In today’s stressful society, many people suffer from excessive stress, leading to subclinical and clinical depression. A variety of biological abnormalities associated with stress and depression have been reported, and among them, abnormalities in the hypothalamic‐pituitary‐adrenal (HPA) axis and immune/inflammatory system, both of which are centrally involved in the stress response, are thought to hold the key. However, findings on the HPA axis and inflammatory system in depression are somewhat inconsistent, and its etiology and pathophysiology have not been elucidated. To clarify the involvement of stress in depression, we have conducted studies targeting the HPA axis and inflammatory system, and also performed data‐driven transcriptome analyses using peripheral blood RNA. In doing this, we focused on adverse childhood experiences, personality characteristics, and circadian rhythms. The results suggested that psychological and physical stress vulnerabilities caused by severe stress that begins early in life, and by long‐term or repetitive stress, can represent one important route leading to the development of depression.

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Serotonin reuptake inhibitors and other serotonin‐related drugs are widely used to treat psychiatric disorders, but their therapeutic effects are inadequate and often accompanied by severe side effects, and their mechanisms of action are unclear. One reason for this may be that previous studies have used neurotoxin or pharmacological methods, and thus the possibility of secondary, compensatory, or non‐selective effects could not be ruled out. However, with the rapid development of optogenetics and gene editing technologies in recent years, the above problems can theoretically be avoided. This paper will introduce some examples of our research using these technologies to elucidate the serotonergic pathways involved in depression and its treatment.

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Glucocorticoid, also known as a “stress hormone”, has been considered to play a central mediator role in the detrimental effects of chronic stress on the brain, cognition, and mental health. Yet, physical exercise, despite activating the HPA axis and increasing glucocorticoid, exerts many beneficial effects to the brain, cognition, and mental health. Here, we will introduce this Exercise‐Glucocorticoid Paradox and propose three potential solutions to the paradox, 1) , exercise buffers the HPA‐axis response to novel stressors, 2) , exercise does not downregulate or even increases glucocorticoid receptors, and 3) , exercise increases medial prefrontal dopamine. Via examining the Exercise‐Glucocorticoid Paradox, we hope to provide an opportunity to reconsider the functional role of glucocorticoid in stress coping and in the pathophysiology of chronic stress and depression.

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Memory bias is a cognitive/behavioral tendency to more preferentially encode/retrieve emotionally negative stimuli than non-negative ones, and to show difficulty recalling specific contextual information of an experienced event. It is a form of cognitive bias that contributes to the development and maintenance of stress-related mental disorders, and its modification has been demonstrated to alleviate stress-related symptoms including anxiety and depression. Memory bias is thus a major target of the cognitive bias modification; however, research on memory bias modification has not progressed as expected, since memory complicatedly changes over time. This review discusses the findings of previous research focusing on the neurobiological mechanisms underlying memory bias, towards the development of memory bias modification in the future.

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Currently available antidepressants based on the monoamine hypothesis of depression (e. g. selective serotonin reuptake inhibitors) have significant limitations, including delayed onset of therapeutic response and low efficacy : approximately one‐third of depressed patients fail to respond to multiple antidepressant treatments and are considered treatment‐resistant. In contrast, ketamine, an N‐methyl‐D‐aspartate receptor antagonist, produces rapid and sustained antidepressant effects in patients with treatment‐resistant depression. Previous preclinical studies have demonstrated that brain‐derived neurotrophic factor (BDNF) ‐mediated neuronal plasticity in the medial prefrontal cortex (mPFC) is essential for the antidepressant actions of ketamine. We have recently shown that neuronal vascular endothelial growth factor (VEGF) in the mPFC also plays an important role in the antidepressant and neuroplastic effects of ketamine in rodents. Moreover, we have demonstrated that a heterologous interplay between BDNF and VEGF signaling in the mPFC is required to produce ketamine‐like antidepressant effects of these neurotrophic factors. This review provides an overview of the roles of BDNF and VEGF in the antidepressant actions of ketamine, especially focusing on our recent findings.

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Schizophrenia is a multifactorial disease in which genetic and environmental factors are intricately intertwined. Currently, the molecular pathogenesis of the disease remains unclear. Considering many patients are not adequately treated with the major antipsychotic drugs, it is important to stratify the disease based on molecular pathogenesis and to clarify the molecular pathogenesis of each patient group individually in order to understand the disease and to develop patient‐selective treatment strategies. Analysis of iPSC‐derived neurons from patients will directly lead to the clarification of the molecular pathology of the disease. It is also important to conduct not only molecular and cellular level analyses using iPSC‐derived neurons from patients, but also neural circuit level and behavioral level analyses using mouse models of the disease, which are generated by introducing the genetic mutations occurring in the patients. In these studies, the use of patient‐derived iPSCs enables cross‐species verification. CNS drug discovery has an extremely low success rate. In the future, research using iPSC technology will not only clarify the molecular pathogenesis of the disease, but will also lead to molecular pathogenesis‐based stratification of the disease, construction of model systems for the development of therapeutic drugs, and ultimately to the success of CNS drug discovery.

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In the first half of this article, we will outline the large genomic copy number variants (CNVs) that are strongly implicated in the risk of schizophrenia. Although individual CNVs account for less than 1% of the patient population, some, such as the 22q11.2 deletion, the 3q29 deletion, and the 15q11‐q13 duplication, increase the risk of developing the disorder more than tenfold. These CNVs are involved not only in schizophrenia but also in the risk of neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, and attention deficit hyperactivity disorder, making them cross‐disease risk variants. In the latter half of the article, we will introduce the ARHGAP10 gene, which we found to be associated with schizophrenia based on our CNV study. We found developmental abnormalities in ARHGAP10 variant based model mice and patient‐derived iPS cells. We hypothesize that the abnormal activation of RhoA and Rho kinase caused by the loss‐of‐function variant of ARHGAP10 gene underlines these abnormalities. We will describe our drug discovery research for schizophrenia targeting this signal.

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Biotype is a biological classification of psychiatric disorders that is not limited to conventional diagnostic methods based on symptoms. This biological classification is based on patient measurement data, and is intended to examine the relationship with treatment responsiveness and eventually lead to new diagnostic criteria. In recent years, classification studies that are not based on a specific hypothesis, but are obtained using methods such as machine learning, have become popular. As a biotype of schizophrenia, intermediate phenotypes such as cognitive function, neurophysiological function, and brain neuroimaging, which are biological phenotypes that differ from normal subjects in schizophrenia, are often considered. Examples of biotype Ⅰ, “within the framework of the current diagnosis based on symptoms and course,” include clozapine treatment of treatment‐resistant schizophrenia and cognitive dysfunction in schizophrenia, while biotype Ⅱ, “without any consideration of the current diagnosis based on symptoms and course, ” defines treatment responsiveness to a common outcome measure for all patients. The current status and prospects of Type Ⅰ and Ⅱ will be outlined.

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Social implementation research is defined as “research that aims to bring benefits to society by applying new knowledge and technologies obtained through research to the real world in order to solve social issues.” In the field of pharmacotherapy for schizophrenia, following the research to develop drugs, it is necessary to implement evidence‐based methods for the successful use of drugs in society. The EGUIDE project aims to educate and test the effectiveness of pharmacotherapy guidelines for schizophrenia through workshops for psychiatrists. The EGUIDE project is a project to educate psychiatrists on the pharmacotherapy guidelines for schizophrenia through workshops and to verify their effectiveness. It is hoped that the evidence will be implemented in society through this project.

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