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Objective A growing body of evidence reports on the effect of different types of childhood abuse on the structural and functional architecture of the brain. In the present study, we aimed to investigate the differences in cortical thickness according to specific types of childhood abuse between patients with major depressive disorder (MDD) and healthy controls (HCs).Methods A total of 61 patients with MDD and 98 HCs were included in this study. All participants underwent T1-weighted magnetic resonance imaging, and the occurrence of childhood abuse was assessed using the Childhood Trauma Questionnaire. We investigated the association between whole-brain cortical thickness and exposure to any type of childhood abuse and specific type of childhood abuse in the total sample using the FreeSurfer software.Results No significant difference was reported in the cortical thickness between the MDD and HC groups nor between the “any abuse” and “no abuse” groups. Compared to no exposure to childhood sexual abuse (CSA), exposure to CSA was significantly associated with cortical thinning in the left rostral middle frontal gyrus (p=0.00020), left (p=0.00240), right fusiform gyri (p=0.00599), and right supramarginal gyrus (p=0.00679).Conclusion Exposure to CSA may lead to cortical thinning of the dorsolateral prefrontal cortex, which is deeply involved in emotion regulation, to a greater extent than other types of childhood abuse.

Major depressive disorder (MDD) is one of the most common psychiatric disorders, and present various symptoms such as the dysregulation of mood, cognition, and behavior. The purpose of the present study was to investigate the morphometric change in MDD patients by voxel-based morphometry (VBM) and sulcal depth analyses. Forty-six MDD patients (mean age, SD; 36.07±14.34), and 23 age- and sex-matched normal controls (NML) (mean age, SD; 36.78±14.42) were included. Coronal 3D T1 magnetic resonance imaging (MRI) was obtained with the resolution of isotropic 1.0 mm. To check morphological changes of brain, T1 MRIs were objectively processed by VBM and sulcal depth methods. In sulcal depth analysis, depressed patients showed reduced sulcal depth in the areas of left posterior ramus of the lateral sulcus, superior frontal sulcus, supramarginal gyrus, central sulcus (Rolando's fissure), and Heschl's gyrus. And right posterior ramus of the lateral sulcus, temporal plane of the superior temporal gyrus, anterior transverse collateral sulcus, and central sulcus (Rolando's fissure) were also reduced compared to NML. But, VBM analyses did not showed significant finding. Reduced sulcal depth in the motor and emotion related areas were found in patients with MDD. Especially reduced sulcal depth in bilateral central sulci which are connecting between primary motor cortex and primary sensory cortex seems to be related with social and physical anhedonia in MDD.

Objective Considerable evidence suggests that neuroinflammation plays an important role in the pathophysiology of major depressive disorder (MDD). However, the relationship between serum C4 binding protein (C4BP) and white matter (WM) tract integrity in MDD has not been investigated.Methods We obtained diffusion tensor images of 44 patients with MDD and 44 healthy controls and performed TRActs Constrained by UnderLying Anatomy (TRACULA) analysis to assess WM tract integrity. Serum C4-binding protein alpha chain (C4BPA) and C4- binding protein beta chain (C4BPB) levels were measured and in-between group comparisons were obtained. The correlation between serum C4BP levels and WM tract integrity was examined.Results In comparison to healthy controls, both serum C4BPA and C4BPB were higher in MDD. Also, fractional anisotropy (FA) was increased in the left cingulum-angular bundle (CAB) in MDD, but not healthy controls (HCs). A significant correlation was found between serum C4BP and FA levels in the right cingulum-cingulate gyrus bundle (CCG) in MDD.Conclusion This study is the first to investigate the correlation between serum C4BP levels and WM tract integrity in MDD. We identified an increase in WM integrity in the left CAB region in MDD. Furthermore, serum C4BP levels were higher in MDD, and this finding correlated with increased WM integrity in the right CCG region.

Background: Late-life depression (LLD) is one of the most common psychiatric disorders. However, LLD is often undetected or inadequately treated by clinicians. This review summarizes the recent research on pharmacotherapy for LLD, updates information on monotherapy using recommended antidepressants, and discusses the clinical features and diagnostic criteria for LLD.Current Concepts: The diagnostic criteria for depression in both elderly and young adults are identical. Clinical features of the elderly with depression more likely include more comorbid medical conditions and cognitive impairment than those of young adults. Depression in the elderly tends to have a more chronic course with frequent recurrences or relapses.Discussion and Conclusion: The current pharmacological treatment guidelines for LLD recommend the use of selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor, bupropion, mirtazapine, and vortioxetine as first-line medications. SSRIs, among them, are recommended first because they present fewer serious adverse effects and more clinical evidence than those of other antidepressants. Before starting antidepressant treatment for LLD, clinicians should consider patients’ comorbid medical conditions, drug interactions, possible adverse effects of antidepressants, and polypharmacy. The starting dose of antidepressants for elderly patients should be half of that prescribed for young adults to minimize the adverse effects; however, most elderly patients need the same antidepressant doses as that prescribed for young patients. After remission, a 1-year maintenance treatment is required to prevent recurrence or relapse of LLD.

