcome associations were tested using negative binomial models, which were adjusted for metabolic and sociodemographic factors. Serum IL-6 levels at age 9y were associated with the total number of depressive episodes between 10 and 28y in the base model (n = 4835; β = 0.066; 95%CI:0.020-0.113; pFDR = 0.041) which was weaker when adjusting for metabolic and sociodemographic factors. Weak associations were observed between inflammatory markers (serum IL-6 and CRP DNAm scores) and total number of PEs. Other inflammatory markers were not associated with depression or PEs. Early-life inflammatory markers are associated with the burden of depressive episodes and of PEs subsequently from childhood to adulthood. These findings support a potential role of early-life inflammation in the aetiology of depression and psychosis and highlight inflammation as a potential target for treatment and prevention.
| S-EPMC9582583 | biostudies-literature
Project description:In previous work we developed a pharmacogenetic predictor of antipsychotic (AP) induced extrapyramidal symptoms (EPS) based on four genes involved in mTOR regulation. The main objective is to improve this predictor by increasing its biological plausibility and replication. We re-sequence the four genes using next-generation sequencing. We predict functionality "in silico" of all identified SNPs and test it using gene reporter assays. Using functional SNPs, we develop a new predictor utilizing machine learning algorithms (Discovery Cohort, N = 131) and replicate it in two independent cohorts (Replication Cohort 1, N = 113; Replication Cohort 2, N = 113). After prioritization, four SNPs were used to develop the pharmacogenetic predictor of AP-induced EPS. The model constructed using the Naive Bayes algorithm achieved a 66% of accuracy in the Discovery Cohort, and similar performances in the replication cohorts. The result is an improved pharmacogenetic predictor of AP-induced EPS, which is more robust and generalizable than the original.
| S-EPMC6293322 | biostudies-literature
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| S-EPMC10479465 | biostudies-literature
Project description:Hypoglycemic episodes are associated with worse hospital outcomes. All adult patients admitted to our burn center from 2015 to 2019 were retrospectively reviewed. Patient demographics and burn characteristics were recorded. The primary outcome was mortality, and secondary outcomes were total length-of-stay and intensive care unit length-of-stay. All patients experiencing at least one hypoglycemic episode were compared to patients who did not experience hypoglycemia. There were 914 patients with acute burns admitted during the study period, 33 of which (4%) experienced hypoglycemic episodes. Of these, 17 patients (52%) experienced a single hypoglycemic episode, while the remainder experienced multiple hypoglycemic episodes. Patients with one or more hypoglycemic events were matched to non-hypoglycemic controls using propensity matching. Patients that experienced hypoglycemia had significantly less TBSA involvement (5% vs. 13%,median, p < 0.0002), higher prevalence of diabetes (48% vs. 18%, p < 0.0001), higher mortality (18% vs. 7%, p = 0.01), longer total length-of-stay (22 vs. 8 days, median, p < 0.0001), and longer ICU length-of-stay (12 vs. 0 days, median, p < 0.0001). A single hypoglycemic episode was associated with prolonged total (IRR = 1.91, p < 0.0001) and ICU length-of-stay (IRR = 3.86, p < 0.0001). Hypoglycemia was not associated with higher mortality in the survival analysis (p = 0.46).
| S-EPMC8527897 | biostudies-literature
Project description:BackgroundEnvironmental factors that influence wheezing in early childhood in the developing world are not well understood and may be useful in predicting respiratory outcomes. Therefore, our objective was to determine the factors that can predict wheezing.MethodsChildren from Dhaka, Bangladesh were recruited at birth and episodes of wheezing were measured alongside nutritional, immunological and socioeconomic factors over a one-year period. Poisson Regression with variable selection was utilized to determine what factors were associated with wheezing.ResultsElevated serum IL-10 (rate ratio (RR) = 1.51, 95% confidence interval (CI): 1.22-1.87), IL-1β (RR = 1.55, 95% CI: 1.26-1.93) C-reactive protein (CRP) (RR = 1.41, 95% CI: 1.03-1.93) in early life, and male gender (RR = 1.52, 95% CI: 1.27-1.82) predicted increased wheezing episodes. Conversely, increased fecal alpha-1-antitrypsin (RR = 0.87, 95% CI: 0.76-1.00) and family income (RR = 0.98, 95% CI: 0.97-0.99) were associated with a decreased number of episodes of wheezing.ConclusionsSystemic inflammation early in life, poverty, and male sex placed infants at risk of more episodes of wheezing during their first year of life. These results support the hypothesis that there is a link between inflammation in infancy and the development of respiratory illness later in life and provide specific biomarkers that can predict wheezing in a low-income country.
| S-EPMC4698242 | biostudies-literature
Project description:Unipolar psychotic depression (PD) is a highly debilitating condition, which needs intense monitoring and treatment. Among patients with recurrent PD, delusions tend to be very similar or identical over several separate episodes during the course of illness, but case-reports illustrating this clinical phenomenon in detail are lacking from the literature. Case report describing the 45-year-old Ms. J, who has experienced multiple episodes of PD. The report is based on a review of her medical file. The delusional theme of Ms. J's initial episode of PD reappeared at several subsequent episodes. During the majority of admissions, Ms. J was treated with electroconvulsive therapy, which resulted in significant improvement in the depressive, psychotic and catatonic features. Ms. J's case illustrates that PD can be a stable phenotype over many episodes and that it is important to recognize psychotic symptoms in order to prescribe the best possible treatment.
