Kyung-Yeol Bae

Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression

Childhood adversities have been associated with onset and worse clinical presentations of depression. Epigenetic changes may reflect childhood adversities, while their effects on clinical characteristics of depression are unknown. This study aimed to investigate whether epigenetic changes were associated with childhood adversities, pretreatment characteristics, and treatment outcomes in depressive patients. In 108 patients with major depressive disorders, the methylation status in the promoter of gene encoding serotonin transporter (SLC6A4) was measured. Childhood adversities, socio-demographic and clinical characteristics including assessment scales for depression (Hamilton Depression Rating Scale, HAMD), anxiety (Hamilton Anxiety Rating Scale, HAMA), functioning (Social and Occupational Functioning Assessment Scale, SOFAS), disability (World Health Organization Disability Assessment Schedule-12, WHODAS-12), and quality of life (World Health Organization Quality of Life-Abbreviated form, WHOQOL-BREF) were evaluated at baseline. After a 12-week treatment with antidepressants, the assessment scales were reevaluated. To avoid type I error by multiple comparisons, Bonferroni corrections were applied. Higher SLC6A4 promoter methylation status was significantly associated with childhood adversities, worse clinical presentation (family history of depression, higher perceived stress, and more severe psychopathology assessed by SOFAS, WHODAS-12, and WHOQOL-BREF), but was not associated with treatment outcomes after considering multiple comparisons. SLC6A4 methylation status could be a proxy marker for childhood adversities and a clinical biomarker for certain presentations of depression.

BDNF promoter methylation and suicidal behavior in depressive patients

INTRODUCTION Suicide is a major health problem, and depression is a major psychiatric cause of suicide. Suicide is influenced by the multifactorial interaction of many risk factors. Therefore, epigenetic research may lead to understandings that are applicable to suicide. This study investigated whether epigenetic changes are associated with suicidal behavior and evaluated the treatment outcome of suicidal ideation in depressive patients. METHODS In 108 patients with major depression, the promoter methylation of the gene encoding brain-derived neurotrophic factor (BDNF) was measured. Sociodemographic and clinical characteristics including a history of previous depressive episodes, age at onset, duration of illnesses, family history of depression, and number of stressful life events as well as subjective perception of stress and assessment scales for depression (HAMD), anxiety (HAMA), function (SOFAS), disability (WHODAS-12), and quality of life (WHOQOL-BREF) were evaluated at baseline. Suicidal behavior was ascertained using a semistructured clinical interview with questions about severity and intent. Beck Scale for Suicide Ideation (BSS) was administered during 12 weeks of treatment with antidepressants. RESULTS A higher BDNF promoter methylation status was significantly associated with a previous suicidal attempt history, suicidal ideation during treatment, and suicidal ideation at last evaluation as well as with higher BSS scores and poor treatment outcomes for suicidal ideation. LIMITATIONS Methylation status was investigated with limited area of the BDNF gene and sample size was relatively small. CONCLUSIONS BDNF methylation status could be a proxy marker for previous suicidal attempts and a clinical biomarker for poor treatment outcomes of suicidal ideation in depression.

Risperidone versus olanzapine for the treatment of delirium

This study compared the effectiveness of risperidone and olanzapine in the treatment of delirium.

Serotonergic and BDNF genes and risk of depression after stroke

BACKGROUND Polymorphisms of serotonin transporter (5-HTT) and brain-derived neurotrophic factor (BDNF) have been investigated as candidate genes for post-stroke depression (PSD). Serotonin 2a receptor (5-HTR2a) genes have not been yet investigated in PSD. This study aimed to investigate whether the 5-HTT, 5-HTR2a, and BDNF genes are associated with PSD independently and/or interactively in a Korean sample with high prevalence of risk alleles. METHODS In 276 stroke cases, depression was diagnosed using DSM-IV at 2 weeks after stroke, further classified to major PSD (N=29), all (major plus minor) PSD (N=77), and control (N=199) groups. Associations between PSD and 5-HTTLPR, STin2 VNTR, 5-HTR2a 1438A/G, 5-HTR2a 102T/C, and BDNF val66met genotypes were estimated using logistic regression models, and gene-gene interactions were investigated using the generalized multifactor dimensionality reduction method. RESULTS 5-HTR2a 1438 A/A genotype was associated with major PSD, while 5-HTTLPR s/s and BDNF met/met genotypes were associated with all PSD. There was a significant interaction between 5-HTR2a 1438A/G and BDNF val66met polymorphisms for major PSD and a borderline significant interaction between 5-HTTLPR and BDNF val66met polymorphisms for all PSD. CONCLUSIONS In a large cohort, we found evidence for serotonin and BDNF polymorphisms as susceptibility factors and gene-gene interactions between these systems for depression at 2 weeks post-stroke.