Objective Advances in surface-based morphometric methods have allowed researchers to separate cortical volume into cortical thickness (CTh) and surface area (SA). Although CTh alterations in major depressive disorder (MDD) have been observed in numerous studies, few studies have described significant SA alterations. Our study aimed to measure patients’ SAs and to compare it with their CTh to examine whether SA exhibits alteration patterns that differ from those of CTh in drug-naïve patients with MDD.Methods A total of 71 drug-naïve MDD patients and 111 healthy controls underwent structural magnetic resonance imaging, and SA and CTh were analyzed between the groups.Results We found a smaller SA in the left superior occipital gyrus (L-SOG) in drug-naïve patients with MDD. In the CTh analysis, the bilateral fusiform gyrus, left middle occipital gyrus, left temporal superior gyrus, and right posterior cingulate showed thinner cortices in patients with MDD, while the CTh of the bilateral SOG, right straight gyrus, right posterior cingulate, and left lingual gyrus were increased.Conclusion Compared with the bilateral occipito-temporal changes in CTh, SA alterations in patients with MDD were confined to the L-SOG. These findings may improve our understanding of the neurobiological mechanisms of SA alteration in relation to MDD.

Objective Although bipolar II disorder (BD II) is not simply a mitigated form of bipolar I disorder (BD I), their neurobiological differences have not been elucidated. The present study aimed to explore cortical thickness (CT) and surface area (SA) in patients with BD I and BD II and healthy controls (HCs) to investigate the shared and unique neurobiological mechanisms of BD subtypes.Methods We enrolled 30 and 44 patients with BD I and BD II, respectively, and 100 HCs. We evaluated CT and SA using FreeSurfer and estimated differences in CT and SA among the three groups (BD I vs. BD II vs. HC). We adjusted for age, sex, educational level, and intracranial volume as confounding factors.Results We found widespread cortical thinning in the bilateral frontal, temporal, and occipital regions; cingulate gyrus; and insula in patients with BD. Alterations in SA, including increased SA of the pars triangularis and decreased SA of the insula, were noted in patients with BD. Overall, we found BD II patients demonstrated decreased SA in the right long insula compared to BD I patients.Conclusion Our results suggest that decreased SA in the right long insula is crucial for differentiating BD subtypes.

Alexithymia is characterized by impairments in the processing of emotions. Although the disruptions in the white matter (WM) integrity in Major depressive disorder (MDD) has frequently been reported, the underlying relationship with alexithymia remains unclear. In the present study, we investigated WM tracts with Tracts Constrained by UnderLying Anatomy approach to discover potential associations between alexithymia and WM integrity to identify the neural basis of impaired emotional self-awareness in MDD. 101 patients with MDD and 99 healthy sex- and age-matched individuals underwent diffusion-weighted imaging. All participants were assessed with the 20-item Toronto Alexithymia Scale (TAS). TAS scores were significantly higher in MDD patients than in controls. Patients with MDD exhibited significantly lower FA values in the left inferior longitudinal fasciculus and it also showed negative associations with TAS. These results contribute to the neurobiological evidence on the association between MDD and alexithymia. Additionally, they suggest that reduced white matter integrity in the regions constitutes a principal pathophysiology underlying impaired emotional recognition and description in MDD.

The Nod-like receptor pyrin containing 3 (NLRP3) inflammasome has been reported to be a convergent point linking the peripheral immune response induced by psychological stress and neuroinflammatory processes in the brain. We aimed to identify differences in the methylation profiles of the NLRP3 gene between major depressive disorder (MDD) patients and healthy controls (HCs). We also investigated the correlation of the methylation score of loci in NLRP3 with cortical thickness in the MDD group using magnetic resonance imaging (MRI) data. A total of 220 patients with MDD and 82 HCs were included in the study, and genome-wide DNA methylation profiling of the NLRP3 gene was performed. Among the total sample, 88 patients with MDD and 74 HCs underwent T1-weighted structural MRI and were included in the neuroimaging–methylation analysis. We identified five significant differentially methylated positions (DMPs) in NLRP3. In the MDD group, the methylation scores of cg18793688 and cg09418290 showed significant positive or negative correlations with cortical thickness in the occipital, parietal, temporal, and frontal regions, which showed significant differences in cortical thickness between the MDD and HC groups. Our findings suggest that NLRP3 DNA methylation may predispose to depression-related brain structural changes by increasing NLRP3 inflammasome-related neuroinflammatory processes in MDD.

Trait impulsivity is a known risk factor for suicidality, and the prefrontal cortex plays a key role in impulsivity and its regulation. However, the relationship between trait impulsivity, neural basis, and suicidality has been inconsistent. Therefore, this study aimed to explore the relationship between impulsivity and its structural correlates (prefrontal gray matter volume), suicidal ideation, and actual suicide attempts. A total of 87 individuals with major depressive disorder participated in study, and the gray matter volume of the prefrontal regions was extracted from T1 images based on region of interest masks. The variables for the mediation models were selected based on correlation analysis and tested for their ability to predict suicide attempts, with impulsivity and suicidal ideation as the mediation variables and gray matter volume as the independent variable. A significant correlation was observed between suicidal ideation and the left dorsolateral prefrontal cortex and right dorsomedial prefrontal cortex. The dual-mediation model revealed a significant indirect relationship between gray matter volume in both regions and suicide attempts mediated by motor impulsivity and suicidal ideation. The counterintuitive positive relationship between gray matter volume and suicidality was also discussed.

