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Objective The pathology of post-traumatic stress disorder (PTSD) is associated with changes in brain structure and function, especially in the amygdala, medial prefrontal cortex, hippocampus, and insula. Survivors of tragic accidents often experience psychological stress and develop post-traumatic stress symptoms (PTSS), regardless of the diagnosis of PTSD. This study aimed to evaluate electroencephalographic changes according to PTSS in victims of a single traumatic event. Methods This study enrolled 60 survivors of the Sewol ferry disaster that occurred in 2014 from Danwon High School and collected electroencephalographic data through 19 channels twice for each person in 2014 and 2015 (mean 451.88 [standard deviation 25.77] days of follow-up). PTSS was assessed using the PTSD Checklist-Civilian Version (PCL-C) and the participants were divided into two groups according to the differences in PCL-C scores between 2014 and 2015. Electroencephalographic data were converted to three-dimensional data to perform low-resolution electrical tomographic analysis. Results Significant electroencephalographic changes over time were observed. The group of participants with worsened PCL-C score showed an increased change of delta slow waves in Brodmann areas 13 and 44, with the largest difference in the insula region, compared to those with improved PCL-C scores. Conclusion Our findings suggests that the electrophysiological changes in the insula are associated with PTSS changes.

Objective There are animal models associating dopamine dysfunction with behavioral impairments that model attention deficit hyperactivity disorder (ADHD). Erythropoietin (EPO) has trophic effects on dopaminergic neurons. The aim of this study was to examine the EPO plasma levels and determine whether there was any correlation between plasma EPO levels and clinical characteristics of ADHD. Methods Plasma EPO levels were measured in 78 drug-naive children with ADHD and in 81 healthy children. The severity of ADHD symptoms was determined by scores on the Korean ADHD Rating Scale (K-ARS) in ADHD children and healthy controls. Results The difference between median plasma EPO levels in ADHD children and in healthy controls was not statistically significant. Adjusting for age and sex, a linear regression analysis showed that inattention score was significantly higher in the second highest tertile of plasma EPO compared to those in the lowest tertile. Hyperactivity-impulsivity score was significantly higher in the highest tertile of plasma EPO compared to those in the lowest tertile. Moreover, total K-ARS scores were significantly higher in the second highest tertile of plasma EPO compared to those in the lowest tertile. Conclusion These findings suggest that plasma EPO levels were related to some ADHD symptoms, which could be used in the monitoring of the disorder.

Alzheimer’s disease is the most common form of dementia. Due to the lack of effective interventions, early and accurate diagnosis for new interventions are emphasized. However, significant neuronal loss and neuropathological lesions can damage the brain substantially before diagnosis. With our growing knowledge of the role of neuroinflammation in the pathogenesis of Alzheimer’s disease, inflammatory biomarkers are attracting increasing interest in the context of diagnosis. This review is focused on the use of inflammatory biomarkers detected through neuroimaging, cerebrospinal fluid, and peripheral blood for diagnosing Alzheimer’s disease, and also suggests clinical implications. This review includes the following biomarkers: neuroimaging, various ligands binding to the translocator protein (TSPO); cerebrospinal fluid, soluble triggering receptor expressed on myeloid cells (sTREM2), human cartilage glycoprotein-39 (YKL-40), and monocyte chemoattractant protein 1 (MCP-1), and various biomarkers in peripheral blood. Although accumulating evidence has suggested the potential role of these inflammatory biomarkers in diagnosing AD, there are limitations to their use. However, combining these biomarkers with conventional diagnostic clues such as genotype and amyloid pathology may improve the stratification and selection of patients for targeted early interventions.

To identify the reliable and consistent grey matter volume (GMV) abnormalities associated with major depressive disorder (MDD), we excluded the influence of confounding clinical characteristics, comorbidities and brain degeneration on brain morphological abnormalities by inclusion of non-comorbid and non-geriatric drug-naïve MDD individuals experiencing first episode depressive.The PubMed, Scopus, Web of Science, Science Direct and Google scholar databases were searched for papers published in English up to April 2020.A total of 21 voxel based morphometric (VBM) studies comparing 845 individuals in the first depressive episode and medication-naïve with 940 healthy control subjects were included. The results showed a grey matter volumes reductions in the orbitofrontal cortex (OFC), prefrontal cortex (PFC), frontal and temporal gyri, temporal pole, insular lobe, thalamus, basal ganglia, cerebellum, hippocampus, cingulate cortex, and amygdala. In addition, increased grey matter volumes in the postcentral gyrus, superior frontal gyrus, insula, basal ganglia, thalamus, amygdala, cuneus, and precuneus differentiated the first depressive episode in medication-naïve individuals from healthy subjects.The present systematic review provided additional support for the involvement of grey matter structural abnormalities in limbic-cortical circuits as possibly specific structural abnormalities in the early stage of MDD.Key pointsDistinct brain regions in MDD patients might be associated with the early stages of illness, and thus it is critical to study the causal relationship between brain structures and the onset of the disease to improve the evaluation in clinic.Grey matter alterations in the fronto-limbic networks in the first episode, medication-naïve MDD might suggest that these abnormalities may play an important role in the neuropathophysiology of MDD at its onset.First episode, medically naïve depressive patients show grey matter volume alterations in brain regions mainly associated with emotion regulation including parietal-temporal regions, PFC, insular lobe, thalamus, basal ganglia, cerebellum and limbic structures that may be specific changes in early stage of MDD.Genotype-diagnosis interaction effects on brain morphology in the cortico-limbic-striatal circuits, including the PFC, amygdala, hippocampus and striatum that might be implicated in the dysfunctional regulation of emotion in first-episode MDD patients.Future longitudinal and prospective studies should be conducted to identify the core structural brain changes in people at-risk for MDD and explore the association of their brain volumes with symptom onset.