Comorbidity of Depression with Physical Disorders: Research and Clinical Implications

Depression is prevalent in patients with physical disorders, particularly in those with severe disorders such as cancer, stroke, and acute coronary syndrome. Depression has an adverse impact on the courses of these diseases that includes poor quality of life, more functional impairments, and a higher mortality rate. Patients with physical disorders are at higher risk of depression. This is particularly true for patients with genetic and epigenetic predictors, environmental vulnerabilities such as past depression, higher disability, and stressful life events. Such patients should be monitored closely. To appropriately manage depression in these patients, comprehensive and integrative care that includes antidepressant treatment (with considerations for adverse effects and drug interactions), treatment of the physical disorder, and collaborative care that consists of disease education, cognitive reframing, and modification of coping style should be provided. The objective of the present review was to present and summarize the prevalence, risk factors, clinical correlates, current pathophysiological aspects including genetics, and treatments for depression comorbid with physical disorders. In particular, we tried to focus on severe physical disorders with high mortality rates, such as cancer, stroke, and acute coronary syndrome, which are highly comorbid with depression. This review will enhance our current understanding of the association between depression and serious medical conditions, which will allow clinicians to develop more advanced and personalized treatment options for these patients in routine clinical practice.

Role of BDNF val66met polymorphism on the association between physical activity and incident dementia

BACKGROUND Increased physical activity may have beneficial effects on cognitive outcomes; a role of brain-derived neurotrophic factor (BDNF) has been suggested in animal models but not yet tested in humans. This study investigated modification by BDNF val66met polymorphism of the association between physical activity, incident dementia and other cognitive outcomes. METHODS Of 732 community elders, 107 had dementia at baseline, and 518 (83%) of the remainder were followed over 2.4 years. Cognitive impairment and decline were defined from Mini-Mental State Examination scores. Self-reported level of physical activity was recorded on a 4-point scale. BDNF val66met and apolipoprotein E genotypes were ascertained. Covariates included age, sex, education, depression, vascular risk factors, and instrumental activities of daily living. RESULTS Baseline lower physical activity was significantly associated with incident dementia as well as with baseline dementia and cognitive impairment and incident cognitive decline. BDNF val66met polymorphism itself was not associated with any cognitive outcome. However, the strength of association between lower activity and all cognitive outcomes increased incrementally with the number of met alleles, and was strongest in those with the met/met genotype. BDNF×activity interaction terms were stronger for prospective outcomes (incident dementia, cognitive decline) compared to cross-sectional outcomes (prevalent dementia, cognitive impairment no dementia). CONCLUSIONS This study supports a previously suggested neurobiological basis for the effects of physical activity on dementia involving the BDNF system since the met allele is recognised to be associated with lower activity-dependent secretion of BDNF.

Comparative validity of depression assessment scales for screening poststroke depression

INTRODUCTION This study aimed to compare screening properties of four assessment scales for poststroke depression (PSD) at 2 weeks and 1 year after index stroke, and investigated factors contributing to misclassification. METHODS A total of 423 patients were evaluated 2 weeks after stroke and 288 (68%) were followed 1 year later, and were diagnosed as having major and minor PSD applying DSM-IV criteria gold standards. The Beck Depression Inventory (BDI), Hospital Anxiety and Depression Scale-depression subscale (HADS-D), Hamilton Rating Scale for Depression (HAMD), and Montgomery-Asberg Depression Rating Scale (MADRS) were administered. The balance of sensitivity and specificity was assessed using receiver operating characteristics (ROC) analysis. RESULTS Discriminating abilities of all the scales for major and all PSD were good (area under ROC values 0.88-0.93 and 0.88-0.92 at 2 weeks; and 0.93-0.96 and 0.89-0.91 at 1 year, respectively). Misclassification was influenced by demographic characteristics and stroke severity particularly for the BDI and HAMD, was more marked for all PSD than for major PSD, and was more prominent at 2 weeks than at 1 year after stroke. LIMITATIONS Patients with only mild to moderate stroke severity were included. CONCLUSIONS Although there were no marked differences in the screening abilities for PSD between the scales, differences were found in factors influencing misclassification. Assessment scales with less somatic items may be recommended for the screening of PSD, particularly at the acute phase of stroke.