This cohort study uses data from the Korean National Health Insurance Service database to assess the association of depression with the development of new-onset atrial fibrillation., Key Points Question Is depression associated with increased risk of new-onset atrial fibrillation (AF)? Findings In this cohort study of 5 031 222 individuals with a follow-up of 43 115 042 person-years, depression was associated with a higher cumulative incidence of new-onset AF. Recurrent episodes of depression were associated with an even higher risk of new-onset AF, and young age and female sex had a significant interaction with depression. Meaning Results of this study suggest that depression is associated with an increased risk of new-onset AF, suggesting the need for adequate screening for AF in people with depression., Importance The risk of atrial fibrillation (AF) in people with depression is not fully known. Depression is associated with sympathetic activation and emotional stress, which might increase the risk of new-onset AF. Objective To assess the incidence of new-onset AF in those with and without depression using data from a nationwide health care database. Design, Setting, and Participants This cohort study obtained data from the Korean National Health Insurance Service database and enrolled people who underwent a nationwide health checkup in 2009. People younger than 20 years and those with a history of heart valve surgery, previous diagnosis of mitral stenosis, or who were diagnosed with AF between January 1, 2002 and December 31, 2008 were excluded. The risk of new-onset AF (occurring between 2009 and 2018) was compared in people who were and were not diagnosed with depression within a year before the 2009 nationwide health checkup. Data were analyzed between August 1, 2020 and October 31, 2020. Exposure Previous diagnosis of depression. Main Outcomes and Measures Cumulative incidence and risk of new-onset AF between 2009 and 2018 in participants with and without depression. Kaplan-Meier analysis was conducted to assess incidence of AF, and Cox proportional hazards regression was used to calculate adjusted and unadjusted hazard ratios (HRs) and 95% CIs. Results A total of 5 031 222 individuals with a mean (SD) age of 46.99 (14.06) years (2 771 785 men [55.1%]) were included in the analysis; of these individuals, 148 882 (3.0%) had a diagnosis of depression in the year before the 2009 health checkup and 4 882 340 (97%) did not. People with depression vs those without depression were older (aged 56.7 vs 46.7 years) and more likely to be women (96 472 [64.8%] vs 2 162 965 [44.3%]). Prevalence of hypertension, diabetes, dyslipidemia, and heart failure was higher in the depression group. The cumulative incidence of new-onset AF was significantly higher in people with depression vs without depression in the Kaplan-Meier analysis and showed steady divergence throughout 10 years of follow-up (cumulative incidence, 4.44% vs 1.92%; log-rank P

Depressive symptoms have been found to be associated with decreased hand-grip strength (HGS) and low socioeconomic status (SES) in older adults. We aimed to investigate the potential moderating effect of SES on the association between HGS and depressive symptoms and the potential mediating effect of HGS on the association between SES and depressive symptoms using a nationally representative sample of older adults.Data from 3169 community-dwelling adults aged 60 years or older were acquired from the Korea National Health and Nutrition Examination Survey conducted in 2014 and 2016. HGS was measured using a digital hand-grip dynamometer. Depressive symptoms were evaluated using the 9-item version of the Patient Health Questionnaire-9 (PHQ-9). SES was assessed using equivalent monthly household income and education level.Older adults in the lowest tertile of HGS measures were more likely to have experienced depressive symptoms compared to those in the highest tertile (odds ratio = 1.95, 95% confidence interval = 1.25-2.74). A significant moderating effect of household income level was observed on the association between HGS and PHQ-9 score (P = 0.014). Older adults with a low income had a stronger inverse correlation between HGS and PHQ-9 score compared to those with a high income (low income: beta = -0.162, P 0.001; high income: beta = -0.119, P = 0.036). HGS partially mediated the association between low income and depressive symptoms.Our findings indicate that there may be a stronger relationship between low HGS and depressive symptoms in socioeconomically deprived older people. Further research on muscle strength and income level in older adults is required regarding depression risk assessment.

Objective This study aimed to demonstrate that the Patient Health Questionnaire (PHQ)-8 is not less useful than the PHQ-9 as a screening test for major depressive disorder (MDD). Methods We performed a retrospective analysis of 567 patients in psychiatric outpatient units. The Mini International Neuropsychiatric Interview was used to diagnose MDD. We derived the validity and reliability of the PHQ-8 and PHQ-9. To evaluate the ability of the PHQ-8 and PHQ-9 to discriminate MDD, we drew receiver operating characteristic (ROC) curves and compared the areas under the curves (AUCs). Results Of the 567 participants, 207 (36.5%) were diagnosed with MDD. Cronbach's αs for the PHQ-8 and PHQ-9 were 0.892 and 0.876, respectively. Similar to the PHQ-9, the PHQ-8 was also associated with scores on the Hamilton Depression Rating Scale in a correlation analysis. When we drew ROC curves for the PHQ-8 and PHQ-9, there was no statistically significant difference in the AUCs. With a cutoff score of 10, the PHQ-8 showed a sensitivity of 58.3%, specificity of 83.1%, positive predictive value of 53.4%, and negative predictive value of 85.7%. Conclusion In a psychiatric outpatient sample, the PHQ-8 was as useful as the PHQ-9 for MDD screening.

