Metabolic changes of Japanese schizophrenic patients transferred from hospitalization to outpatients.

It is well known that schizophrenic patients have high incidence of metabolic syndrome and life-style related diseases. There are reports that the rates of these diseases are increased more in outpatients than inpatients, but are also reports that the rates are not different between both patient groups. These differences might be related to the length of hospitalization. Hospitalization of Japanese psychiatric patients is about 300 days, much longer than western countries (below 50 days). Therefore, we investigated lipid and glucose metabolism of schizophrenic patients transferred from hospitalization to outpatients at Kohnodai hospital with a mean of 80 days hospitalization period to clarify metabolic characteristics in Japanese patients. Study participants were 144 schizophrenia inpatients and 109 outpatients at Kohnodai Hospital. These 109 outpatients were followed for approximately 2 years, without changes of administrated drugs, and from 144 inpatients. Data from outpatients were obtained at 6 months, 1 year and 2 years after their discharge. Outpatients 2 years after discharge had significantly higher levels of total cholesterol, triglyceride and non-high density lipoprotein (non-HDL) cholesterol than inpatients, accompanied with an increase of body weight. Serum HDL-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels had no significant difference between both groups. These lipids and glucose levels also showed the same tendency in outpatients 0.5 year and 1 year after discharge as those after 2 years. We found that schizophrenic patients in our study appeared to have changes of lipid metabolism 2 years after their discharge, but no significant changes of glucose metabolism, such as FPG and HbA1c.

A cross-sectional study on metabolic similarities and differences between inpatients with schizophrenia and those with mood disorders.

BACKGROUND: One of the main causes of death in psychiatric patients is cardiovascular diseases which are closely related with lifestyle-related diseases. Psychiatric disorders include schizophrenia and mood disorders, whose symptoms and treatment medicines are different, suggesting that they might have different metabolic disorders. Thus, we studied the differences of lifestyle-related diseases between schizophrenia and mood disorders in Japan. METHODS: This cross-sectional study was performed from 2015 to 2017. Study participants were 189 Japanese hospitalized patients (144 schizophrenia group, 45 mood disorders group) in the department of psychiatry at Kohnodai hospital. We examined physical disorders, metabolic status of glucose and lipid, estimated glomerular filtration rate (eGFR) and brain magnetic resonance imaging. We compared these data between schizophrenia and mood disorders groups using analysis of covariance or logistic regression analysis. In comparisons between inpatients with schizophrenia or mood disorders group and the standard, we quoted 'The National Health and Nutrition Survey in Japan 2015' by Ministry of Health, Labor and Welfare as the standard. RESULTS: eGFR and prevalence of smoking were significantly lower in patients with mood disorder group than those with schizophrenia group by adjustment for age. In comparisons between patients with schizophrenia group or mood disorders group and each standard, the ratio of silent brain infarction (SBI) and cerebral infarction were significantly high in both groups. Schizophrenia group showed significantly higher prevalence of diabetes, low high-density lipoprotein (HDL) cholesterolemia, metabolic syndrome and smoking than the standard. Mood disorders group had significantly high prevalence of low HDL-cholesterolemia compared with the standard. Fasting blood glucose and HbA1c were significantly higher in schizophrenia group and female mood disorders group than the standard. Female mood disorders group had significantly decreased eGFR with increased ratio of eGFR < 60 ml/min than the standard. CONCLUSIONS: Participants of both groups had increased ratio of SBI and cerebral infarction, accompanied with glucose and lipid disorders. Compared with schizophrenia group, mood disorders group showed significantly low eGFR and prevalence of smoking.

Suicidal ideation, suicidal behaviors, and attitudes towards suicide of adolescents enrolled in the Alternative Learning System in Manila, Philippines-a mixed methods study.

