5-HTTLPR-rs25531 and Antidepressant Treatment Outcomes in Korean Patients with Major Depression.

INTRODUCTION: Despite the ethnic differences in 5-HTTLPR (S allele relates to better antidepressant response in Korean and Japanese people, while L allele with better response in Caucasians), it is unclear whether 5-HTTLPR and its high expression locus rs25531 are interactively associated with antidepressant treatment outcome. We investigated the individual and interaction effects of these polymorphisms on antidepressant treatment outcomes in the Korean population. METHODS: A total of 464 Korean subjects with major depressive disorder completed 6 weeks of antidepressant monotherapy. Venous blood was extracted for genotyping 5-HTTLPR and rs25531 by polymerase chain reaction and DNA sequencing. We used logistic regression analyses to verify the main and interaction effects of 5-HTTLPR and rs25531 on response and remission after antidepressant treatment. RESULTS: After adjusting for covariates, the SS genotype of 5-HTTLPR was significantly associated with better treatment outcomes (p<0.001, odds ratio [OR] [95% confidence interval (CI)]=2.435 [1.551, 3.823] in response; p<0.001, OR [95% CI]=2.912 [1.730, 4.903] in remission), while G-containing genotype (AG+GG) of rs25531 was only associated with remission (p=0.034, OR [95% CI]=2.104 [1.058, 4.181]). The interaction effect of 5-HTTLPR and rs25531 on response and remission was insignificant (all p>0.05). DISCUSSION: Our findings suggest variations in allelic frequency and functionality of 5-HTTLPR and rs25531 among the different ethnicities. We found a minor advantage of rs25531 in achieving remission. However, there was no interaction effect with 5-HTTLPR.

CD80CD86 deficiency disrupts regulatory CD4+FoxP3+T cell homoeostasis and induces autoimmune-like alopecia.

Alopecia areata (AA) is an autoimmune disease that results in spot baldness in humans. Adequate animal models for AA are currently lacking. The objective of this study was to elucidate the mechanism of autoimmune-like alopecia (ALA) in C57BL/6.CD80CD86-deficient (B6.CD80CD86-/- ) mice. Incidence and severity of alopecia were analysed in 58 B6.CD80CD86-/- mice using histological examination, flow cytometry, multiplex enzyme-linked immunosorbent assay, quantitative RT-PCR and CD25 inhibition test. Both male and female B6.CD80CD86-/- mice showed almost 100% incidence of hair loss at 40 weeks of age. Moreover, CD4+FoxP3+Treg (Treg) cell population in B6.CD80CD86-/- mice was significantly lower than in B6 mice, which presumably underlined autoimmune reaction. Histologically, B6.CD80CD86-/- mice showed CD4+ and CD8+ T-cell infiltration around terminal follicle region and exhibited hair follicle destruction in the anagen or catagen stage. Negative correlation between the number of CD4+FoxP3+ Tregs and ALA was confirmed by the CD25 depletion test in B6 mice, as follicle destruction was similar to that observed in B6.CD80CD86-/- animals. CD80CD86 deficiency disrupted CD4+FoxP3+ Treg homoeostasis and prompted the development of ALA. We demonstrated that B6.CD80CD86-/- mice might have several advantages as an ALA model, because they exhibited high incidence of disease phenotype and epipathogenesis similar to that observed in human AA.

Amyloid deposition and its association with depressive symptoms and cognitive functions in late-life depression: a longitudinal study using amyloid-ß PET images and neuropsychological measurements.

BACKGROUND: Although depression is linked to an increased risk of dementia, the association between late-onset depression (LOD) and amyloid burden remains unclear. This study aimed to determine amyloid deposition in patients with LOD compared to healthy controls (HC) using amyloid-beta (Aß) positron emission tomography (PET) images and neuropsychological assessments. METHODS: Forty patients first diagnosed with major depressive disorder after the age of 60 (LOD) and twenty-one healthy volunteers (HC) were enrolled. Depression and anxiety were evaluated using the 17-item Hamilton Depression Scale, Hamilton Anxiety Rating Scale, and Clinical Global Impression Scale. Cognitive function was assessed using the Korean versions of the Mini-Mental Status Examination, Montreal Cognitive Assessment, and Seoul Neuropsychological Screening Battery at baseline and 3-month follow-up. 18F-florbetapir PET images were co-registered with T1-weighted magnetic resonance images. RESULTS: There was no significant difference in Aß deposition between LOD and HC groups. No significant correlation between Aß burden and depressive symptom severity was found in LOD patients. Higher somatic anxiety was correlated with lower Aß burden in multiple brain regions, including the left inferior frontal lobe (p = 0.009), right anterior cingulate (p = 0.003), and right superior frontal lobe (p = 0.009). Despite cognitive recovery in areas such as attention (Digit Span Forward, p = 0.026), memory (Auditory Verbal Learning Test Recall Total, p = 0.010; Rey Complex Figure Test Delayed Recall, p = 0.039), and frontal executive function (Contrasting Program, p = 0.033) after three months of antidepressant treatment, cognitive improvement showed no association with amyloid deposition. CONCLUSIONS: These findings suggest distinct mechanisms may underlie amyloid deposition in neurodegenerative changes associated with depression. While amyloid burden in specific brain regions negatively correlated with somatic anxiety, it showed no significant correlation with the severity of depression or overall cognitive function.