Background:The hippocampus is not a uniform structure, but rather consists of multiple, functionally specialized subfields. Few studies have explored hippocampal subfield volume difference in the same sample of major depressive disorder (MDD) and bipolar disorder (BD) cases. We aimed to investigate the difference of hippocampal subfield volume between patents with MDD and BD and healthy controls (HCs).Methods:A total of 102 MDD and 55 BD patients and 135 HCs were recruited and underwent T1-weighted image. Hippocampal subfield volume was calculated by automated segmentation and volumetric procedures developed by Iglesias et al. and implemented in FreeSurfer. Volume differences between the groups were analyzed using the analysis of covariance and controlling for age, sex, and total intracranial cavity volume.Results:Patients with MDD had significantly reduced volumes in the bilateral cornu ammonis 1 (CA1), CA4, the granule cell layer (GCL), molecular layer (ML), whole hippocampus, the left CA2/3, and right presubiclum and subiculum. Patients with BD had significantly reduced volumes in the right CA1, GCL, and the whole hippocampus as compared to HCs. No significant volume differences were observed between the MDD and BD groups. Illness duration was negatively correlated with volumes of the left CA1, CA4, ML, presubiculum, subiculum, and the whole hippocampus in patients with BD.Conclusion:We observed hippocampal subfield volume reductions in both MDD and BD, a finding which more prominent in MDD. The inverse correlation between BD illness duration and hippocampal subfield volume may evidence the neuroprogressive nature of BD.

Background Previous pharmaco-epidemiological studies have reported increases in the prescription of psychotropic medications after a disaster, reflecting post-disaster changes in psychiatric conditions and mental health service utilization. We investigated changes in the prescription of psychotropic medications in the Danwon district of Ansan city (Ansan Danwon) compared to a control community before and after the Sewol Ferry disaster on April 16, 2014. Methods Data was collected from the Korean Health Insurance Review and Assessment Service database. We analyzed the prescription rates of psychotropic medications including antidepressants, anxiolytics, and sedatives/hypnotics, and investigated whether the time-series pattern of monthly prescriptions per 100,000 people was different in Ansan Danwon compared to that in Cheonan city after the Sewol Ferry disaster through difference-in-differences regression analysis. Results Ansan Danwon showed a significantly greater increase (5.6%) in the prescription rate of antidepressants compared to Cheonan city following the Sewol Ferry disaster. There were no significant differences in changes in the prescription rates of anxiolytics or sedatives/hypnotics. In the secondary analysis, a significantly greater increase in the prescription rate of antipsychotics was observed in Ansan Danwon compared to a control community after the disaster. Limitations We could not exclude the possibility that other events influenced changes in the prescription rates of psychotropic medications during the study period. Conclusions Pharmaco-epidemiological studies on psychotropic medication prescription after a disaster provide important information about population-level mental health. Our results suggest that the Sewol Ferry disaster exerted a harmful effect on the mental health status of the affected community., Highlights • The Sewol Ferry disaster caused 305 deaths in Ansan, Korea on April 16, 2014. • Psychotropic prescriptions rates were examined in Ansan Danwon after the disaster. • Antidepressant prescriptions were increased in Ansan Danwon versus a control city. • There were no differences in anxiolytic or sedative/hypnotic prescription rates. • Post-disaster prescription rates are a useful reflection of community mental health.

Substance P (SP) has been implicated in major depressive disorder (MDD), with SP antagonists being studied as potential antidepressants. Although impaired neural plasticity is considered a key mechanism in MDD pathophysiology, the association between SP and brain structural changes in depression has not been investigated. We investigated the correlations between SP levels and white matter (WM) integrity in 42 medication-naive patients with MDD and 57 healthy controls (HCs). Plasma levels of SP were determined, and diffusion tensor imaging (DTI) was performed to investigate microstructural changes in WM tracts. In patients, negative correlations between SP levels and fractional anisotropy (FA) values of the forceps minor of the corpus callosum, and positive correlations between SP levels and radial diffusivity (RD) and mean diffusivity (MD) values of the right corticospinal tract (CST) were observed, with no significant correlations in HCs. Linear regression analyses showed SP levels to significantly predict FA values of the forceps minor, and RD and MD values of the right CST in patients, but not in HCs. We consider our findings to contribute to the neurobiological evidence on the association between SP and brain structural changes in depression, which may be related with the pathophysiology and treatment of MDD.