BACKGROUND: Globally, suicide is a significant cause of death among adolescents. Previous studies conducted in high-income countries suggest that students in alternative schools are more likely to engage in suicidal behaviors than those in formal schools. This study aimed to document suicidal ideation and behaviors among adolescent learners enrolled in the Alternative Learning System (ALS) in Manila, Philippines. METHODS: A mixed methods study was conducted in 24 ALS centers in the city of Manila. ALS centers were stratified according to congressional district and selected using probability proportionate sampling. A cross-sectional survey to determine attitudes towards suicide and prevalence of suicidal ideation and behaviors was administered to 171 learners aged 13 to 17 years old. In-depth interviews with 18 teachers and 12 learners were conducted to explore the school psychosocial environment's role on learners' suicidal ideation and behaviors. Exploratory factor analysis was used to extract attitude factors. Fisher's exact test and Student's t-test were used to identify differences in sociodemographic characteristics and attitudes towards suicide between learners with or without suicidal ideation or behaviors. Qualitative data were analyzed using thematic analysis. RESULTS: Non-specific active thoughts were the most common type of lifetime suicidal ideation (40.9%) while passive ideation was the most common in the past month (13.5%). Aborted suicide attempt was the most frequent behavior in both lifetime (16.4%) and in the past month (4.7%). Non-fatal suicide attempt in the past month was 2.3%, reaching 12.9% for the entire lifetime. Age, sex, education, and attitudes towards suicide were significantly associated with suicidal ideation or behavior. Thematic analysis showed five themes: (1) fostering belongingness, (2) securing learners' safety, (3) teaching philosophy, (4) teacher and learner beliefs towards suicidal behavior, and (5) availability of school-offered and community-based services. CONCLUSION: Suicidal ideation and behaviors are prevalent among adolescent ALS learners. This study also showed a significant difference in attitudes towards suicide and sociodemographic characteristics between learners with and without suicidal ideation behaviors. It also suggests that the school psychosocial environment, through social norms and learner-teacher interactions, can potentially prevent progression of suicidal ideation to behavior, influence help-seeking, and promote mental health among learners.

Addressing challenges in children's mental health in disaster-affected areas in Japan and the Philippines - highlights of the training program by the National Center for Global Health and Medicine.

BACKGROUND AND PURPOSE: Natural disasters such as earthquakes, typhoons, floods, and volcanic eruptions frequently occur in Republic of Philippines and mental health care for children affected by these natural disasters is a major public health concern. Aiming to train health professionals on children's mental health, to conduct a situational analysis to identify the local needs and resources for children's mental health, and to propose a mental health program for children that can be transferred from Japan to the Philippines, the National Center for Global Health and Medicine (NCGM) conducted a training program for children's mental health in disaster-affected areas in Japan and the Philippines in June, October, and December, 2017. The training was organized by NCGM for the Program for International Promotion of Japan's Healthcare Technologies and Services funded by Ministry of Health, Labour, & Welfare, Japan in relation to the Memorandum of Understanding in the Field of Healthcare between NCGM in Japan and University of the Philippines Manila, College of Public Health. KEY HIGHLIGHTS: The training program consisted of classroom trainings, site visits, and round table discussions in Japan and the Philippines. The classroom trainings and site visits focused on two points: the experiences of individuals and families who survived the Great East Japan Earthquake (GEJE) in 2011 and super typhoon Haiyan in 2013 and the program and activities, especially on mental health, of various government and non-government organizations in helping the affected families and communities. The round table discussion, on the other hand, was conducted to identify challenges related to children's mental health in disaster-affected areas and to develop recommendations to address these challenges.The major recommendations for the Philippines were to give equal emphasis to physical and psychosocial preparedness and to develop a comprehensive program to care for carers. In Japan, public health and mental health should be integrated in the Disaster Medical Service. Experts from both countries should also generate evidence on the effectiveness of interventions in reducing mental health stigma and collaborate with school personnel and communities in order to learn more about psychosocial preparedness. Finally, mental health must be mainstreamed in programs not only in Japan but also in other countries. IMPLICATIONS: The training program enabled key stakeholders to describe the current situation of mental health in Japan and the Philippines, to identify mental health challenges common to disaster-affected areas in both countries, and to propose short- and long-term plans and recommendations. The training program is expected to address the mental health needs of children in disaster-affected areas through a responsive community-based support network. The training participants agreed to form a network and build partnerships toward the common goal of mainstreaming community-based support for children's mental health in disaster-affected areas in Japan and the Philippines.