Background: A research on mood disorder pathophysiology has hypothesized abnormalities in glutamatergic neurotransmission, by suggesting further investigation on glutamatergic N-methyl-Daspartate (NMDA) receptor modulators in treating Major Depressive Disorder (MDD). Esketamine (ESK), an NMDA receptor antagonist able to modulate glutamatergic neurotransmission has been recently developed as an intranasal formulation for treatment-resistant depression (TRD) and for rapid reduction of depressive symptomatology, including suicidal ideation in MDD patients at imminent risk for suicide. Objective: The present study aims at investigating recent clinical findings on research on the role of the glutamatergic system and ESK in treating suicidal depression in MDD and TRD. Methods: A systematic review was here carried out on PubMed/Medline, Scopus and the database on U.S. N.I.H. Clinical Trials (https://clinicaltrials.gov) and the European Medical Agency (EMA) (https://clinicaltrialsregister.eu) from inception until October 2019. Results: Intravenous infusion of ESK is reported to elicit rapid-acting and sustained antidepressant activity in refractory patients with MDD and TRD. In phase II studies, intranasal ESK demonstrated a rapid onset and a persistent efficacy in patients with TRD as well as in MDD patients at imminent risk for suicide. However, some data discrepancies have emerged in phase III studies. Conclusion: The U.S. Food and Drug Administration (FDA) granted fast track and Breakthrough Therapy Designation to Janssen Pharmaceuticals®, Inc. for intranasal ESK in 2013 for treatment-resistant depression (TRD) and in 2016 for the treatment of MDD with an imminent risk of suicide. However, further studies should be implemented to investigate the long-term efficacy and safety of intranasal ESK.

Obsessive-compulsive disorder is often associated with schizophrenia and may represent a significant challenge in the treatment as this comorbidity may not respond properly to antipsychotic medication and usually require a pharmacological and psychotherapeutic add-on. In the present case report, we present the case of a 26-year-old male blue-collar subject who developed obsessive-compulsive disorder after a year of complete remission of schizophrenia symptoms under paliperidone long-acting injection that rapidly resolved after low-dosage cariprazine add-on. No adverse effects were reported due to cariprazine- paliperidone long-acting injection combination.

Objective:We aimed to evaluate the effects of various antipsychotics on the in vitro production of C-reactive protein (CRP) in whole blood cell cultures from healthy volunteers. The evaluation was performed using haloperidol, quetiapine, clozapine, amisulpride, and chlorpromazine.Methods:Antipsychotic agents were added to the participants' whole blood samples, and the resulting CRP levels were measured. For each agent, three different concentrations were tested: the therapeutic concentration, one-tenth the therapeutic concentration, and ten times the therapeutic concentration. The differences in CRP concentrations before and after drug administration were investigated.Results:The Friedman test showed that haloperidol, amisulpride, and chlorpromazine significantly increased CRP levels in the blood culture samples; however, clozapine and quetiapine did not increase CRP levels. In the case of chlorpromazine, elevated CRP levels were noted at all concentrations tested.Conclusion:Our study suggests that some antipsychotics elevate CRP levels in vitro. These results agree with previous studies showing that antipsychotics have immunomodulatory effects. Future research will clarify our findings and our understanding of antipsychotic drugs and their impact on immune regulation.

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.

The heterogeneity of post-traumatic stress disorder (PTSD) symptoms indicates that multiple neurobiological mechanisms underlie the pathophysiology of the condition. However, no generally accepted PTSD biomarkers in clinical practice currently exist. The sequential responses to recurrent and chronic stress by the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) system are considered to play a significant role in the onset and progression of PTSD. Decreased activity of the HPA axis and parasympathetic nervous system, along with increased activity of the sympathetic nervous system, have been observed in PTSD, which may lead to increased levels of proinflammatory cytokines. Such heightened activity of the immune system may cause alterations in the structure and function of brain regions-for example, the amygdala, hippocampus, medial prefrontal cortex, anterior cingulate cortex, and insula-through changes in levels of serotonin and kynurenine pathway metabolites, and direct neurotoxic effects of cytokines. Although chronic inflammation-induced alterations in brain regions critical in controlling emotional behavior and fear regulation may represent a strong candidate biomarker of PTSD, future studies are necessary to further elucidate inflammation-associated neural biomarkers of PTSD. Continued research on therapeutic methods that involve the normalization of the HPA axis, ANS, and immune system is expected to contribute to the development of novel ways to treat PTSD.

The etiology of depression is characterized by the interplay of genetic and environmental factors and brain structural alteration. Childhood adversity is a major contributing factor in the development of depression. Interactions between childhood adversity and candidate genes for depression could affect brain morphology via the modulation of neurotrophic factors, serotonergic neurotransmission, or the hypothalamus-pituitary-adrenal (HPA) axis, and this pathway may explain the subsequent onset of depression. Childhood adversity is associated with structural changes in the hippocampus, amygdala, anterior cingulate cortex (ACC), and prefrontal cortex (PFC), as well as white matter tracts such as the corpus callosum, cingulum, and uncinate fasciculus. Childhood adversity showed an interaction with the brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism, serotonin transporter-linked promoter region (5-HTTLPR), and FK506 binding protein 51 (FKBP5) gene rs1360780 in brain morphologic changes in patients with depression and in a non-clinical population. Individuals with the Met allele of BDNF Val66Met and a history of childhood adversity had reduced volume in the hippocampus and its subfields, amygdala, and PFC and thinner rostral ACC in a study of depressed patients and healthy controls. The S allele of 5-HTTLPR combined with exposure to childhood adversity or a poorer parenting environment was associated with a smaller hippocampal volume and subsequent onset of depression. The FKBP5 gene rs160780 had a significant interaction with childhood adversity in the white matter integrity of brain regions involved in emotion processing. This review identified that imaging genetic studies on childhood adversity may deepen our understanding on the neurobiological background of depression by scrutinizing complicated pathways of genetic factors, early psychosocial environments, and the accompanying morphologic changes in emotion-processing neural circuitry.