Suicide is among the most important global health concerns; accordingly, an increasing number of studies have shown the risks for suicide attempt(s) in terms of brain morphometric features and their clinical correlates. However, brain studies addressing suicidal vulnerability have been more focused on demonstrating impairments in cortical structures than in the subcortical structures. Using local shape volumes (LSV) analysis, we investigated subcortical structures with their clinical correlates in depressed patients who attempted suicide. Then we compared them with depressed patients without a suicidal history and age‐ and sex‐matched healthy controls (HCs; i.e., 47 suicide attempters with depression, 47 non‐suicide attempters with depression, and 109 HCs). Significant volumetric differences were found between suicidal and nonsuicidal depressed patients in several vertices: 16 in the left amygdala; 201 in the left hippocampus; 1,057 in the left putamen; and 140 in the left pallidum; 1 in the right pallidum; and 6 in the bilateral thalamus. These findings indicated subcortical alterations in LSV in components of the limbic–cortical–striatal–pallidal–thalamic circuits. Moreover, our results demonstrated that the basal ganglia was correlated with perceived stress levels, and the thalamus was correlated with suicidal ideation. We suggest that suicidality in major depressive disorder may involve subcortical volume alterations., Using local shape volumes (LSV) analysis, significant volumetric differences were found between suicidal and nonsuicidal depressed patients in the left amygdala, left hippocampus, left putamen, bilateral pallidum, and thalamus. These findings propose that suicidality in major depressive disorder may involve subcortical volumetric alterations.

Treating patients with major depressive disorder is challenging because it takes several months for antidepressants prescribed for the patients to take effect. This limitation may result in increased risks and treatment costs. To address this limitation, an accurate antidepressant response prediction model is needed. Recently, several studies have proposed models that extract useful features such as neuroimaging biomarkers and genetic variants from patient data, and use them as predictors for predicting the antidepressant responses of patients. However, it is impossible to utilize all the different types of predictors when making a clinical decision on what drugs to prescribe for a patient. Although a machine learning-based antidepressant response prediction model has been proposed to overcome this problem, the model cannot find the most effective antidepressant for a patient. Based on a neural network, we propose an Antidepressant Response Prediction Network (ARPNet) model capturing high-dimensional patterns from useful features. Based on a literature survey and data-driven feature selection, we extract useful features from patient data, and use the features as predictors. In ARPNet, the patient representation layer captures patient features and the antidepressant prescription representation layer captures antidepressant features. Utilizing the patient and antidepressant prescription representation vectors, ARPNet predicts the degree of antidepressant response. The experimental evaluation results demonstrate that our proposed ARPNet model outperforms machine learning-based models in predicting antidepressant response. Moreover, we demonstrate the applicability of ARPNet in downstream applications in use case scenarios.

Study ObjectivesTo investigate the association between weekend catch-up sleep (WCS) and the levels of high-sensitivity C-reactive protein (hsCRP)—a serum inflammatory maker—in adultsMethodsData of 5,506 adults aged 19 years or older were obtained from the nationwide cross-sectional Korea National Health and Nutrition Examination Surveys conducted in 2016. Serum hsCRP level, weekday and weekend sleep durations, and sociodemographic and health-related characteristics were assessed. Participants whose weekend sleep duration was more than 1 h longer than their weekday sleep duration were included in the WCS group. hsCRP level was categorized into quartiles (i.e. highest, middle-high, middle-low, and lowest). Obesity was defined by body mass index ≥ 25.0 kg/m2.ResultsThe WCS group included 1,901 participants (34.5%). In the logistic regression analysis controlling for all variables, adults in the WCS group were significantly less likely to show the highest hsCRP level (versus the lowest level) compared with those without WCS in the complete sample (adjusted odds ratio = 0.795, 95% confidence interval [CI] = 0.662 to 0.955). In a subgroup analysis, this association was significant only for those with weekday sleep duration of 6 h or lower. Longer WCS (≥3 h) was not associated with hsCRP levels. Non-obese people with WCS demonstrated a lower risk for high hsCRP levels, while there was no significant difference in obese people with WCS.ConclusionsOur findings indicate that WCS may be beneficial for low-grade systemic inflammation in adults, particularly among those with shorter weekday sleep durations. WCS may also interact with obesity.

This narrative review discusses how peripheral and central inflammation processes affect brain function and structure in depression, and reports on recent peripheral inflammatory marker-based functional and structural magnetic resonance imaging (MRI) studies from the perspective of neural-circuit dysfunction in depression. Chronic stress stimulates the activity of microglial cells, which increases the production of pro-inflammatory cytokines in the brain. In addition, microglial activation promotes a shift from the synthesis of serotonin to the synthesis of neurotoxic metabolites of the kynurenine pathway, which induces glutamate-mediated excitotoxicity in neurons. Furthermore, the region specificity of microglial activation is hypothesized to contribute to the vulnerability of specific brain regions in the depression-related neural circuits to inflammation-mediated brain injury. MRI studies are increasingly investigating how the blood levels of inflammatory markers such as C-reactive protein, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α are associated with functional and structural neuroimaging markers in depression. Functional MRI studies have found that peripheral inflammatory markers are associated with aberrant activation patterns and altered functional connectivity in neural circuits involved in emotion regulation, reward processing, and cognitive control in depression. Structural MRI studies have suggested that peripheral inflammatory markers are related to reduced cortical gray matter and subcortical volumes, cortical thinning, and decreased integrity of white matter tracts within depression-related neural circuits. These neuroimaging findings may improve our understanding of the relationships between neuroinflammatory processes at the molecular level and macroscale in vivo neuralcircuit dysfunction in depression.

