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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.

Aim: This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive–Compulsive and Posttraumatic Stress Disorders (published in 2002, revised in 2008). Method: A consensus panel of 33 international experts representing 22 countries developed recommendations based on efficacy and acceptability of available treatments. In total, 1007 RCTs for the treatment of these disorders in adults, adolescents, and children with medications, psychotherapy and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medications. Result: This paper, Part I, contains recommendations for the treatment of panic disorder/agoraphobia (PDA), generalised anxiety disorder (GAD), social anxiety disorder (SAD), specific phobias, mixed anxiety disorders in children and adolescents, separation anxiety and selective mutism. Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line medications. Cognitive behavioural therapy (CBT) is the first-line psychotherapy for anxiety disorders. The expert panel also made recommendations for patients not responding to standard treatments and recommendations against interventions with insufficient evidence. Conclusion: It is the goal of this initiative to provide treatment guidance for these disorders that has validity throughout the world.

Aim: This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive–Compulsive and Posttraumatic Stress Disorders which was published in 2002 and revised in 2008. Method: A consensus panel of 34 international experts representing 22 countries developed recommendations based on efficacy and acceptability of the treatments. In this version, not only medications but also psychotherapies and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medication treatments. Result: The present paper (Part II) contains recommendations based on published randomised controlled trials (RCTs) for the treatment of OCD (n = 291) and PTSD (n = 234) in children, adolescents, and adults. The accompanying paper (Part I) contains the recommendations for the treatment of anxiety disorders. For OCD, first-line treatments are selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioural therapy (CBT). Internet-CBT was also superior to active controls. Several second-line medications are available, including clomipramine. For treatment-resistant cases, several options are available, including augmentation of SSRI treatment with antipsychotics and other drugs. Other non-pharmacological treatments, including repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS) and others were also evaluated. For PTSD, SSRIs and the SNRI venlafaxine are first-line treatments. CBT is the psychotherapy modality with the best body of evidence. For treatment-unresponsive patients, augmentation of SSRI treatment with antipsychotics may be an option. Conclusion: OCD and PTSD can be effectively treated with CBT and medications.

Pro-inflammatory systemic conditions that can cause neuroinflammation and subsequent alterations in brain regions involved in emotional regulation have been suggested as an underlying mechanism for the pathophysiology of major depressive disorder (MDD). A prominent feature of MDD is disruption of circadian rhythms, of which melatonin is considered a key moderator, and alterations in the melatonin system have been implicated in MDD. Melatonin is involved in immune system regulation and has been shown to possess anti-inflammatory properties in inflammatory conditions, through both immunological and non-immunological actions. Melatonin has been suggested as a highly cytoprotective and neuroprotective substance and shown to stimulate all stages of neuroplasticity in animal models. The ability of melatonin to suppress inflammatory responses through immunological and non-immunological actions, thus influencing neuroinflammation and neurotoxicity, along with subsequent alterations in brain regions that are implicated in depression, can be demonstrated by the antidepressant-like effects of melatonin. Further studies that investigate the associations between melatonin, immune markers, and alterations in the brain structure and function in patients with depression could identify potential MDD biomarkers.

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

To conceptualize a novel bio-psychosocial-behavioral treatment model of panic disorder (PD), it is necessary to completely integrate behavioral, psychophysiological, neurobiological, and genetic data. Molecular genetic research on PD is specifically focused on neurotransmitters, including serotonin, neuropeptides, glucocorticoids, and neurotrophins. Although pharmacological interventions for PD are currently available, the need for more effective, faster-acting, and more tolerable pharmacological interventions is unmet. Thus, glutamatergic receptor modulators, orexin receptor antagonists, corticotrophin-releasing factor 1 receptor antagonists, and other novel mechanism-based anti-panic therapeutics have been proposed. Research on the neural correlates of PD is focused on the dysfunctional "cross-talk" between emotional drive (limbic structure) and cognitive inhibition (prefrontal cortex) and the fear circuit, which includes the amygdala-hippocampus-prefrontal axis. The neural perspective regarding PD supports the idea that cognitive-behavioral therapy normalizes alterations in top-down cognitive processing, including increased threat expectancy and attention to threat. Consistent with the concept of "personalized medicine," it is speculated that Research Domain Criteria can enlighten further treatments targeting dysfunctions underlying PD more precisely and provide us with better definitions of moderators used to identify subgroups according to different responses to treatment. Structuring of the "negative valence systems" domain, which includes fear/anxiety, is required to define PD. Therefore, targeting glutamate- and orexin-related molecular mechanisms associated with the fear circuit, which includes the amygdala-hippocampus-prefrontal cortex axis, is required to define a novel bio-psychosocial-behavioral treatment model of PD.