Substance P, which is encoded by tachykinin precursor 1 gene (TAC1), has been implicated in the regulation of stress responses and the pathogenesis of major depressive disorder (MDD). We evaluated the association of 10 SNPs on TAC1 with MDD susceptibility in 111 patients with MDD and 79 control subjects, and with 17-item Hamilton depression rating scale (HAMD17) score in MDD patients. In all subjects, haplotype (ht) 2 homozygous individuals showed higher plasma substance P levels than subjects carrying one or no copy of ht2. The minor allele frequency of rs1397202 was higher in patients with MDD than that in control subjects. Patients homozygous for the minor allele of rs1397202 showed significantly lower HAMD17 scores than patients carrying the common allele. Our results suggest a possible involvement of genetic variants of TAC1 with the plasma level of substance P and symptom severity of MDD.

Posttraumatic stress disorder (PTSD) is prevalent, disabling, and frequently becomes chronic. Despite this, only two selective serotonergic reuptake inhibitors have been approved to date for its treatment by the United States Food and Drug Administration, and treatment results are often disappointing, with a remission rate of

Background We investigated the interactive effects of depressive symptoms and chronic diseases on health care utilization among elderly people and explored the potential moderating effect of gender and the mediating effect of self-rated health (SRH) on the association between depressive symptoms and health care utilization. Method We analyzed data from 5223 people aged 60 years or older living in the community from the Korea Welfare Panel Study in 2015. Depressive symptoms were measured using an 11-item version of the Center for Epidemiologic Studies Depression (CES-D-11) Scale and morbidity within 28 disease categories was assessed. Health care utilization was evaluated as the number of outpatient visits (OV), number of hospitalizations (NH), and number of days spent in the hospital (DH) during past year. Hierarchical moderated regression analyses were applied to investigate the interactive effects. We also adopted the mediation analysis method by Hayes and Preacher. Results A significant interactive effect of CES-D-11 score and chronic disease on OV was found. A positive correlation between CES-D-11 score and OV was only observed in those with chronic disease. Gender had a moderating effect on the association of depression symptoms with OV, NH, and DH among elderly people with chronic disease. SRH had mediating effects on the association of CES-D-11 with OV, NH, and DH only among those with chronic disease. Limitations The severity or multimorbidity of chronic diseases, which could affect health care utilization among elderly were not considered. Conclusions We elucidated the complex aspects of the relationship between depressive symptoms and chronic disease and their interactive effects on health care utilization among elderly people, and identified important roles of gender and SRH.

The prediction of acute and maintenance lithium treatment response carries major clinical and neurobiological implications, warranting systematic review. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant review searched major electronic databases from inception until December 2017 for studies documenting a clinical diagnosis of bipolar disorder (BD) made according to the mainstream diagnostic manuals and confirmed by a structured interview. Eligible studies allowed a quantitative comparison of endpoint vs baseline mean values of a given biomarker, regardless of the mood phase of patients with BD, and the disorder was assessed for severity using validated rating tool(s). Owing to the purposely applied stringent selection criteria, 16 acute and 12 maintenance studies could be included. The anticipated publication bias limited the chances of reportable generalizable findings, hindering a side-by-side comparison of different records across varying biomarkers and subsequent meta-analyses. The PRISMA approach was nonetheless preferred; it aimed at enhancing the homogeneity of the included results and minimizing the chances of “apples and oranges” with respect to the present research theme. The present critical review confirms the need for future research to specifically assess either pretreatment and/or posttreatment putative biomarkers of patients with BD and treated with lithium. © 2018 Elsevier B.V.

We review the association of the microbiota-gut-brain axis and anxiety disorder or stress. The microbiota–gut–brain axis mechanism encompasses a bidirectional relationship between the brain and gastrointestinal organs. Dysregulation of the microbiota–gut–brain axis has been actively revealed in the context of various psychiatric diseases such as neurodevelopmental disorders, schizophrenia, anxiety disorders, and depression. We suggest that onset of anxiety disorders may be correlated with activation of a microbiota–gut–brain mechanism involving the immune system, neurotransmitters, and the hormonal system. By applying a microbiota–gut–brain axis mechanism, the possibility of using gastrointestinal system drugs such as probiotics and antibiotics as treatments for anxiety disorders is a possibility. Although modification of the microbiota–gut–brain axis mechanism has yet to be adopted clinically, it is expected that novel strategies employing this mechanism will be developed and deployed as new treatments not only for anxiety disorders, but also other psychiatric diseases.

