Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- tisková chyba MeSH
Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with "exemplary phenotypes"-those whose clinical features are reliably associated with LiR and non-response (LiNR)-are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a "clinical exemplar score," which measures the degree to which a subject's clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the "best clinical exemplars") were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the "poor clinical exemplars"). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer's amyloid-secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.
Bipolar disorder (BD) is a major healthcare and socio-economic challenge. Despite its substantial burden on society, the research activity in BD is much smaller than its economic impact appears to demand. There is a consensus that the accurate identification of the underlying pathophysiology for BD is fundamental to realize major health benefits through better treatment and preventive regimens. However, to achieve these goals requires coordinated action and innovative approaches to boost the discovery of the neurobiological underpinnings of BD, and rapid translation of research findings into development and testing of better and more specific treatments. To this end, we here propose that only a large-scale coordinated action can be successful in integrating international big-data approaches with real-world clinical interventions. This could be achieved through the creation of a Global Bipolar Disorder Foundation, which could bring government, industry and philanthropy together in common cause. A global initiative for BD research would come at a highly opportune time given the seminal advances promised for our understanding of the genetic and brain basis of the disease and the obvious areas of unmet clinical need. Such an endeavour would embrace the principles of open science and see the strong involvement of user groups and integration of dissemination and public involvement with the research programs. We believe the time is right for a step change in our approach to understanding, treating and even preventing BD effectively.
- MeSH
- big data * MeSH
- bipolární porucha diagnóza epidemiologie terapie MeSH
- celosvětové zdraví * MeSH
- klinické zkoušky jako téma metody MeSH
- lidé MeSH
- strojové učení trendy MeSH
- translační biomedicínský výzkum metody trendy MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: The microcirculation is responsible for distribution of blood within tissues, delivery of oxygen and other nutrients, and regulation of blood pressure. The objective of this study was to compare the sublingual microcirculation of pregnant participants to that of comparable non-pregnant volunteers. METHODS: Two groups of participants were recruited: a group of pregnant, non-laboring women with singleton pregnancies at term gestation and a control group of age-comparable non-pregnant volunteers. A sidestream dark field imaging device was applied to the sublingual mucosal surface obtaining a steady image for at least 20 s duration, in five visual fields. The resultant five video clips per participant were analyzed blindly and at random to prevent coupling between images. The mean microvascular flow index values for each group were compared using a paired t-test. RESULTS: Thirty-seven participants were recruited (19 pregnant, 18 non-pregnant); a single pregnant participant was withdrawn because of technical issues. Baseline characteristics were similar with the exception of weight and body mass index. The mean microvascular flow index was significantly higher in the pregnant group 2.7 ± 0.2 compared to the non-pregnant group 2.5 ± 0.3 (P = 0.021), while the perfused vessel density and proportion of perfused vessels were not significantly different (P = 0.707 and 0.403, respectively). CONCLUSION: The microvascular flow index of pregnant women is higher than a comparable non-pregnant group, which appears to correlate with the physiological changes of pregnancy.
- MeSH
- audiovizuální záznam metody MeSH
- dospělí MeSH
- lidé MeSH
- mikrocirkulace fyziologie MeSH
- prospektivní studie MeSH
- těhotenství MeSH
- ústní spodina krevní zásobení MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
