Recent research has demonstrated that complex ‘epigenetic’ mechanisms, which regulate gene transcription without altering the DNA code, could play a critical role in the pathophysiology of psychiatric disorders. The present review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in several psychiatric disorders such as depression, schizophrenia and Rett syndrome. The gene transcriptions of the key molecules such as brain-derived neurotrophic factor (BDNF) or reelin that play a role in on psychiatric disorders are regulated with histone modification or DNA methylation. Furthermore, one potential mechanism whereby stress can disrupt prenatal and/or neonatal development is through epigenetics, because the key issue of epigenetics is its long-term influence. The present review also focuses on the roles of brain 5-HT_1A receptor-mediated epigenetic mechanisms in the development of resistance to emotional stress. Behavioral pharmacological studies have demonstrated that treatment with a 5-HT_1A receptor agonist 24 h before testing suppressed the decrease in emotional behaviors induced by acute restraint stress. Studies with DNA microarray technology have revealed that histone deacetylase genes decreased in the hippocampus of mice that had been pretreated with a 5-HT_1A receptor agonist 24 h beforehand. In addition, we found that acetylated histone H3 increased. Interestingly, similar to a 5-HT_1A receptor agonist, the histone deacetylase inhibitor trichostatin A also protected against the emotional changes induced by acute restraint stress, as well as histone H3 acetylation. The present findings suggest that the epigenetic mechanisms of gene regulation may play an important role in the development of emotional resistance to stress stimuli. A better understanding of epigenetic regulation might provide new therapeutic avenues for disorders such as depression, schizophrenia, Rett syndrome and neurodevelopmental diseases.

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Psychosocial stress (stress) is one of the environmental factors associated with asthma exacerbation. However, little is known about the mechanism by which how stress influences asthma phenotypes. Epigenetic modifications, such as DNA methylation, histone remodeling, and microRNAs, have been recently reported as new mechanisms of environmental factors-induced asthma. For instance, we have reported that dietary factors can modify the heritable risk of asthma during a vulnerable period of fetal development through epigenetic mechanisms in mice. Chen et al have reported that epigenetic and genetic variants in ADCYAP1R1, which is linked to post-traumatic stress disorder in adults and anxiety in children, are associated with asthma in Puerto Rican children. In this paper, we review current topics of epigenetic regulations in terms of asthma and psychosocial stress, and discuss the possible link between stress and asthma pathogenesis.

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The term epigenetic refers to long-lasting changes in gene expression that are beyond the DNA base sequence. Mounting evidences suggest that epigenetic regulation of brain functions is important in the aetiology of psychiatric disorders. We previously reported that pretreatment of mice with 5-HT_1A receptor agonists 24 hr before testing suppressed the decrease in emotional behaviors induced by exposure to acute restraint stress. In addition, DNA microarray analysis showed that such a pretreatment with 5-HT_1A receptor agonist produces changes in several gene transcriptions including the reduction of histone deacetylase 10 (HDAC10). These findings have led us to investigate epigenetic mechanisms in stress resistance. The aim of this review was to summarize our recent findings on the association between the development of stress resistance or stress adaptation and histone acetylation. We found that acetylated histone H3 increased in the hippocampus of mice that had developed resistance to emotional stress by pretreatment with 5-HT_1A receptor agonists 24 hr before testing. On the other hand, pretreatment with benzodiazepine anxiolytic diazepam did not have similar effects. Interestingly, similar to 5-HT_1A receptor agonists, the histone deacetylase inhibitor trichostatin A also protected against the emotional changes induced by acute restraint stress, as well as histone H3 acetylation. In addition, an increase of histone H3 acetylation was observed in the hippocampus of mice that has been developed stress adaptation. The present findings suggest that the epigenetic mechanisms of gene regulation may play an important role in the development of stress resistance or stress adaptation.

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Increasing evidences have suggested that the non-protein-coding genome is functionally important for regulation of cellular processes. MicroRNAs (miRNAs) are a class of small non-coding RNAs approximately 22 nucleotides in length. They bind to partially complementary sites within the 3’UTR of target mRNAs and inhibit their translation. More than 2,000 miRNAs are discovered in human cells, and sufficiently expressed miRNAs typically target hundreds of different mRNAs. The important roles of miRNAs are to control and maintain normal physiological functioning of the central nervous system, including neuron maturation, neurogenesis, and synaptic plasticity. Various stressors influence the processing of miRNA, recognition of mRNA targets, and miRNA expression. Recent papers have reported that miRNAs play an essential role in regulation of stress response. Interestingly, experimental animals with mutant miRNAs appear to normally develop, while they cannot cope with stressful conditions. Both acute and chronic stressors change miRNA expression profiles in a brain region-dependent fashion and changes in miRNA expression. We previously investigated that psychological stress-related changes in miRNA expression were also detectable in peripheral tissues, such as peripheral blood leukocytes. Taken together, the stress-mediated miRNA response may activate a program of gene expression that is essential for the production of adaptive response to the stressor.

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DNA methylation is one of the essential factors in the control of gene expression. Alteration of the DNA methylation pattern has been linked to various neurological, behavioral, and neurocognitive dysfunctions. Recent studies have pointed out the importance of epigenetics in brain development and functions including learning and memory. Consolidation and extinction of fearful memory affect the symptoms of anxiety-related mental illnesses such as post-traumatic stress disorder and panic disorder, thus epigenetic mechanism might underlie the pathogenesis. In this review, possible role of DNA methylation on the vulnerability or treatment resistance for such mental illnesses is discussed thorough our results, which suggested chronic dietary lack of methyl donors in the developmental period affected learning, memory and gene expressions in the hippocampus. Changed behavior affected by the alteration of epigenetic status might be inherited to next generations, although future studies are needed.