Anxiety and mood disorders are prevalent, disabling, and frequently difficult to treat. Such disorders are often comorbid and share similar characteristics. For more accurate diagnosis and improved treatment, a deeper understanding of the pathophysiology of anxiety and mood disorders is important. Oxytocin, a neuropeptide synthesized in the hypothalamus, affects human psychology and behaviors such as social and affiliative behaviors, fear and emotion processing, and stress regulation. Thus, oxytocin is believed to exert anxiolytic and antidepressant-like effects. This review article provides an overview of clinical studies on relationships between the oxytocin system and anxiety and mood disorders, focusing on oxytocin-related biomarker findings. Biomarkers used in such studies include central and peripheral oxytocin levels, analysis of oxytocin-related genes, and expression levels of oxytocin and oxytocin receptor genes in postmortem brains. Although a growing number of studies support the presence of oxytocinergic effects on anxiety and mood disorders, study results are heterogeneous and inconclusive. Moderating factors such as the characteristics of study populations, including sex, age, context, early life adversity, and attachment styles in patient cohorts, might affect the heterogeneity of the study results. Limitations in existing research such as small sample sizes, large dependence on peripheral sources of oxytocin, and inconsistent results between immunoassay methods complicate the interpretation of existing findings.

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.

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.

The Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM-IV) was revised based on a combination of a categorical and a dimensional approach such that in the DSM, Fifth Edition (DSM-5), depressive disorders have been separated as a distinctive disease entity from bipolar disorders, consistent with the deconstruction of Kraepelinian dualism. Additionally, the diagnostic thresholds of depressive disorders may be reduced due to the addition of "hopelessness" to the subjective descriptors of depressed mood and the removal of the "bereavement exclusion." Manic/hypomanic, psychotic, and anxious symptoms in major depressive disorder (MDD) and other depressive disorders are described using the transdiagnostic specifiers of "with mixed features," "with psychotic features," and "with anxious distress," respectively. Additionally, due to the polythetic and operational characteristics of the DSM-5 diagnostic criteria, the heterogeneity of MDD is inevitable. Thus, 227 different symptom combinations fulfill the DSM-5 diagnostic criteria for MDD. This heterogeneity of MDD is criticized in view of the Wittgensteinian analogy of language game. Depression subtypes determined by disturbances in monoamine levels and the severity of the disease have been identified in the literature. According to a review of the Gottesman and Gould criteria, neuroticism, morning cortisol, cortisol awakening response, asymmetry in frontal cortical activity on electroencephalography (EEG), and probabilistic reward learning, among other variables, are evidenced as endophenotypes for depressive disorders. Network analysis has been proposed as a potential method to compliment the limitations of current diagnostic criteria and to explore the pathways between depressive symptoms, as well as to identify novel and interesting relationships between depressive symptoms. Based on the literature on network analysis in this field, no differences in the centrality index of the DSM and non-DSM symptoms were repeatedly present among patients with MDD. Furthermore, MDD and other depressive syndromes include two of the Research Domain Criteria (RDoC), including the Loss construct within the Negative Valence Systems domains and various Reward constructs within the Positive Valence Systems domain.

Major depressive disorder (MDD) shows a high prevalence and is associated with increased disability. While traditional studies aimed to investigate global characteristic neurobiological substrates of MDD, machine learning-based approaches focus on individual people rather than a group. Therefore, machine learning has been increasingly conducted and applied to clinical practice. Several previous neuroimaging studies used machine learning for stratifying MDD patients from healthy controls as well as in differentially diagnosing MDD apart from other psychiatric disorders. Also, machine learning has been used to predict treatment response using magnetic resonance imaging (MRI) results. Despite the recent accomplishments of machine learning-based MRI studies, small sample sizes and the heterogeneity of the depression group limit the generalizability of a machine learning-based predictive model. Future neuroimaging studies should integrate various materials such as genetic, peripheral, and clinical phenotypes for more accurate predictability of diagnosis and treatment response.

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.

Phenotype networks enable clinicians to elucidate the patterns of coexistence and interactions among the clinical symptoms, negative cognitive styles , neurocognitive performance, and environmental factors in major depressive disorder (MDD). Results of phenotype network approach could be used in finding the target symptoms as these are tightly connected or associated with many other phenomena within the phenotype network of MDD specifically when comorbid psychiatric disorder(s) is/are present. Further, by comparing the differential patterns of phenotype networks before and after the treatment, changing or enduring patterns of associations among the clinical phenomena in MDD have been deciphered.Brain structural covariance networks describe the inter-regional co-varying patterns of brain morphologies, and overlapping findings have been reported between the brain structural covariance network and coordinated trajectories of brain development and maturation. Intra-individual brain structural covariance illustrates the degrees of similarities among the different brain regions for how much the values of brain morphological features are deviated from those of healthy controls. Inter-individual brain structural covariance reflects the degrees of concordance among the different brain regions for the inter-individual distribution of brain morphologic values. Estimation of the graph metrics for these brain structural covariance networks uncovers the organizational profile of brain morphological variations in the whole brain and the regional distribution of brain hubs.