It is hypothesized that major depression disorder (MDD) is associated with impaired neuronal plasticity, and that antidepressant treatments restore neuroplasticity. Brain-derived neurotrophic factor (BDNF) and erythropoietin (Epo) show neurotrophic and neuroprotective effects. We evaluated plasma Epo and BDNF levels in 50 MDD inpatients before treatment and in 50 healthy controls. The MDD inpatients consisted of 20 MDD patients without and 30 MDD patients with a recent suicide attempt. The plasma Epo level was significantly higher in nonsuicidal and suicidal MDD patients than in healthy controls (p ≤ 0.001), while the plasma BDNF level was significantly lower in suicidal MDD than in nonsuicidal MDD patients and healthy controls (p ≤ 0.001). When classifying study participants into low-Epo and high-Epo and low-BDNF and high-BDNF subgroups based on the cutoff of Epo or BDNF calculated using receiver operating characteristics (ROC) curve analysis, logistic regression analysis revealed that high-Epo and low-BDNF status correlated with a respective significant odds ratio of 7.367 (p = 0.015) and 33.123 (p ≤ 0.001) for suicidal MDD. In conclusion, plasma BDNF level was decreased in untreated MDD patients, which was presumed to be a dysfunctional effect of the onset of MDD. However, an increase in plasma Epo was observed in MDD in connection with a recent suicide attempt, indicating that this triggers hypoxic stress to induce a compensatory increase in Epo.

Alzheimer’s disease (AD) is the most common type of dementia, and depression is a risk factor for developing AD. Epidemiological studies provide a clinical correlation between late-life depression (LLD) and AD. Depression patients generally remit with no residual symptoms, but LLD patients demonstrate residual cognitive impairment. Due to the lack of effective treatments, understanding how risk factors affect the course of AD is essential to manage AD. Advances in neuroimaging, including resting-state functional MRI (fMRI), have been used to address neural systems that contribute to clinical symptoms and functional changes across various psychiatric disorders. Resting-state fMRI studies have contributed to understanding each of the two diseases, but the link between LLD and AD has not been fully elucidated. This review focuses on three crucial and well-established networks in AD and LLD and discusses the impacts on cognitive decline, clinical symptoms, and prognosis. Three networks are the (1) default mode network, (2) executive control network, and (3) salience network. The multiple properties emphasized here, relevant for the hypothesis of the linkage between LLD and AD, will be further developed by ongoing future studies.

A leading goal in the field of biological psychiatry for depression is to find a promising diagnostic biomarker and selection of specific psychiatric treatment mode that is most likely to benefit patients with depression. Recent neuroimaging studies have characterized the pathophysiology of major depressive disorder (MDD) with functional and structural alterations in the neural circuitry involved in emotion or reward processing. Particularly, structural and functional magnetic resonance imaging (MRI) studies have reported that the brain structures deeply involved in emotion regulation or reward processing including the amygdala, prefrontal cortex (PFC), anterior cingulate cortex (ACC), ventral striatum, and hippocampus are key regions that provide useful information about diagnosis and treatment outcome prediction in MDD. For example, it has been consistently reported that elevated activity of the ACC is associated with better antidepressant response in patients with MDD. This chapter will discuss a growing body of evidence that suggests that diagnosis or prediction of outcome for specific treatment can be assisted by a neuroimaging-based biomarker in MDD.

According to the neurotrophic hypothesis of major depressive disorder (MDD), impairment in growth factor signaling might be associated with the pathology of this illness. Current evidence demonstrates that impaired neuroplasticity induced by alterations of neurotrophic growth factors and related signaling pathways may be underlying to the pathophysiology of MDD. Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophic factor involved in the neurobiology of MDD. Nevertheless, developing evidence has implicated other neurotrophic factors, including neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), glial cell-derived neurotrophic factor (GDNF), and fibroblast growth factor (FGF) in the MDD pathophysiology. Here, we summarize the current literature on the involvement of neurotrophic factors and related signaling pathways in the pathophysiology of MDD.

This chapter reviews the roles of cytokines and glial cells in chronic pain and in psychiatric disorders, especially depression. One important role of cytokines is in communicating between activated glia and neurons, at all levels of the nervous system. This process of neuroinflammation plays important roles in pain and depression. Cytokines may also directly regulate neuronal excitability. Many cytokines have been implicated in both pain and psychiatric disorders, including interleukin-1β‎ (IL-1β‎), tumor necrosis factor-α‎, and IL-6. More generally, an imbalance between type 1, pro-inflammatory cytokines and type 2, anti-inflammatory cytokines has been implicated in both pain and psychiatric disorders. Activation of the sympathetic nervous system can contribute to both pain and psychiatric disorders, in part through its actions on inflammation and the cytokine profile.

Postpartum depression occurs in 10–15% of mothers. Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that plays a role in neuroplasticity. We hypothesized that the concentration of BDNF is related to reproduction and childbirth, and that women with postpartum depression show alteration in BDNF level. A total of 104 pregnant women was selected as subjects, and 60 non-pregnant women were selected as normal controls. Symptoms of depression were evaluated in the pregnant study subjects using the diagnostic criteria outlined in the Edinburgh Postnatal Depression Scale (EPDS). The pregnant subjects were divided into three groups of perinatal non-depressed controls (n = 61), postpartum depression-recovery (n = 18), and postpartum depression (n = 25). The plasma concentration of BDNF was higher in the pregnant group than in non-pregnant controls and lower in the postpartum depression group at 6 weeks after delivery than in the perinatal non-depressed group. In the postpartum depression-recovery group, the BDNF concentration increased at 6 weeks after delivery compared to that at 24 weeks of gestation. This study found significant changes in plasma BDNF concentration in depressed pregnant women.