Development of diabetes mellitus associated with quetiapine: A case series.

We aimed to describe the characteristics and clinical course of patients who developed diabetes associated with the use of quetiapine.This study included patients who received quetiapine for over a month between April 2008 and November 2013, and were diagnosed as having new-onset diabetes after initiation of quetiapine. We excluded patients who developed diabetes more than 1 year after discontinuation of quetiapine. We identified new-onset diabetes by hemoglobin A1c or prescriptions of antidiabetic drugs.Among 1688 patients who received quetiapine, hemoglobin A1c had been measured in 595 (35.2%) patients at least once during the observation period, and 33 (2.0%) patients had received hypoglycemic drugs. Eighteen (1.1%) patients were considered to have developed new-onset diabetes associated with quetiapine after a median of 1.6 years following initiation of quetiapine. Median (interquartile range) age was 54.5 (29.8) years, 8 patients were male, and median (interquartile range) duration of mental illness was 15.3 (13.8) years. Median hemoglobin A1c and body mass index (BMI) were 7.1 (1.4) % and 28.4 (7.0) kg/m, respectively. Seventeen patients had dyslipidemia when diabetes was discovered. All of these discontinued quetiapine within 3 months after the diagnosis of diabetes, and the diabetes in 4 patients had ameliorated without hypoglycemic drugs. Of 13 patients who had received either oral hypoglycemic drugs or insulin, 2 patients achieved well-controlled hemoglobin A1c without hypoglycemic drugs, and 10 patients had hemoglobin A1c 5.0% to 7.7% with the continued use of hypoglycemic drugs.We demonstrated that almost all patients who developed quetiapine-associated diabetes had dyslipidemia and increased BMI. There was no life-threatening hyperglycemia and diabetes was ameliorated just by discontinuation of quetiapine in several patients. The monitoring of metabolic parameters during antipsychotic treatment is important to diagnose and treat diabetes earlier.

Correlation between brain damage, associated biomarkers, and medication in psychiatric inpatients: A cross-sectional study.

BACKGROUND: We clarified the correlation between brain damage, associated biomarkers and medication in psychiatric patients, because patients with schizophrenia have an increased risk of stroke. METHODS: The cross-sectional study was performed from January 2013 to December 2015. Study participants were 96 hospitalized patients (41 men and 55 women) in the Department of Psychiatry at Kohnodai Hospital, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan. Patients were classified into schizophrenia (n=70) and mood disorders (n=26) by psychiatric diagnoses with DSM-IV-TR criteria. RESULTS: The incidence of brain damage [symptomatic and silent brain infarctions (SBIs) and white matter hyperintensity (WMH)] was correlated more with mood disorders than with schizophrenia. It has been previously shown that the concentrations of protein-conjugated acrolein (PC-Acro) and interleukin-6 (IL-6) increased in plasma of brain infarction patients together with C-reactive protein (CRP). The concentration of PC-Acro was significantly higher in patients with mood disorders than in those with schizophrenia. The concentration of IL-6 in both groups was nearly equal to that in the control group, but that of CRP in both groups, especially in mood disorders, was higher than that in the control group. Accordingly, the relative risk value for brain infarction was higher in patients with mood disorders than with schizophrenia. Medication with atypical antipsychotics reduced PC-Acro significantly in all psychiatric patients and reduced IL-6 in mood disorder patients. CONCLUSION: Measurement of 3 biomarkers (CRP, PC-Acro and IL-6) are probably useful for judgement of severity of brain damage and effectiveness of medication in psychiatric patients.

Genome-Wide Association Study Identifies ZNF354C Variants Associated with Depression from Interferon-Based Therapy for Chronic Hepatitis C.