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Morita therapy is a psychotherapy established by Masatake Morita in the 1920s. The background of Morita’s development of the therapy is in his own real-life experience. Due to belated remittance from his father, anger toward and antipathy to his father grew in Morita before he was to take exams for moving up to the next grade in college, but he left such feelings as they were and concentrated on study, which resulted in good grades. Key concepts of Morita therapy, including law of emotion, psychic interaction, and conflict between ideal and real, grew out of such experience. “The first words” given to a sufferer in introducing Morita therapy are “What do you want to do if you do not have the symptom you wish to be cured?” The words prompt raising awareness of the existence of “desire to live fully.” Key concepts of Morita therapy are used to explain how the current suffering is generated and to show the direction Morita therapy, which is about to begin, is heading for.

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The drug therapy for skin symptoms, the investigation and elimination of aggravating factors, and the application of moisturizer to supplement the barrier function of skin form the basis of the treatment of atopic dermatitis. Stress as one of the aggravating factors increases itchy sensations and intensifies scratching. On the other hand, scratching can be a part of stress coping behavior, and in the cases that scratching behavior had become a habit, the dermatological treatment could not have sufficient effect without dropping the habit. However, many of the refractory cases show that the patients are obsessed with itchy sensations and scratching, who often claim that the more they try to stop scratching the harder it becomes to stop it. For such patients, I apply outpatient Morita therapy to aim at changing their way of living and thinking, without instructing them “not to scratch”. The patients are guided to lead a behavior-oriented life and to gain the “arugamama” way of life. As the way of life changes, the patients are released from the obsession, improving the stressful condition, which then naturally leads to resolve the dermatitis.

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As for outpatient Morita therapy in my clinic to neurosis and psychosomatic disease, weight is given to diary instruction. In Morita Therapy, it is the most important point that the daily life attitude fulling of prepossession to symptoms is broken down by active and constructive life experience. However, in the outpatient, unlike inpatient, it is impossible to observe the daily life behavior directly. Diary can know the day-to-day behavior of patient and do practical and concrete instruction, it can play an important role in outpatient therapy. It’s also useful for relationship of mutual trust between patient and doctor. Diary instruction guidelines in my clinic are as follows. The mentioning contents assume the behavior and impression of the day in the main, and it is said that mentioning of symptom is minimum. Standard instruction period is held every two weeks for 12 times. As a principal, I do not answer the appeal to the symptoms (Fumon). On the other hand, I perform positive comments on the constructive movements and attitudes in view of the facts. I exhibited the instruction of the specific examples (Panic disorder, Functional dyspepsia with anxiety disorder).

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Objectives : Diagnostic criteria for the Diagnostic and Statistical Manual (DSM)-5 include several revisions designed to reduce the preponderance of eating disorder not otherwise specified (EDNOS) diagnoses. The most dramatic revision involves the formal recognition of binge-eating disorder (BED). This study compares DSM-Ⅳ and DSM-5 diagnostic criteria on the number of EDNOS cases and validity. Subject and Method : Participants included 251 treatment seeking adults who met criteria for DSM-Ⅳ eating disorders. All participants completed structured clinical interviews. Results : Using DSM-Ⅳ versus DSM-5 criteria, 49 (19.6%) versus 75 (29.9%) had anorexia nervosa, 91 (36.3%) versus 85 (33.9%) had bulimia nervosa (BN) and 93 (37.1%) had EDNOS versus 70 (27.9%) had BED and 21 (8.4%) had other specified feeding and eating disorder (OSFED)/unspecified feeding or eating disorder (UFED), respectively, reflecting a significant decrease in EDNOS. The BED group reported the highest body mass index (BMI), the mean (SD) of 24.0 (6.2) kg/m², among the 5 groups of DSM-5 eating disorders. “Kashoku”, the Japanese translation of binge eating in the Japanese version of DSM-5, include several eating behaviors, such as continual snacking and overeating with control over eating as well as binge-eating. Accordingly, we need a careful assessment for the complaint of “Kashoku” . Conclusion : DSM-5 diagnostic criteria for eating disorders significantly reduced reliance on EDNOS. Boundary between non-purging BN and BED in non-obese people is an important topics for future investigation. We discussed concerns on the Japanese translation of binge-eating, “Kasyoku”, and BED, “Kasyokuseisyogai”, in the Japanese version of DSM-5.

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Objective : When physicians treat a psychosomatic disease, they are prone to focus on its psychosocial factors rather than its physical abnormalities. We report 2 patients who can be diagnosed as eating disorder. Thier illnesses had been suspected to be psychogenic and finally turned out to be caused by obvious physical abnormalities. Therefore, we consider the elements of what make difficult to diagnose physical abnormalities. Case 1 : A female in 40’s. She has had a mental illness and a gastric banding surgery to reduce her weight in the past. Her illness was suspected to be psychogenic because her vomiting and back pain occurred when she felt much stress. The fluoroscopic study on gastric motility showed her gastric band slipping and obstruction to the passage of barium. She was given surgery for it and got well. Case 2 : A female in 60’s. She has had a surgery for stomach cancer. She had frequent diarrhea and lost weight. As no one could find the causes, they were suspected to be psychogenic. The fluoroscopic study on intestinal motility showed that her total colon was spastic, and her symptom of diarrhea got better by taking scopolia extract. Conclusion : Patients’ past histories, illness behavior, or psychosocial problems often make it difficult for physicians to find the physical causes for their illness.

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