Stress-induced changes in the immune system, which lead to neuroinflammation and consequent brain alterations, have been suggested as possible neurobiological substrates of anxiety disorders, with previous literature predominantly focusing on panic disorder, agoraphobia, and generalized anxiety disorder, among the anxiety disorders. Anxiety disorders have frequently been associated with chronic stress, with chronically stressful situations being reported to precipitate the onset of anxiety disorders. Also, chronic stress has been reported to lead to hypothalamic–pituitary–adrenal axis and autonomic nervous system disruption, which may in turn induce systemic proinflammatory conditions. Preliminary evidence suggests anxiety disorders are also associated with increased inflammation. Systemic inflammation can access the brain, and enhance pro-inflammatory cytokine levels that have been shown to precipitate direct and indirect neurotoxic effects. Prefrontal and limbic structures are widely reported to be influenced by neuroinflammatory conditions. In concordance with these findings, various imaging studies on panic disorder, agoraphobia, and generalized anxiety disorder have reported alterations in structure, function, and connectivity of prefrontal and limbic structures. Further research is needed on the use of inflammatory markers and brain imaging in the early diagnosis of anxiety disorders, along with the possible efficacy of anti-inflammatory interventions on the prevention and treatment of anxiety disorders.

Alzheimer's disease (AD) is the most common form of dementia worldwide. β-amyloid peptide (Aβ) is currently assumed to be the main cause of synaptic dysfunction and cognitive impairments in AD, but the molecular signaling pathways underlying its neurotoxic consequences have not yet been completely explored. Additional investigations regarding these pathways will contribute to development of new therapeutic targets. In context, developing evidence suggest that Aβ decreases brain-derived neurotrophic factor (BDNF) mostly by lowering phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) protein. In fact, it has been observed that brain or serum levels of BDNF appear to be beneficial markers for cognitive condition. In addition, the participation of transcription mediated by CREB has been widely analyzed in the memory process and AD development. Designing pharmacologic or genetic therapeutic approaches based on the targeting of CREB-BDNF signaling could be a promising treatment potential for AD. In this review, we summarize data demonstrating the role of CREB-BDNF signaling pathway in cognitive status and mediation of Aβ toxicity in AD. Finally, we also focus on the developing intervention methods for improvement of cognitive decline in AD based on targeting of CREB-BDNF pathway.

Ketamine was initially used as an anesthetic which could induce cognitive impairment and psychomimetic effects. In initial randomized controlled trials (RCTs) that mostly included a small sample size and were investigator-initiated, ketamine reportedly exerted antidepressant effects 1 to 2 h after a single intravenous infusion in patients with major depressive episodes, particularly treatment-resistant depression (TRD). Interest in ketamine was reported in systematic reviews and meta-analyses, however, many were primarily focused on the rapid onset of ketamine effects without equal attention to its safety and tolerability. Furthermore, several meta-analyses were based on many duplicated RCTs. The initial trends emphasized the clinical utility of ketamine as an antidepressant. The development of esketamine nasal spray by a pharmaceutical company led to an RCT with a large sample size and segmented therapeutic strategy, which provided results applicable to patients with TRD in the real-world clinical environment. However, possible effects of ketamine on cognitive function have not yet been investigated in RCTs. In numerous studies, chronic, recreational use of ketamine reportedly substantially impaired cognitive function in most domains. Although results of several human and animal studies indicated the therapeutic use of ketamine for treatment of depression did not induce cognitive impairment, this issue should be further investigated. Based on the current knowledge about ketamine, future antidepressants are expected to be glutamatergic drugs without ketamine-like adverse events (e.g., psychomimetic symptoms and cognitive impairment), but having only ketamine-like therapeutic properties (e.g., rapid antidepressants effects without time lag).

Chronic low-grade inflammation contributes to the pathophysiology of major depressive disorder (MDD). This study aimed to examine the association between serum levels of FAM19A5, a novel chemokine-like peptide that reflects reactive astrogliosis and inflammatory activation in the brain, and the neurodegenerative changes of MDD by investigating the correlation between serum FAM19A5 levels and cortical thickness changes in patients with MDD. We included 52 drug-naive patients with MDD and 60 healthy controls (HCs). Serum FAM19A5 levels were determined in peripheral venous blood samples using a sandwich enzyme-linked immunosorbent assay. All participants underwent T1-weighted structural magnetic resonance imaging. Serum FAM19A5 levels were greater in patients with MDD than in HCs. In the MDD group, there were significant inverse correlations between serum FAM19A5 levels and cortical thickness in the prefrontal regions (i.e., the left inferior and right medial superior frontal gyri), left posterior cingulate gyrus, right cuneus, and both precunei, which showed significantly reduced thickness in patients with MDD compared to HCs. However, no correlation between serum FAM19A5 level and cortical thickness was observed in the HC group. The results of our study indicate that serum FAM19A5 levels may reflect reactive astrogliosis and related neuroinflammation in MDD. Our findings also suggest that serum FAM19A5 may be a potential biomarker for the neurodegenerative changes of MDD.

Although anxiety and depression have been considered as two distinct entities according to the diagnostic criteria, anxious depression (comorbid anxiety and depression) is relatively a common syndrome. According to the DSM-5 criteria, it uses "with anxious distress specifier" to define anxious depression in its MDD section. Anxious depression is known to have different neurobiological profiles compared to non-anxious depression. Several studies have revealed significant differences between anxious depression and non-anxious depression regarding the hypothalamic-pituitary-adrenal (HPA) axis function, structural and functional brain imaging findings, inflammation markers, etc. Patients with anxious depression were significantly more likely to be found in primary care setting and more likely to be associated with female gender, non-single, unemployed, less educated, and more severe depression. Previous reports also showed that patients with anxious depression had more frequent episodes of major depression and a higher risk of suicidal ideation and previous suicide attempts than those with non-anxious depression. Although anxious depression is known to be associated with poor treatment outcomes in several studies, recent researches have sought to find better treatment strategy to improve patients with anxious depression.