The tryptophan hydroxylase-2 (TPH2) gene is considered a promising genetic candidate regarding its association with a predisposition to major depressive disorder (MDD). Local gyrification reflects the early neural development of cortical connectivity, and is regarded as a potential neural endophenotype in psychiatric disorders. They aimed to investigate the alterations in the cortical gyrification of the prefrontal cortex and anterior cingulate cortex and their association with the TPH2 rs4570625 polymorphism in patients with MDD. One hundred and thirteen patients with MDD and eighty-six healthy controls underwent T1-weighted structural magnetic resonance imaging and genotyping for TPH2 rs4570625. The local gyrification index of 22 cortical regions in the prefrontal cortex and anterior cingulate cortex was analyzed using the FreeSurfer. The patients with MDD showed significant hypergyria in the right rostral anterior cingulate cortex (P = 0.001), medial orbitofrontal cortex (P = 0.003), and frontal pole (P = 0.001). There was a significant genotype-by-diagnosis interaction for the local gyrification index in the right rostral anterior cingulate cortex (P = 0.003). Their study revealed significant hypergyria of the anterior cingulate cortex and prefrontal cortex and an interactive effect between the diagnosis of MDD and the genotype in the anterior cingulate cortex. This might be associated with the dysfunction of neural circuits mediating emotion processing, which could contribute to pathophysiology of MDD. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.

OBJECTIVE We aimed to develop the clinical guideline for headache by the systematic review and synthesis of existing evidence-based guidelines. The purpose of developing the guideline was to improve the appropriateness of diagnosis and treatment of headache disorder, and consequently, to improve patients' pain control and quality of life. The guideline broadly covers the differential diagnosis and treatment of tension-type headache, migraine, cluster headache, and medication-overuse headache. METHODS This is a methodological study based on the ADAPTE methodology, including a systematic review of the literature, quality assessment of the guidelines using the Appraisal of Clinical Guidelines for REsearch & Evaluation II (AGREE II) Instrument, as well as an external review using a Delphi technique. The inclusion criteria for systematic search were as follows: topic-relevant, up-to-date guidelines including evidence from within 5 years, evidence-based guidelines, guidelines written in English or Korean, and guidelines issued by academic institutions or government agencies. RESULTS We selected five guidelines and conducted their quality assessment using the AGREE II Instrument. As a result, one guideline was found to be eligible for adaptation. For 13 key questions, a total of 39 recommendations were proposed with the grading system and revised using the nominal group technique. CONCLUSION Recommendations should be applied to actual clinical sites to achieve the ultimate goal of this guideline; therefore, follow-up activities, such as monitoring of guideline usage and assessment of applicability of the recommendations, should be performed in the future. Further assessment of the effectiveness of the guideline in Korea is needed.

A single nucleotide polymorphism of rs1360780 in the FKBP5 gene is associated with a predisposition to developing major depressive disorder (MDD). We investigated the interactive effects of FKBP5 rs1360780 allelic variants, DNA methylation, and the diagnosis of MDD on structural changes of the entire brain. One hundred and fourteen patients with MDD and eighty-eight healthy controls underwent T1-weighted structural magnetic resonance imaging and FKBP5 rs1360780 genotyping, including DNA methylation of intron 7. We analyzed the volume of cortical and subcortical regions and cortical thickness using FreeSurfer. Significant genotype-by-diagnosis interactions were observed for volumes of the left pars triangularis, supramarginal gyrus, superior parietal lobule, right frontomarginal, and posterior midcingulate gyrus. The T allele was associated with significant volume reductions in these brain regions only in the MDD group except for the right posterior midcingulate gyrus. FKBP5 DNA methylation showed a positive correlation with the thickness of the right transverse frontopolar gyrus in the C allele homozygote group. Our findings suggest that the FKBP5 gene and its epigenetic changes could have influence on morphologic changes of several brain regions involved in emotion regulation, and that this process may be associated with the development of MDD.

Background The SLC6A15 gene has been identified as a novel candidate gene for major depressive disorder (MDD). It is presumed to be involved in the pathophysiology of MDD through regulation of glutamate transmission in the brain. However, the involvement of this gene in microstructural changes in white matter (WM) tracts remains unclear. We aimed to investigate the influence of a polymorphism of this gene (rs1545853) on the structural integrity of WM tracts in the cortico-limbic network. Methods Eighty-six patients with MDD and 64 healthy controls underwent T1-weighted structural magnetic resonance imaging, including diffusion tensor imaging (DTI), and genotype analysis. We selected the genu of the corpus callosum, the uncinate fasciculus, cingulum, and fornix as regions of interest, and extracted fractional anisotropy (FA) values using the FMRIB Diffusion Toolbox software. Results FA values for the left parahippocampal cingulum (PHC) was significantly reduced in the patients with MDD compared to healthy control participants (p = 0.004). We also found that MDD patients with the A allele showed reduced FA values for the left PHC than did healthy controls with the A allele (p = 0.012). There was no significant difference in the FA value of left PHC for the comparison between the G homozygotes of MDD and healthy control group. Conclusions We observed an association between the risk allele of the SLC6A15 gene rs1545843 and the WM integrity of the PHC in MDD patients, which is known to play an important role in the neural circuit involved in emotion processing.

