Hee-Ju Kang

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.

Associations of BDNF Genotype and Promoter Methylation with Acute and Long-Term Stroke Outcomes in an East Asian Cohort

Background Brain derived neurotrophic factor (BDNF) has been shown to play an important role in poststroke recovery. BDNF secretion is influenced by genetic and epigenetic profiles. This study aimed to investigate whether BDNF val66met polymorphism and promoter methylation status were associated with outcomes at two weeks and one year after stroke. Methods and Findings A total of 286 patients were evaluated at the time of admission and two weeks after stroke, and 222 (78%) were followed one year later in order to evaluate consequences of stroke at both acute and chronic stages. Stroke outcomes were dichotomised into good and poor by the modified Rankin Scale. Stroke severity (National Institutes of Health Stroke Scale), physical disability (Barthel Index), and cognitive function (Mini-Mental State Examination) were measured. Associations of BDNF genotype and methylation status on stroke outcomes and assessment scale scores were investigated using logistic regression, repeated measures ANOVA and partial correlation tests. BDNF val66met polymorphism was independently associated with poor outcome at 2 weeks and at 1 year, and with worsening physical disability and cognitive function over that period. Higher BDNF promoter methylation status was independently associated with worse outcomes at 1 year, and with the worsening of physical disability and cognitive function. No significant genotype-methylation interactions were found. Conclusions A role for BDNF in poststroke recovery was supported, and clinical utility of BDNF genetic and epigenetic profile as prognostic biomarkers and a target for drug development was suggested.

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.

A longitudinal study of BDNF promoter methylation and genotype with poststroke depression

INTRODUCTION Brain derived neurotrophic factor (BDNF) has been shown to play an important role in the pathophysiology of mood disorders including poststroke depression (PSD). BDNF secretion is influenced by epigenetic and genetic profiles. This study aimed to investigate whether BDNF gene promoter methylation status and val66met polymorphism were associated with depression ascertained at two weeks and one year after stroke. METHODS A total of 286 patients were evaluated two weeks after stroke, and 222 (78%) were followed one year later. Depression (major or minor depressive disorder) was diagnosed according to DSM-IV criteria, and classified into prevalent, persistent, and incident PSD according to presence at the two examinations. Depression severity was assessed by the Hospital Anxiety and Depression Scale-depression subscale and the Hamilton Depression Rating Scale. The effects of BDNF methylation status and genotype on PSD status were investigated using multivariate logistic regression models. The associations of BDNF methylation status and genotype with score on depression assessment scales were estimated using partial correlation tests and general linear models, respectively. RESULTS Higher BDNF methylation status was independently associated with prevalent, persistent and particularly with incident PSD, and with worsening depressive symptoms over follow-up but not with baseline severity. The BDNF val66met polymorphism was independently associated with prevalent PSD, but not with persistent and incident PSD nor with depressive symptoms severity. No significant methylation-genotype interactions were found. LIMITATIONS Methylation status was investigated with limited area of the BDNF gene and sample size was relatively small. CONCLUSIONS A role for BDNF in PSD was supported, and associations with BDNF gene methylation status may represent a target for drug development.

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.

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.

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.

Determinants of suicidal ideation in patients with breast cancer.

Breast cancer survivors are at higher risk of psychological problems including suicidal ideation. However, studies on suicidal ideation in breast cancer survivors have been rare and have not been investigated prospectively. This study aimed to investigate the prevalence and independent risk factors for suicidal ideation within 1 week and at 1 year after breast surgery for breast cancer.

White Matter Hyperintensities and Functional Outcomes at 2 Weeks and 1 Year after Stroke

Background: Many stroke survivors remain at a functionally disabled state. Early prediction of functional outcome is an important step in the treatment and care of stroke patients. Brain imaging measures have received particular attention as one of the predictors of stroke outcomes. However, the associations between white matter hyperintensities (WMHs) and post-stroke recovery have been controversial. This study aimed to investigate whether deep and periventricular WMHs (DWMHs and PVWMHs, respectively) were associated with functional outcomes at 2 weeks and 1 year after stroke separately and interactively. Methods: A total of 408 patients were evaluated at the time of admission and 2 weeks after stroke, and 284 (78%) were followed 1 year later in order to evaluate consequences of stroke at both acute and chronic stages. Stroke outcomes were dichotomized into good and poor by applying a modified Rankin Scale (mRS) score cutoff of 1 (no significant disability)/2 (slight disability). Measures of stroke severity (National Institutes of Health Stroke Scale: NIHSS), physical disability (Barthel Index: BI), and cognitive function (Mini-Mental State Examination: MMSE) were administered. Brain magnetic resonance imaging (MRI) was performed at admission. DWMHs and PVWMHs were rated visually on axial FLAIR images using the 4-point modified Fazeka’s scale and categorized into mild (grades 0 and 1) or severe (grades 2 and 3). The demographic and clinical covariates of age, gender, years of education, previous history of stroke, depression, stroke location, and vascular risk factors were obtained. Associations of WMHs with stroke outcomes (mRS) and other measures (NIHSS, BI, and MMSE) at 2 weeks and at 1 year after stroke were investigated using logistic regression and repeated measures ANOVA after adjustment for the potential covariates. Results: Severe PVWMHs, but not severe DWMHs, were significantly associated with worse outcomes both at 2 weeks and at 1 year after stroke. Furthermore, significant interactive effects of PVWMHs and DWMHs on poor outcomes were found. Significant PVWMH group by time interactions on NIHSS and BI scores, and significant group effects of both DWMHs and PVWMHs on MMSE score were found. Conclusions: PVWMHs predicted poorer functional outcomes after stroke both in the acute and chronic phases, independently and interactively with DWMHs. In addition, PVWMHs were independently associated with worsening of stroke severity and physical disability. More careful evaluation and management of stroke patients with a high risk of functional dependence are indicated. Overall, PVWMH might be a prognostic marker of short- and long-term stroke outcomes.