Objective Brain-derived neurotrophic factor (BDNF) has possible neurobiologic impact on etiology of schizophrenia. We hypothesized that the specific allele or the genotype such as two single nucleotide polymorphisms (SNPs) , 196G/A (rs6265), 11757G/C(rs16917204) is associated with schizophrenia or its clinical features. Methods 241 normal controls and 157 schizophrenia patients are included. The differences in allele or genotype distribution for the patients and normal controls were analyzed. We also analyzed clinical variables among patients. Results We found no significant difference in genotype or allele distributions of two studied SNPs between the patient group and the control group. However, history of suicide attempt was relatively higher in patients with genotype with A allele, compared to patients with genotype G/G for 196G/A (p-value=0.045). Conclusion Our results suggest that it is possible to use BDNF gene allele and genotype as a predictor for suicide attempt in schizophrenia patients. It can help manage the schizophrenia patients regarding suicidal behavior and furthermore, mortality.

Background Recently, neuroinflammation and the immune-kynurenine pathway have received increased attention in the psychoimmunology field of major depressive disorder (MDD), while studies related to anxiety disorders have been very limited. Objective This study reviewed possible mechanisms by which stress or inflammation modulate anxiety through tryptophan metabolism and the kynurenine pathway. Methods Relevant literature was identified through a search of MEDLINE via PubMed. Results Accumulating evidence has indicated the modulatory effects of the immune-kynurenine pathway on anxiety. The tryptophan catabolites (TRYCATs) in the kynurenine pathway imbalanced by stress or inflammation induce serotonin and melatonin deficiency, making anxiety reactions more sensitive. In addition, TRYCATs cause or sustain anxiety by acting as endogenous anxiogens or anxiolytics, an NMDA agonist or antagonist, or a free radical generator. Conclusion We hope that our understanding of the psychoimmunological mechanisms of anxiety will be expanded and anxiety-related studies will receive greater attention.

Several studies have suggested a pathophysiological role of blood cell apoptosis in major depressive disorder (MDD). The aim of this study was to evaluate mRNA expression levels of Bcl-2, Bax, and Fas in peripheral blood mononuclear cells (PBMCs) of MDD patients with a high risk for suicide relative to those without a high risk for suicide as well as healthy subjects. The mRNA expression of Bcl-2, Bax, and Fas as well as the Bcl-2/Bax ratio was examined in the PBMCs of 30 MDD patients with a high risk for suicide, 30 MDD patients without a high risk for suicide, and 30 healthy controls. The mRNA expression of target genes was measured using real-time quantitative Polymerase Chain Reaction (PCR). FAS mRNA expression was significantly increased, and Bcl-2 mRNA expression and the Bcl-2/Bax expression ratio were significantly decreased, in the PBMCs of MDD patients with or without a high risk for suicide attempts compared to healthy controls (p

The serotonin-transporter-linked polymorphic region (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have been implicated in the pathophysiology of major depressive disorder (MDD). We aimed to investigate the effects of genetic variants of the 5-HTTLPR and BDNF Val66Met polymorphisms and their interactions with MDD on cortical volume and white matter integrity. Ninety-five patients with MDD and 65 healthy participants aged 20-65 years were recruited. The subjects were genotyped for the 5-HTTLPR and BDNF Val66Met polymorphisms and scanned with T1-weighted and diffusion tensor imaging. The gray matter volumes of 24 gyri in the prefrontal and anterior cingulate cortices and the fractional anisotropy values of nine white matter tracts in both hemispheres were determined. In the pooled sample of subjects from both groups, 5-HTTLPR L-allele carriers had significantly decreased cortical volume in the right anterior midcingulate gyrus compared to S-allele homozygotes. A significant effect of the interaction of the BDNF Val66Met polymorphism and MDD on the fractional anisotropy values of the right uncinate fasciculus was observed. Our results suggested that these genetic polymorphisms play important roles in the neurostructural changes of emotion-processing regions in subjects with MDD.

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.

Recently, there has been a major shift in the field of psychiatry towards the exploration of complex relationships between blood-based biomarkers and the pathophysiology of psychiatric and neuropsychiatric disorders. However, issues with study reproducibility, validity and reliability have hindered progress towards the identification of clinically relevant biomarkers for psychiatry. The achievement of laboratory validity is a crucial first step for the posterior development of clinical validity. There is evidence that the variability observed in blood-based research studies may be minimised with the implementation of standardised pre-analytical methods and uniform clinical protocols (i.e., pre-venipuncture). It has been documented that errors made in the pre-analytical phase account for 46–68.2% of laboratory testing errors. Thus, standardising clinical assessment, ethical procedures and pre-analytical phase of clinical research is essential for the reproducibility, validity and reliability of blood marker assessment, and reducing the risk of invalid test results. Various other areas of research have already moved towards guidelines for the standardised collection of blood-based biomarkers. Here we aim to provide a set of guidelines that we believe would improve biomarker research: (1) pre-venipuncture information and documentation, (2) ethics of participant consent and (3) pre-analytical methods. Ultimately, we hope this will assist study planning and will improve data comparison across studies allowing for the discovery of biomarkers in psychiatry with both laboratorial and clinical validity.

