Rapid-Acting Antidepressants and Underlying Mechanisms

Loss of glial cells with resulting atrophy of the medial prefrontal cortex (mPFC) as well as the hippocampal area is demonstrated in depressed patients by brain imaging and postmortem studies. The mPFC is the master control of mood and emotional response. The hippocampus is part of the limbic system, the main function of which is to regulate emotions. The mPFC depends on the hippocampus for rapid learning and memory consolidation. Unlike monoamine reuptake inhibitor antidepressants, which take 6 to 8 weeks to exert their full effects, and with 30 - 40% unresponsive rate, ketamine acts rapidly, within a couple of hours, and has higher responsive rates. It suggests that in theory, due to its rapid effect, Ketamine could well serve as a bridging remedy to lower the rate of suicidal risk before Selective serotonin re-uptake inhibitors (SSRIs) reach their full effect for long-term depression management. Yet, ketamine has long been linked with abusive potential and possible neurotoxicity if used in large doses over a prolonged period. Even though there are no collected data to prove the associated adverse effects, awareness of this negative aspect of ketamine is sufficiently widespread to propel the psychiatric community to look for other rapidly acting antidepressant alternatives. Recent studies have shown that scopolamine, the Yueju pill, and magnesium are rapid-onset antidepressants that have mechanisms comparable to that of ketamine. These rapid-acting antidepressant agents promise to be effective and safer choices for depression management in the future, providing that further studies and investigations to produce a better and fuller understanding of their effects and limitations

Estimating effect sizes and expected replication probabilities from GWAS summary statistics

Genome-wide Association Studies (GWAS) result in millions of summary statistics (“z-scores”) for single nucleotide polymorphism (SNP) associations with phenotypes. These rich datasets afford deep insights into the nature and extent of genetic contributions to complex phenotypes such as psychiatric disorders, which are understood to have substantial genetic components that arise from very large numbers of SNPs. The complexity of the datasets, however, poses a significant challenge to maximizing their utility. This is reflected in a need for better understanding the landscape of z-scores, as such knowledge would enhance causal SNP and gene discovery, help elucidate mechanistic pathways, and inform future study design. Here we present a parsimonious methodology for modeling effect sizes and replication probabilities, relying only on summary statistics from GWAS substudies, and a scheme allowing for direct empirical validation. We show that modeling z-scores as a mixture of Gaussians is conceptually appropriate, in particular taking into account ubiquitous non-null effects that are likely in the datasets due to weak linkage disequilibrium with causal SNPs. The four-parameter model allows for estimating the degree of polygenicity of the phenotype and predicting the proportion of chip heritability explainable by genome-wide significant SNPs in future studies with larger sample sizes. We apply the model to recent GWAS of schizophrenia (N = 82,315) and putamen volume (N = 12,596), with approximately 9.3 million SNP z-scores in both cases. We show that, over a broad range of z-scores and sample sizes, the model accurately predicts expectation estimates of true effect sizes and replication probabilities in multistage GWAS designs. We assess the degree to which effect sizes are over-estimated when based on linear-regression association coefficients. We estimate the polygenicity of schizophrenia to be 0.037 and the putamen to be 0.001, while the respective sample sizes required to approach fully explaining the chip heritability are 106 and 105. The model can be extended to incorporate prior knowledge such as pleiotropy and SNP annotation. The current findings suggest that the model is applicable to a broad array of complex phenotypes and will enhance understanding of their genetic architectures

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry

Effect of the 3'APOB-VNTR polymorphism on the lipid profiles in the Guangxi Hei Yi Zhuang and Han populations