Improvement within 2 weeks and later treatment outcomes in patients with depressive disorders: The CRESCEND study

BACKGROUND Although antidepressants are conventionally given for 4-6 weeks before deciding on response, several reports suggest that early improvement predicts later outcomes. In a naturalistic national cohort study, we sought to investigate the predictive value of early improvement on Hamilton Depression Rating Scale (HAMD) score for later outcomes (depression (HAMD), anxiety (HAMA), global severity (CGI-s) and functioning (SOFAS)), as well as socio-demographic and clinical correlates of early improvement. METHODS Participants were recruited from 18 hospitals across South Korea. All met DSM-IV criteria for depressive disorders, scored ≥14 on the HAMD and received antidepressant treatment for up to 12 weeks. Treatment was naturalistic in that each clinician freely decided the types, doses, and regimes of antidepressant and concomitant medications. Early improvement was defined as a reduction in HAMD score of ≥20% compared with baseline within 2 weeks of treatment. Later treatment outcomes were measured at 4, 8, and 12 weeks. RESULTS In a recruited sample of 568 patients, early improvement predicted 12 week treatment outcomes with high sensitivity and high negative predictive values. The predictive values for HAMD and HAMA 12-week responses were higher compared to CGI-s and SOFAS responses. Early improvement was associated with higher monthly income, baseline lower anxiety and higher functioning levels. The patients with early improvement more frequently received antidepressant monotherapy. LIMITATIONS The study was observational, and the treatment modality was naturalistic. CONCLUSIONS Early antidepressant improvement strongly predicted later outcomes, and was associated with higher income, lower anxiety, and higher function.

Escitalopram treatment for depressive disorder following acute coronary syndrome: a 24-week double-blind, placebo-controlled trial.

OBJECTIVE Depression is common after acute coronary syndrome (ACS) and has adverse effects on prognosis. There are few evidence-based interventions for treating depression in ACS. This study investigated the efficacy and safety of escitalopram in treating depressive disorders identified 2-14 weeks after a confirmed ACS episode. METHOD A total of 217 patients with DSM-IV depressive disorders (121 major and 96 minor) and ACS were randomly assigned to receive escitalopram in flexible doses of 5-20 mg/d (n = 108) or placebo (n = 109) for 24 weeks. The study was conducted from 2007 to 2013. The primary outcome measure was the Hamilton Depression Rating Scale (HDRS). Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), Clinical Global Impressions-Severity of Illness scale (CGI-S), Social and Occupational Functioning Assessment Scale (SOFAS), and World Health Organization Disability Assessment Schedule-12. Cardiovascular safety outcomes included echocardiography, electrocardiography, laboratory test, body weight, and blood pressure results. RESULTS Escitalopram was superior to placebo in reducing HDRS scores (mean difference = 2.3, P = .016, effect size = 0.38). Escitalopram was also superior to placebo in decreasing depressive symptoms evaluated by the MADRS, BDI, and CGI-S and in improving SOFAS functioning level. Escitalopram was not associated with any harmful changes in cardiovascular safety measures. Dizziness was significantly more frequently reported in the escitalopram group (P = .018), but there were no significant differences in any other adverse events. CONCLUSIONS These results indicate that escitalopram has clinically meaningful antidepressant effects with no evidence of reduced cardiovascular safety in depressive disorder following ACS. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00419471.

Apolipoprotein E4 Genotype and Depressive Symptoms as Risk Factors for Dementia in an Older Korean Population

Objective Growing evidence suggests the separate associations of apolipoprotein E e4 allele (apo E4) and depression with incident dementia. This study investigated the separate and combined effects of apo E4 and depression on the incidence of dementia in both men and women. Methods Of 625 elderly without dementia at baseline, 518 (83%) were followed over a 2.4-year period and were assessed clinically for incident dementia. The apo E polymorphism was ascertained, and depression was identified using the Korean version of the Geriatric Depression Scale (KGDS). Covariates included age, gender, education, disability, alcohol history, physical activity, and vascular risk factors. Results The incidence of dementia was significantly higher in elderly Koreans with both apo E4 and depression compared to those without both factors [adjusted odds ratio (95% CI)=5.85 (1.77-19.38)]. This interaction was significant in men (p=0.049), but not in women (p=0.354). Conclusion Depressed elderly people are at great risk for incident dementia in the presence of apo E4. Potential gender differences require further evaluation.