Background The 15-item geriatric depression scale (GDS-15) is a short form of GDS and is used to screen, diagnose, and evaluate depression in elderly individuals. Most previous studies evaluated the ability of GDS-15 to discriminate between depressive and non-depressive states. In this study, we investigated the multi-stage discriminating ability of GDS-15. Methods A total of 774 participants, over 65 years of age were included (normal, n = 650; minor depressive disorder [MnDD], n = 94; major depressive disorder [MDD], n = 30). Multi-category receiver operating characteristic (ROC) surfaces were evaluated to identify three stages of geriatric depression. The optimal cutoff points were selected based on the volume under the ROC surface (VUS) and the Youden index. Results In the results of multi-category classification analyses, VUS of the GDS-15 of 0.61 was obtained, and optimal cutoff points of the GDS-15 for multiple stages of depression of 4 (between normal and MnDD) and 11 (between MnDD and MDD) were derived. The Youden index for the GDS-15 was 0.49, and the derived optimal cutoff points were 5 and 10, for the multiple stages, respectively. The overall diagnostic accuracy based on the Youden index was superior to that based on the VUS in the GDS-15. Limitations The participants’ cognitive function has potential to affect the GDS-15 score; nevertheless, the study included those with mild cognitive impairment. Conclusions GDS-15 was a useful tool to classify stages of geriatric depression into either minor or major depressive disorder.

Depressive disorders represent protean psychiatric illnesses with heterogeneous clinical manifestations and a multitude of comorbidities leading to severe disability. In spite of decades of research on the pathophysiogenesis of these disorders, the wide variety of pharmacotherapies currently used to treat them is based on the modulation of monoamines, whose alteration has been considered the neurobiological foundation of depression, and consequently of its treatment. However, approximately one third to a half of patients respond partially or become refractory to monoamine-based therapies, thereby jeopardizing the therapeutic effectiveness in the real world of clinical practice. Recent scientific evidence has been pointing out the essential role of other biological systems beyond monoamines in the pathophysiology of depressive disorders, in particular, the glutamatergic neurotransmission. In the present review, we will discuss the most advanced knowledge on the involvement of glutamatergic system in the molecular mechanisms at the basis of depression pathophysiology, as well as the glutamate-based therapeutic strategies currently suggested to optimize depression treatment (e.g., ketamine). Finally, we will mention further “neurobiological targeted” approaches, based on glutamate system, with the purpose of promoting new avenues of investigation aiming at developing interventions that overstep the monoaminergic boundaries to improve depressive disorders therapy.

The modern society is a so-called era of big data. Whereas nearly everybody recognizes the “era of big data”, no one can exactly define how big the data is a “big data”. The reason for the ambiguity of the term big data mainly arises from the widespread of using that term. Along the widespread application of the digital technology in the everyday life, a large amount of data is generated every second in relation with every human behavior (i.e., measuring body movements through sensors, texts sent and received via social networking services). In addition, nonhuman data such as weather and Global Positioning System signals has been cumulated and analyzed in perspectives of big data (Kan et al. in Int J Environ Res Public Health 15(4), 2018 [1]). The big data has also influenced the medical science, which includes the field of psychiatry (Monteith et al. in Int J Bipolar Disord 3(1):21, 2015 [2]). In this chapter, we first introduce the definition of the term “big data”. Then, we discuss researches which apply big data to solve problems in the clinical practice of psychiatry.

Psychiatric disorders are too multifactorial to be defined as a primarily inflammatory disorder, and increased inflammatory response is not specific to mental disorder only. Numerous factors are involved in neuroinflammation, and there also are many confounding variables, making it difficult to obtain consistent outcomes. Therefore, it is necessary to specify genetic, physiological, and epidemiological attributes of particular population groups vulnerable to inflammatory response as well as the disease subtypes. As of now, definitive inflammatory markers for psychiatric disorders have not been identified, but they could be very useful in patients with minimal vulnerability. In addition, it is possible to use inflammatory markers as depression biomarkers in subtypes of depression, which can serve as bases to develop medications to treat the disorder.

Because of the poor link between psychiatric diagnosis and neurobiological findings, it is difficult to classify mental disorders. The changes made to psychiatric diagnostic systems over the years can be understood in terms of "practical conservatism." The Diagnostic and Statistical Manual of Mental Disorders (DSM)-I and DSM-II were theoretically supported by the psychoanalytic and psychodynamic approach. Subsequently, psychiatric diagnoses of this kind were opposed by the anti-psychiatry movement, as well as by the findings of the Rosenhan experiment. Thus, the DSM-III revolution contained more empiricism, aligning psychiatry with biomedicine. Psychiatric diagnoses are classified and defined in terms of Kraepelinian dualism, using a categorical approach. The empirical trend was continued in the DSM-IV. To overcome the limitations of current psychiatric diagnostic systems and integrate fundamental genetic, neurobiological, behavioral, environmental, and experimental components into psychiatry, the Research Domain Criteria (RDoC) were established. To overcome the limitations of the categorical approach, psychiatrists have considered adopting a dimensional approach. However, their efforts were frustrated in the DSM-5 revision process. Thus, the DSM-5 is characterized by the rearrangement of psychiatric diagnoses, the partial adoption of a dimensional approach, the introduction of new diagnoses, and harmonization with the International Classification of Diseases.