The therapeutic use of interferon (IFN) is known to cause depression that frequently interrupts treatment. To identify genetic variants associated with IFN-induced depression, we conducted a genome-wide association study (GWAS) of 224 Japanese chronic hepatitis C patients receiving IFN-based therapy in a multicenter prospective study and stratified them into two groups according to the Beck Depression Inventory, Second Edition (BDI-II) score. In the GWAS stage, we selected 42 candidate single nucleotide polymorphisms (SNPs) to perform replication analysis in an independent set of 160 subjects. The SNP rs1863918 in strong linkage disequilibrium with SNPs located around the Zinc finger 354C (ZNF354C) gene on chromosome 5 showed a significant association when the results of GWAS and replication were combined (odds ratio = 2.55, P = 7.89×10-8 in the allele frequency model), suggesting that the rs1863918 T allele was associated with IFN-induced depression. Furthermore, logistic regression analysis showed that rs1863918 T allele, a history of depression, and younger age were independent predictive factors for IFN-induced depression. Interestingly, western blotting and immunofluorescence showed that ZNF354C was highly expressed in the hippocampus in mice, a region implicated in the pathology of psychiatric symptoms. In conclusion, we identified rs1863918 as significantly associated with IFN-induced depression, and revealed that the candidate gene ZNF354C is highly expressed in the hippocampus of mice. Our data might be useful for elucidating the pathogenic mechanisms of depression induced by drugs including IFN.

Increased Silent Brain Infarction Accompanied With High Prevalence of Diabetes and Dyslipidemia in Psychiatric Inpatients: A Cross-Sectional Study.

OBJECTIVE: Patients with schizophrenia have increased risk of atherosclerotic diseases. It is already known that lifestyle-related disorders and the use of antipsychotics are closely related with the progression of atherosclerosis in psychiatric patients. Stroke as well as coronary heart disease play an important role in the cause of death in Asia and Japan. Thus, we studied the prevalence of cerebrovascular disease in psychiatric inpatients in Japan using brain magnetic resonance imaging (MRI). METHOD: This cross-sectional study was performed from January 2012 to December 2013. Study participants were 152 hospitalized patients (61 men and 91 women) in the Department of Psychiatry at Kohnodai Hospital, National Center for Global Health and Medicine, Ichikawa City, Japan. Mean ages were 50.0 and 57.1 years old for men and women, respectively. The diagnoses (DSM-IV-TR criteria) of participants were schizophrenia (69.1%), mood disorder (18.4%), and other mental disorders (12.5%). We checked physical status, metabolic status of glucose and lipid levels, and brain MRI within 1 week of admission. RESULTS: The study group showed a significantly high prevalence of diabetes and low high-density lipoprotein (HDL) cholesterolemia in both sexes (n = 61 in men, n = 91 in women, P < .05). In the study group, serum fasting plasma glucose and hemoglobin A1c levels were significantly high (n = 152, P < .05), but serum HDL cholesterol and total cholesterol were significantly low in both sexes (n = 61 in men, n = 90 in women, P < .05), and triglycerides were low in men (n = 61, P < .05). Silent brain infarction was recognized at a higher rate (n = 98, P < .05) compared with healthy controls. CONCLUSIONS: Participants in this study had an increased ratio of silent brain infarction compared with Japanese healthy controls, accompanied with higher ratios of diabetes and low HDL cholesterol.

[Clinical experience with clozapine in 55 cases of treatment-resistant schizophrenia].

Up until October 2012, Kohnodai Hospital had introduced clozapine treatment for 55 cases of treatment-resistant schizophrenia. In all cases, previous antipsychotic medication was discontinued the day before clozapine administration began. Of the 55 cases, 45(85%)are continuing clozapine administration, and 40 cases (73%) are receiving outpatient treatment. The average dose of clozapine was 373.1 mg/day (SD : 160.5). Clozapine was administered for a month or more in 51 cases (93%). BPRS scores improved 20% or more in a month's administration of clozapine in 18 of the cases (35%). The average clozapine dose in the improvement cases was 176 mg/day. The average BPRS score had significantly decreased from the baseline at months 1, 3, 6, and 12 after the start of clozapine administration. Of the 33 cases receiving clozapine treatment for 12 months or more, BPRS improved 20% or more in 27 (82%). BPRS improved 20% or more for the first time after clozapine administration within a month in 12 cases (44%), 3 months in 8 cases (30%), 6 months in 5 cases (19%), and 12 months in 2 cases (7%). These results suggest that clozapine should be administered continuously for over 6 months at the least and 12 months if possible to evaluate the efficacy of clozapine treatment. Of the 43 cases receiving outpatient clozapine therapy, the average GAF score improved significantly from the time of ward admission to discharge (20.6 and 42.0, respectively). Clozapine had to be discontinued in 2 cases of leukopenia, 2 cases of neutropenia, 1 case of reduced left ventricular ejection due to pericardial effusion, 1 case of drug eruption, and 1 case of marked hunger. When introducing clozapine for treatment-resistant schizophrenia, it is important to administer it as a monotherapy, slowly increase the dosage to reduce side effects, and achieve a treatment effect at the minimum required dosage.