Additive interaction of mid- to late-life depression and cerebrovascular disease on the risk of dementia: a nationwide population-based cohort study.

BACKGROUND: Dementia is a progressive neurocognitive disease with a substantial social burden. No apparent breakthroughs in treatment options have emerged so far; thus, disease prevention is essential for at-risk populations. Depression and cerebrovascular disease (CVD) are independent risk factors for dementia, but no studies have examined their interaction effect on dementia risk. This study aimed to identify the association of depression and CVD with the risk of dementia and evaluate whether dementia risk among patients with comorbid depression and CVD is higher than the sum of the individual risk due to each condition. METHODS: A population-based cohort study was conducted to analyze the Korean National Health Insurance Service-National Sample Cohort data of all individuals over 50 years of age. Individuals who had not been diagnosed with dementia at baseline were included and followed up from January 1, 2005, to December 31, 2013. A time-varying Cox proportional hazard regression model adjusted for potential confounding factors was used for the analysis. The interaction between depression and CVD was estimated based on the attributable proportion (AP), relative excess risk due to interaction (RERI), synergy index (SI), and multiplicative-scale interaction. RESULTS: A total of 242,237 participants were included in the analytical sample, of which 12,735 (5.3%) developed dementia. Compared to that for participants without depression or CVD, the adjusted hazard ratio for the incidence of dementia for those with depression alone was 2.35 (95% confidence interval [CI] 2.21-2.49), CVD alone was 3.25 (95% CI 3.11-3.39), and comorbid depression and CVD was 5.02 (95% CI 4.66-5.42). The additive interaction between depression and CVD was statistically significant (AP-0.08, 95% CI 0.01-0.16; RERI-0.42, 95% CI 0.03-0.82; SI-1.12, 95% CI 1.01-1.24). The multiplicative interaction was significant too, but the effect was negative (0.66, 95% CI 0.60-0.73). CONCLUSIONS: In this population-based nationwide cohort with long-term follow-up, depression and CVD were associated with an increased risk of dementia, and their coexistence additively increased dementia risk more than the sum of the individual risks.

Efficient and specific generation of knockout mice using Campylobacter jejuni CRISPR/Cas9 system.

The Streptococcus pyogenes CRISPR/Cas9 (SpCas9) system is now widely utilized to generate genome engineered mice; however, some studies raised issues related to off-target mutations with this system. Herein, we utilized the Campylobacter jejuni Cas9 (CjCas9) system to generate knockout mice. We designed sgRNAs targeting mouse Tyr or Foxn1 and microinjected into zygotes along with CjCas9 mRNA. We obtained newborn mice from the microinjected embryos and confirmed that 50% (Tyr) and 38.5% (Foxn1) of the newborn mice have biallelic mutation on the intended target sequences, indicating efficient genome targeting by CjCas9. In addition, we analyzed off-target mutations in founder mutant mice by targeted deep sequencing and whole genome sequencing. Both analyses revealed no off-target mutations at potential off-target sites predicted in silico and no unexpected random mutations in analyzed founder animals. In conclusion, the CjCas9 system can be utilized to generate genome edited mice in a precise manner.

The development of a korean drug dosing database.

OBJECTIVES: This report describes the development process of a drug dosing database for ethical drugs approved by the Korea Food & Drug Administration (KFDA). The goal of this study was to develop a computerized system that supports physicians' prescribing decisions, particularly in regards to medication dosing. METHODS: The advisory committee, comprised of doctors, pharmacists, and nurses from the Seoul National University Bundang Hospital, pharmacists familiar with drug databases, KFDA officials, and software developers from the BIT Computer Co. Ltd. analyzed approved KFDA drug dosing information, defined the fields and properties of the information structure, and designed a management program used to enter dosing information. The management program was developed using a web based system that allows multiple researchers to input drug dosing information in an organized manner. The whole process was improved by adding additional input fields and eliminating the unnecessary existing fields used when the dosing information was entered, resulting in an improved field structure. RESULTS: A total of 16,994 drugs sold in the Korean market in July 2009, excluding the exclusion criteria (e.g., radioactivity drugs, X-ray contrast medium), usage and dosing information were made into a database. CONCLUSIONS: The drug dosing database was successfully developed and the dosing information for new drugs can be continually maintained through the management mode. This database will be used to develop the drug utilization review standards and to provide appropriate dosing information.