Cognitive behavioral therapy for insomnia (CBT-I) is the treatment of choice for insomnia; however, it is not widely used due to a lack of experienced therapists and its relatively high clinical cost. Recently, Internet and mobile CBT-I have been developed to replace face-to-face CBT-I, and research on this topic has been increasing. In addition, attempts have been made to use wearable devices for sleep-wake estimation. Studies on digital CBT-I thus far have shown favorable treatment effects in general, but the problem of a high dropout rate has not been sufficiently improved. In addition, more sophisticated technology is needed to develop fully automated digital CBT-I. As part of efforts to maximize the treatment effectiveness of future insomnia patients, research and development of mobile and Internet CBT-I and improvement of sleep tracker accuracy and validation studies are needed.

We aimed to investigate the associations between genetic variants of the norepinephrine transporter gene (NET, also known as SLC6A2) and diagnosis of bipolar I disorder. In addition, we examined the relationship between the genetic variants and manic and psychotic symptoms in patients with bipolar I disorder. The three SNPs rs28386840, rs2242446, and rs5569 were genotyped in 326 patients: patients with bipolar I disorder (n = 160) and a control group (n = 166). Subsequently, multivariate logistic regression analysis adjusting for age and sex was conducted to identify independent influences of the SNPs on diagnosis of bipolar I disorder. A possible association between manic and psychotic symptoms and variants of SLC6A2 was also investigated in patients with bipolar I disorder. The rs28836840 SNP in the 5’-UTR of SLC6A2 was significantly associated with bipolar I disorder and with severity of manic and psychotic symptoms in this disorder. Individuals carrying a T allele in the rs28836840 SNP were likely to have a lower risk of bipolar I disorder or lower severity of manic and psychotic symptoms in patients with bipolar I disorder (bipolar I disorder diagnosis: OR = 0.643, 95% Cl = 0.468–0.883, p = 0.006; manic symptoms: β = −2.457, 95% Cl = −4.674 ~ −0.239, p = 0.031; psychotic symptoms: β = −2.501, 95% Cl = −4.700 ~ −0.301, p = 0.027). For the rs2242446 and rs5569 SNPs, there were no significant differences between patients with bipolar I disorder and those without. Our results revealed associations of the rs28386840 SNP with bipolar I disorder diagnosis and with severity of manic and psychotic symptoms. However, the findings reported here require replication in larger samples and various ethnic groups.

Recent neuroimaging studies have characterized the pathophysiology of late-life depression (LLD) as a dysfunction of the brain networks involved in the regulation of emotion, motivational behavior, cognitive control, executive function, and self-referential thinking. In this article, we reviewed LLD-associated structural neuroimaging markers such as white matter hyperintensity (WMH), white matter integrity measured by diffusion tensor imaging, cortical and subcortical volumes, and cortical thickness, which may provide a structural basis for brain network dysfunction in LLD. LLD was associated with greater severity or volumes of deep, periventricular, or overall WMH and with decreased white matter integrity in the brain regions belonging to the fronto-striatal-limbic circuits and reduced white matter tract integrity which connects these circuits, such as the cingulum, corpus callosum, or uncinate fasciculus. Decreased volumes or cortical thickness in the prefrontal cortex, orbitofrontal cortex, anterior and posterior cingulate cortex, several temporal and parietal regions, hippocampus, amygdala, striatum, thalamus, and the insula were associated with LLD. These structural neuroimaging findings were also associated with cognitive dysfunction, which is a prominent clinical feature in LLD. Several structural neuroimaging markers including the WMH burden, white matter integrity, and cortical and subcortical volumes predicted antidepressant response in LLD. These structural neuroimaging findings support the hypothesis that disruption of the brain networks involved in emotion regulation and cognitive processing by impaired structural connectivity is strongly associated with the pathophysiology of LLD.

Carbonization is a low-temperature thermochemical process that converts organic matter in the absence of oxygen mainly into char, gas, and liquids. Bio-coke is a char prepared from a mixture of biomass/charcoal and a coal blend. It can reduce greenhouse gas emissions by replacing coke and reducing coal consumption in the ironmaking process. In this study, the carbonization characteristics such as char conversion, gas and tar composition of bio-coke were determined using a batch-type carbonization reactor. Yellow poplar wood used as a biomass was added to a coking coal in different ratios (0, 10, 15, 20, and 30 wt%) and the resulting raw bio-coke was carbonized at different final temperatures (500–800 °C). The calorific value of bio-coke was higher than 7000 kcal/kg, exceeding the standard value. Moreover, the initiation combustion temperature of the resultant bio-coke determined using TGA was in the range of 400–600 °C. It is concluded that bio-coke is a suitable substitute for conventional fossil fuels reducing CO2 emissions.

Because depression has high prevalence and cause enduring disability, it is important to predict onset of depression among community dwelling adults. In this study, we aimed to build a machine learning-based predictive model for future onset of depression. We used nationwide survey data to construct training and hold-out test set. The class imbalance was dealt with the Synthetic Minority Over-sampling Technique. A tree-based ensemble method, random forest, was used to build a predictive model. Depression was defined by 9 or more on the Center for Epidemiologic Studies – Depression Scale 11 items version. Hyperparameters were tuned throughout the 10-fold cross-validation. A total of 6,588 (6,067 of non-depression and 521 of depression) participants were included in the study. The area under receiver operating characteristics curve was 0.870. The overall accuracy, sensitivity, and specificity were 0.862, 0.730, and 0.866, respectively. Satisfactions for leisure, familial relationship, general, social relationship, and familial income had importance in building predictive model for the onset of future depression. Our study demonstrated that predicting future onset of depression by using survey data could be possible. This predictive model is expected to be used for early identification of individuals at risk for depression and secure time to intervention.