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein (Apo) B is the major component of low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) and chylomicrons. Many genetic polymorphisms of the Apo B have been described, associated with variation of lipid levels. However, very few studies have evaluated the effect of the variable number of tandem repeats region 3' of the Apo B gene (3'APOB-VNTR) polymorphism on the lipid profiles in the special minority subgroups in China. Thus, the present study was undertaken to study the effect of the 3'APOB-VNTR polymorphism on the serum lipid levels in the Guangxi Hei Yi Zhuang and Han populations.</p> <p>Methods</p> <p>A total of 548 people of Hei Yi Zhuang were surveyed by a stratified randomized cluster sampling. The epidemiological survey was performed using internationally standardized methods. Serum lipid and apolipoprotein levels were measured. The 3'APOB-VNTR alleles were determined by polymerase chain reaction (PCR) followed by electrophoresis in polyacrylamide gels, and classified according to the number of repeats of a 15-bp hypervariable elements (HVE). The sequence of the most common allele was determined using the PCR and direct sequencing. The possible association between alleles of the 3'APOB-VNTR and lipid variables was examined. The results were compared with those in 496 people of Han who also live in that district.</p> <p>Results</p> <p>Nineteen alleles ranging from 24 to 64 repeats were detected in both Hei Yi Zhuang and Han. HVE56 and HVE58 were not be detected in Hei Yi Zhuang whereas HVE48 and HVE62 were totally absent in Han. The frequencies of HVE26, HVE30, HVE46, heterozygote, and short alleles (< 38 repeats) were higher in Hei Yi Zhuang than in Han. But the frequencies of HVE34, HVE38, HVE40, homozygote, and long alleles (≥ 38 repeats) were lower in Hei Yi Zhuang than in Han (<it>P </it>< 0.05–0.01). The levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and Apo B in Hei Yi Zhuang but not in Han were higher in VNTR-LS (carrier of one long and one short alleles) than in VNTR-LL (the individual carrying two long alleles) genotypes. The levels of TC, triglycerides (TG), LDL cholesterol, and Apo B in Hei Yi Zhuang were higher in both HVE34 and HVE36 alleles than in HVE32 allele. The levels of TC, TG, HDL-C and Apo B in Hei Yi Zhuang were also higher in homozygotes than in heterozygotes. There were no significant differences in the detected lipid parameters between the VNTR-SS (carrier of two short alleles) and VNTR-LS or VNTR-LL genotypes in both ethnic groups.</p> <p>Conclusion</p> <p>There were significant differences of the 3'APOB-VNTR polymorphism between the Hei Yi Zhuang and Han populations. An association between the 3'APOB-VNTR polymorphism and serum lipid levels was observed in the Hei Yi Zhuang but not in the Han populations.</p

All-cause mortality and risk factors in a cohort of retired military male veterans, Xi'an, China: an 18-year follow up study

<p>Abstract</p> <p>Background</p> <p>Risk factors of all-cause mortality have not been reported in Chinese retired military veterans. The objective of the study was to examine the risk factors and proportional mortality in a Chinese retired military male cohort.</p> <p>Methods</p> <p>A total of 1268 retired military men aged 55 or older were examined physically and interviewed using a standard questionnaire in 1987. The cohort was followed up every two years and the study censored date was June30, 2005 with a follow-up of up to 18 years. Death certificates were obtained from hospitals and verified by two senior doctors. Data were entered (double entry) by Foxbase, and analysis was carried out by SAS for Windows 8.2. Multivariate Cox proportional hazard regression model was used to compute hazard ratio (HR) and 95% confidence interval (CI).</p> <p>Results</p> <p>The total person-years of follow-up was 18766.28. Of the initial cohort of 1268 men, 491 had died, 748 were alive and 29 were lost to follow up. Adjusted mortality (adjusted for age, blood pressure, body mass index, cholesterol, triglycerides, alcohol, exercise, and existing disease) was 2,616 per 100,000 person years. The proportional mortality of cancer, vascular disease and Chronic Obstructive Pulmonary Disease (COPD) were 39.71%, 28.10% and 16.90% respectively. Multivariate analysis showed that age, cigarettes per day, systolic blood pressure, triglyceride, family history of diseases (hypertension, stroke and cancer), existing diseases (stroke, diabetes and cancer), body mass index, and age of starting smoking were associated with all-cause mortality, HR (95%CI) was1.083(1.062–1.104), 1.026(1.013–1.039), 1.009(1.003–1.015), 1.002(1.001–1.003), 1.330(1.005–1.759), 1.330(1.005–1.759), 1.444(1.103–1.890), 2.237(1.244–4.022), 1.462(1.042–2.051), 2.079(1.051–4.115), 0.963(0.931–0.996)and 0.988(0.978–0.999)respectively. Compared with never-smokers, current smokers had increased risks of total mortality [HR 1.369(1.083–1.731)], CHD [HR 1.805 (1.022–3.188)], and lung cancer [HR 2.939 (1.311–6.585)].</p> <p>Conclusion</p> <p>The three leading causes of diseases were cancer, CHD and stroke, and COPD. Aging, cigarette smoking, high systolic blood pressure, high triglyceride, family history of cancer, hypertension and stroke, existing cases recovering from stroke, diabetes and cancer, underweight, younger age of smoking were risk factors for all-cause mortality. Quitting cigarette smoking, maintaining normal blood pressure, triglyceride and weight are effect control strategies to prevent premature mortality in this military cohort.</p