The tryptophan hydroxylase‐2 (TPH2) gene is considered a promising genetic candidate regarding its association with a predisposition to major depressive disorder (MDD). Local gyrification reflects the early neural development of cortical connectivity, and is regarded as a potential neural endophenotype in psychiatric disorders. They aimed to investigate the alterations in the cortical gyrification of the prefrontal cortex and anterior cingulate cortex and their association with the TPH2 rs4570625 polymorphism in patients with MDD. One hundred and thirteen patients with MDD and eighty‐six healthy controls underwent T1‐weighted structural magnetic resonance imaging and genotyping for TPH2 rs4570625. The local gyrification index of 22 cortical regions in the prefrontal cortex and anterior cingulate cortex was analyzed using the FreeSurfer. The patients with MDD showed significant hypergyria in the right rostral anterior cingulate cortex (P = 0.001), medial orbitofrontal cortex (P = 0.003), and frontal pole (P = 0.001). There was a significant genotype‐by‐diagnosis interaction for the local gyrification index in the right rostral anterior cingulate cortex (P = 0.003). Their study revealed significant hypergyria of the anterior cingulate cortex and prefrontal cortex and an interactive effect between the diagnosis of MDD and the genotype in the anterior cingulate cortex. This might be associated with the dysfunction of neural circuits mediating emotion processing, which could contribute to pathophysiology of MDD. Hum Brain Mapp 38:1299–1310, 2017. © 2016 Wiley Periodicals, Inc.

Background DNA methylation in the promoter region of the glucocorticoid receptor gene (NR3C1) is closely associated with childhood adversity and suicide. However, few studies have examined NR3C1 methylation in relation to major depressive disorder (MDD) and hippocampal subfield volumes. We investigated the possible association between NR3C1 methylation and structural brain alterations in MDD in comparison with healthy controls. Methods We compared the degree of NR3C1 promoter methylation in the peripheral blood of non-psychotic outpatients with MDD and that of healthy controls. Correlations among NR3C1 promoter methylation, structural abnormalities in hippocampal subfield volumes and whole-brain cortical thickness, and clinical variables were also analyzed. Results In total, 117 participants (45 with MDD and 72 healthy controls) were recruited. Patients with MDD had significantly lower methylation than healthy controls at 2 CpG sites. In MDD, methylations had positive correlations with the bilateral cornu ammonis (CA) 2–3 and CA4-dentate gyrus (DG) subfields. However, in healthy controls, methylations had positive correlation with the subiculum and presubiculum. There were no differences in total and subfield volumes of the hippocampus between patients with MDD and healthy controls. Compared with healthy controls, patients with MDD had a significantly thinner cortex in the left rostromiddle frontal, right lateral orbitofrontal, and right pars triangularis areas. Conclusions Lower methylation in the NR3C1 promoter, which might have compensatory effects relating to CA2-3 and CA4-DG, is a distinct epigenetic characteristic in non-psychotic outpatients with MDD. Future studies with a longitudinal design and a comprehensive neurobiological approach are warranted in order to elucidate the effects of NR3C1 methylation.

Previous evidence suggests that the serotonin transporter gene (SLC6A4) is associated with the structure of brain regions that are critically involved in dysfunctional limbic-cortical network activity associated with major depressive disorder (MDD). Diffusion tensor imaging (DTI) and tract-based spatial statistics were used to investigate changes in white matter integrity in patients with MDD compared with healthy controls. A possible association between structural alterations in white matter tracts and DNA methylation of the SLC6A4 promoter region was also assessed. Thirty-five medication-naive patients with MDD (mean age: 40.34, male/female: 10/25) and age, gender and education level matched 49 healthy controls (mean age: 41.12, male/female: 15/34) underwent DTI. SLC6A4 DNA methylation was also measured at five CpG sites of the promoter region, and the cell type used was whole-blood DNA. Patients with MDD had significantly lower fractional anisotropy (FA) values for the genu of the corpus callosum and body of the corpus callosum than that in healthy controls (family-wise error corrected, Pr=−0.493, P=0.003) and axial diffusivity (CpG3, Pearson's correlation: r=−0.478, P=0.004) values of the body of the corpus callosum in patients with MDD. These results contribute to evidence indicating an association between epigenetic gene regulation and structural brain alterations in depression. Moreover, we believe this is the first report of a correlation between DNA methylation of the SLC6A4 promoter region and white matter integrity in patients with MDD.

This paper aims to introduce, summarize, and emphasize the importance of the 'Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition'. The guideline broadly covers most aspects of the pharmacological treatment of patients in Korea diagnosed with moderate to severe major depression according to the DSM-IV TR. The guideline establishment process involved determining and answering a number of key questions, searching and selecting publications, evaluating recommendations, preparing guideline drafts, undergoing external expert reviews, and obtaining approval. A guideline adaptation process was conducted for the revised edition. The guideline strongly recommends pharmacological treatment considered appropriate to the current clinical situation in Korea, and should be considered helpful when selecting the appropriate pharmacological treatment of patients diagnosed with major depressive disorder. Therefore, the wide distribution of this guideline is recommended.