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| S-EPMC9826388 | biostudies-literature
Project description:AimDiffusion tensor imaging (DTI) studies suggest that reduced fractional anisotropy (FA) in the inferior longitudinal fasciculus (ILF) and superior longitudinal fasciculus (SLF) occurs among schizophrenia patients and those at risk for psychosis. Nevertheless, there is a dearth of knowledge investigating white matter fibre pathways in non-help-seeking individuals who endorse attenuated positive psychotic symptoms (APPS) across a range of mental disorders. The aim of the current study was to determine if alterations in ILF and SLF microstructures were specific to distressing APPS related to risk for psychosis or to APPS symptoms occurring in multiple mental disorders, which would suggest a shared phenotype among disorders.MethodTwenty-six non-help-seeking young adults were administered the Prodromal Questionnaire. DTI was conducted on participants (n = 13) who endorsed eight or more distressing APPS (D-APPS, a potentially clinically relevant group) and those who endorsed three or fewer distressing APPS (low-APPS; n = 13). Semistructured interviews were administered to determine diagnoses, as well as clinical risk for psychosis status.ResultsResults indicated that the D-APPS group exhibited decreased FA in the left ILF compared with the low-APPS group, even after removing four D-APPS participants who were considered at risk for psychosis.ConclusionFindings suggest that white matter microstructure is altered in individuals experiencing APPS across a range of disorders, independent of clinical high risk for psychosis status. Reduced FA in the left ILF may not be specific to psychosis risk, but rather for APPS that occur in a number of mental disorders.
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Project description:Acute Lymphoblastic Leukemia (ALL) is the most common cancer in children. Differences are found among ethnic groups in the results of the treatment of pediatric ALL. In general, children with a high level of native American ancestry tend to respond less positively to ALL treatments, which may be related to specific genomic variants found in native American groups. Despite the evidence, few data are available on the distribution of the pharmacogenomic variants relevant to the treatment of ALL in traditional Amerindian populations, such the those of the Amazon region. Given this, the present study investigated 27 molecular markers related to the treatment of ALL in Amerindians from Brazilian Amazonia and compared the frequencies with those recorded previously on five continents, that are available in the 1,000 Genomes database. The variation in the genotype frequencies among populations was evaluated using Fisher's exact test. The False Discovery Rate method was used to correct the results of the multiple analyses. Significant differences were found in the frequencies of the majority of markers between the Amerindian populations and those of other regions around the world. These findings highlight the unique genetic profile of the indigenous population of Brazilian Amazonia, which may reflect a distinct therapeutic profile for the treatment of ALL in these populations.
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Project description:It is important to identify accurate markers of psychiatric illness to aid early prediction of disease course. Subclinical psychotic experiences (PEs) are important risk factors for later mental ill-health and suicidal behaviour. This study used machine learning to investigate neuroanatomical markers of PEs in early and later stages of adolescence. Machine learning using logistic regression using Elastic Net regularization was applied to T1-weighted and diffusion MRI data to classify adolescents with subclinical psychotic experiences vs. controls across 3 timepoints (Time 1:11-13 years, n = 77; Time 2:14-16 years, n = 56; Time 3:18-20 years, n = 40). Neuroimaging data classified adolescents aged 11-13 years with current PEs vs. controls returning an AROC of 0.62, significantly better than a null model, p = 1.73e-29. Neuroimaging data also classified those with PEs at 18-20 years (AROC = 0.59;P = 7.19e-10) but performance was at chance level at 14-16 years (AROC = 0.50). Left hemisphere frontal regions were top discriminant classifiers for 11-13 years-old adolescents with PEs, particularly pars opercularis. Those with future PEs at 18-20 years-old were best distinguished from controls based on left frontal regions, right-hemisphere medial lemniscus, cingulum bundle, precuneus and genu of the corpus callosum (CC). Deviations from normal adolescent brain development in young people with PEs included an acceleration in the typical pattern of reduction in left frontal thickness and right parietal curvature, and accelerated progression of microstructural changes in right white matter and corpus callosum. These results emphasise the importance of multi-modal analysis for understanding adolescent PEs and provide important new insights into early phenotypes for psychotic experiences.
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