The characteristics of impaired fasting glucose associated with obesity and dyslipidaemia in a Chinese population

<p>Abstract</p> <p>Background</p> <p>Different populations have diverse patterns of relationships between Impaired Fasting Glucose (IFG) and obesity and lipid markers, it is important to investigate the characteristics of associations between IFG and other related risk factors including body mass index (BMI), waist circumstance (WC), serum lipids and blood pressure (BP) in a Chinese population.</p> <p>Methods</p> <p>This was a case-control study of 648 IFG subjects and 1,296 controls derived from a large-scale, community-based, cross-sectional survey of 10,867 participants. Each subject received a face-to-face interview, physical examination, and blood tests, including fasting blood glucose and lipids. Student's <it>t</it>-test, Chi-square test, Spearman correlation and multiple logistic regressions were used for the statistical analyses.</p> <p>Results</p> <p>Fasting plasma glucose (FPG) was positively correlated with BMI, WC, systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG), and total cholesterol (TC), and was negatively correlated with high density lipoprotein-cholesterol (HDL-C) (all p < 0.05). BMI was more strongly correlated with IFG than with WC. The correlation coefficient of FPG was remarkably higher with TG (0.244) than with TC (0.134) and HDL-C (-0.192). TG was an important predictor of IFG, with odds ratios of 1.76 (95%CI: 1.31-2.36) for subjects with borderline high TG level (1.70 mmol/l ≤ TG < 2.26 mmol/l) and 3.13 (95% CI: 2.50-3.91) for those with higher TG level (TG ≥ 2.26 mmol/l), when comparing to subjects with TG < 1.70 mmol/l. There was a significant dose-response relationship between the number of abnormal variables and increased risk of IFG.</p> <p>Conclusions</p> <p>In this Chinese population, both BMI and WC were important predictors of IFG. Abnormal TG as a lipid marker was more strongly associated with IFG than were TC and HDL-C. These factors should be taken into consideration simultaneously for prevention of IFG.</p

Implantable or External Defibrillators for Individuals at Increased Risk of Cardiac Arrest: Where Cost-Effectiveness Hits Fiscal Reality

Objcetives:  Implantable cardioverter defibrillators (ICDs) are highly effective at preventing cardiac arrest, but their availability is limited by high cost. Automated external defibrillators (AEDs) are likely to be less effective, but also less expensive. We used decision analysis to evaluate the clinical and economic trade-offs of AEDs, ICDs, and emergency medical services equipped with defibrillators (EMS-D) for reducing cardiac arrest mortality. Methods:  A Markov model was developed to compare the cost-effectiveness of three strategies in adults meeting entry criteria for the MADIT II Trial: strategy 1, individuals experiencing cardiac arrest are treated by EMS-D; strategy 2, individuals experiencing cardiac arrest are treated with an in-home AED; and strategy 3, individuals receive a prophylactic ICD. The model was then used to quantify the aggregate societal benefit of these three strategies under the conditions of a constrained federal budget. Results:  Compared with EMS-D, in-home AEDs produced a gain of 0.05 quality-adjusted life-years (QALYs) at an incremental cost of $5225 ($104,500 per QALY), while ICDs produced a gain of 0.90 QALYs at a cost of $114,660 ($127,400 per QALY). For every $1 million spent on defibrillators, 1.7 additional QALYs are produced by purchasing AEDs (9.6 QALYs/$million) instead of ICDs (7.9 QALYs/$million). Results were most sensitive to defibrillator complication rates and effectiveness, defibrillator cost, and adults’ risk of cardiac arrest. Conclusions:  Both AEDs and ICDs reduce cardiac arrest mortality, but AEDs are significantly less expensive and less effective. If financial constraints were to lead to rationing of defibrillators, it might be preferable to provide more people with a less effective and less expensive intervention (in-home AEDs) instead of providing fewer people with a more effective and more costly intervention (ICDs).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74790/1/j.1524-4733.2006.00118.x.pd