Seon-Cheol Park, MD, PhD, Seung-Hwan Sung, MD, Kyu-Man Han, MD, Eun-Soo Won, MD, Hwa-Young Lee, MD, PhD, Jong-Woo Paik, MD, PhD, Hong Jin Jeon, MD, PhD, Moon-Soo Lee, MD, PhD, Se-Hoon Shim, MD, PhD, Young-Hoon Ko, MD, PhD, Kang-Joon Lee, MD, PhD, Changsu Han, MD, PhD, Byung-Joo Ham, MD, PhD, Joonho Choi, MD, PhD, Heeyoung Lee, MD, MPH, Tae-Yeon Hwang, MD, PhD, Kang-Seob Oh, MD, PhD, Yong-Chon Park, MD, PhD, Min-Soo Lee, MD, PhD and Sang-Woo Hahn, MD, PhD Department of Psychiatry, Yong-In Mental Hospital, Yongin, Korea 2 Department of Psychiatry, College of Medicine, Soonchunhyang University, Cheonan Hospital, Cheonan, Korea Department of Psychiatry, College of Medicine, Korea University, Anam Hospital, Seoul, Korea 4 Department of Psychiatry, School of Medicine, KyungHee University, KyungHee University Medical Center, Seoul, Korea 5 Department of Psychiatry, School of Medicine, Sungkyunkwan University, Samsung Medical Center, Seoul, Korea Department of Psychiatry, College of Medicine, Korea University, Guro Hospital, Seoul, Korea Department of Psychiatry, College of Medicine, Korea University, Ansan Hospital, Ansan, Korea Department of Psychiatry, College of Medicine, Inje University, Ilsan Baik Hospital, Ilsan, Korea Department of Psychiatry, College of Medicine, Hanyang University, Guri Hospital, Guri, Korea Department of Cancer Control, Gachon University Gil Medical Center, Incheon, Korea 11 Department of Psychiatry, School of Medicine, Sungkyunkwan University, Kangbuk Samsung Medical Center, Seoul, Korea 12 Department of Psychiatry, College of Medicine, Soonchunhyang University, Seoul Hospital, Seoul, Korea

Seung-Hwan Sung, MD, Seon-Cheol Park, MD, PhD, Kyu-Man Han, MD, Eun-Soo Won, MD, Hwa-Young Lee, MD, PhD, Jae-Woo Koo, MD, Jong-Woo Paik, MD, PhD, Kyung-Min Lee, MD, Hong Jin Jeon, MD, PhD, Moon-Soo Lee, MD, PhD, Se-Hoon Shim, MD, PhD, Young-Hoon Ko, MD, PhD, Kang-Joon Lee, MD, PhD, Changsu Han, MD, PhD, Byung-Joo Ham, MD, PhD, Joonho Choi, MD, PhD, Tae-Yeon Hwang, MD, PhD, Kang-Seob Oh, MD, PhD, Yong-Chon Park, MD, PhD, Min-Soo Lee, MD, PhD and Sang-Woo Hahn, MD, PhD Department of Psychiatry, College of Medicine, Soonchunhyang University, Cheonan, Korea Department of Psychiatry, Yong-In Mental Hospital, Yongin, Korea Department of Psychiatry, College of Medicine, Korea University, Seoul, Korea Department of Psychiatry, School of Medicine, KyungHee University, Seoul, Korea Department of Psychiatry, School of Medicine, Sungkyunkwan University, Seoul, Korea Department of Psychiatry, College of Medicine, Inje University, Busan, Korea Department of Psychiatry, College of Medicine, Hanyang University, Seoul, Korea Department of Psychiatry, College of Medicine, Soonchunhyang University, Seoul, Korea

Kyu-Man Han, MD, Seon-Cheol Park, MD, PhD, Eun-Soo Won, MD, Seung-Hwan Sung, MD, Heeyoung Lee, MD, MPH, Jae-Woo Koo, MD, Kyungmin Lee, MD, Hwa-Young Lee, MD, PhD, Jong-Woo Paik, MD, PhD, Hong Jin Jeon, MD, PhD, Moon-Soo Lee, MD, PhD, Se-Hoon Shim, MD, PhD, Young-Hoon Ko, MD, PhD, Kang-Joon Lee, MD, PhD, Changsu Han, MD, PhD, Byung-Joo Ham, MD, PhD, Joonho Choi, MD, PhD, Tae-Yeon Hwang, MD, PhD, Kang-Seob Oh, MD, PhD, Sang-Woo Hahn, MD, PhD, Yong-Chon Park, MD, PhD and Min-Soo Lee, MD, PhD Department of Psychiatry, College of Medicine, Korea University, Seoul, Korea Department of Psychiatry, Yong-In Mental Hospital, Yongin, Korea Department of Psychiatry, College of Medicine, Soonchunhyang University, Cheonan, Korea Department of Cancer Management, Gachon University Gil Medical Center, Incheon, Korea Department of Psychiatry, School of Medicine, KyungHee University, Seoul, Korea Department of Psychiatry, School of Medicine, Sungkyunkwan University, Seoul, Korea Department of Psychiatry, College of Medicine, Inje University, Busan, Korea Department of Psychiatry, College of Medicine, Hanyang University, Seoul, Korea