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.

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.

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.

The Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM-IV) was revised based on a combination of a categorical and a dimensional approach such that in the DSM, Fifth Edition (DSM-5), depressive disorders have been separated as a distinctive disease entity from bipolar disorders, consistent with the deconstruction of Kraepelinian dualism. Additionally, the diagnostic thresholds of depressive disorders may be reduced due to the addition of "hopelessness" to the subjective descriptors of depressed mood and the removal of the "bereavement exclusion." Manic/hypomanic, psychotic, and anxious symptoms in major depressive disorder (MDD) and other depressive disorders are described using the transdiagnostic specifiers of "with mixed features," "with psychotic features," and "with anxious distress," respectively. Additionally, due to the polythetic and operational characteristics of the DSM-5 diagnostic criteria, the heterogeneity of MDD is inevitable. Thus, 227 different symptom combinations fulfill the DSM-5 diagnostic criteria for MDD. This heterogeneity of MDD is criticized in view of the Wittgensteinian analogy of language game. Depression subtypes determined by disturbances in monoamine levels and the severity of the disease have been identified in the literature. According to a review of the Gottesman and Gould criteria, neuroticism, morning cortisol, cortisol awakening response, asymmetry in frontal cortical activity on electroencephalography (EEG), and probabilistic reward learning, among other variables, are evidenced as endophenotypes for depressive disorders. Network analysis has been proposed as a potential method to compliment the limitations of current diagnostic criteria and to explore the pathways between depressive symptoms, as well as to identify novel and interesting relationships between depressive symptoms. Based on the literature on network analysis in this field, no differences in the centrality index of the DSM and non-DSM symptoms were repeatedly present among patients with MDD. Furthermore, MDD and other depressive syndromes include two of the Research Domain Criteria (RDoC), including the Loss construct within the Negative Valence Systems domains and various Reward constructs within the Positive Valence Systems domain.

Phenotype networks enable clinicians to elucidate the patterns of coexistence and interactions among the clinical symptoms, negative cognitive styles , neurocognitive performance, and environmental factors in major depressive disorder (MDD). Results of phenotype network approach could be used in finding the target symptoms as these are tightly connected or associated with many other phenomena within the phenotype network of MDD specifically when comorbid psychiatric disorder(s) is/are present. Further, by comparing the differential patterns of phenotype networks before and after the treatment, changing or enduring patterns of associations among the clinical phenomena in MDD have been deciphered.Brain structural covariance networks describe the inter-regional co-varying patterns of brain morphologies, and overlapping findings have been reported between the brain structural covariance network and coordinated trajectories of brain development and maturation. Intra-individual brain structural covariance illustrates the degrees of similarities among the different brain regions for how much the values of brain morphological features are deviated from those of healthy controls. Inter-individual brain structural covariance reflects the degrees of concordance among the different brain regions for the inter-individual distribution of brain morphologic values. Estimation of the graph metrics for these brain structural covariance networks uncovers the organizational profile of brain morphological variations in the whole brain and the regional distribution of brain hubs.

To decipher the organizational styles of neural underpinning in major depressive disorder (MDD), the current article reviewed recent neuroimaging studies (published during 2015–2020) that applied graph theory approach to the diffusion tensor imaging data or functional brain activation data acquired during task-free resting state. The global network organization of resting-state functional connectivity network in MDD were diverse according to the onset age and medication status. Intra-modular functional connections were weaker in MDD compared to healthy controls (HC) for default mode and limbic networks. Weaker local graph metrics of default mode, frontoparietal, and salience network components in MDD compared to HC were also found. On the contrary, brain regions comprising the limbic, sensorimotor, and subcortical networks showed higher local graph metrics in MDD compared to HC. For the brain white matter-based structural connectivity network, the global network organization was comparable to HC in adult MDD but was attenuated in late-life depression. Local graph metrics of limbic, salience, default-mode, subcortical, insular, and frontoparietal network components in structural connectome were affected from the severity of depressive symptoms, burden of perceived stress, and treatment effects. Collectively, the current review illustrated changed global network organization of structural and functional brain connectomes in MDD compared to HC and were varied according to the onset age and medication status. Intra-modular functional connectivity within the default mode and limbic networks were weaker in MDD compared to HC. Local graph metrics of structural connectome for MDD reflected severity of depressive symptom and perceived stress, and were also changed after treatments. Further studies that explore the graph metrics-based neural correlates of clinical features, cognitive styles, treatment response and prognosis in MDD are required.

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.