A comparison between augmentation with olanzapine and increased risperidone dose in acute schizophrenia patients showing early non-response to risperidone.

We examined whether augmentation with olanzapine would be superior to increased risperidone dose among acute schizophrenia patients showing early non-response to risperidone. We performed a rater-blinded, randomized controlled trial at psychiatric emergency sites. Eligible patients were newly admitted patients with acute schizophrenia. Early response was defined as Clinical Global Impressions-Improvement Scale score ≤3 following 2 weeks of treatment. Early non-responders were allocated to receive either augmentation with olanzapine (RIS+OLZ group) or increased risperidone dose (RIS+RIS group). The 78 patients who completed 2 weeks of treatment were divided into 52 early responders to risperidone and 26 early non-responders to risperidone (RIS+OLZ group, n=13; RIS+RIS group, n=13). No difference in the achievement of ≥50% improvement in Positive and Negative Syndrome Scale total score was observed between RIS+OLZ and RIS+RIS groups. Although time to treatment discontinuation for any cause was significantly shorter in the RIS+RIS group (6.8 weeks [95% confidence interval, 5.2-8.4]) than in early responders to risperidone (8.6 weeks [7.9-9.3]; P=0.018), there was no significant difference between the RIS+OLZ group (7.9 weeks [6.3-9.5]) and early responders to risperidone. Secondary outcomes justify the inclusion of augmentation arms in additional, larger studies comparing strategies for early non-responders.

Difference in early prediction of antipsychotic non-response between risperidone and olanzapine in the treatment of acute-phase schizophrenia.

PURPOSE: We examined whether early response/non-response to risperidone according to the Clinical Global Impressions-improvement scale (CGI-I) at 2 weeks could predict subsequent response. This prediction was also applied to olanzapine. We then investigated whether early non-responders (ENRs) to risperidone or olanzapine who switched to the other showed significantly greater improvement, compared with those staying on the initial antipsychotic. We performed a rater-blinded, randomized controlled trial in 18 psychiatric emergency sites. Eligible patients were newly admitted patients with acute schizophrenia. Early response was defined as CGI-I ≤ 3 following 2 weeks of treatment. The primary outcome measure was achievement of remission and ≥ 50% improvement in the Positive and Negative Syndrome Scale at 4 weeks. RESULTS: At 4 weeks, 53% of risperidone early responders (ERs) went into remission, whereas only 9% of ENRs staying on risperidone (n=11) did (P=0.016). Similarly, at 4 weeks, 81% of risperidone ERs achieved ≥ 50% response, whereas only 9% of ENRs staying on risperidone achieved ≥ 50% response (P < 0.0001). In contrast, 58% of olanzapine ERs (n=33) went into remission, whereas 38% of ENRs staying on olanzapine (n=8) did at 4 weeks (P=0.44). Similarly, 61% of olanzapine ERs achieved ≥ 50% response, whereas 25% of ENRs staying on olanzapine achieved ≥ 50% response (P=0.12). The negative likelihood ratio for the prediction of ≥ 50% response at 4 weeks by early response status to risperidone at 2 weeks was 0.057. CONCLUSION: In newly admitted patients with acute schizophrenia, non-response to risperidone using CGI-I at 2 weeks can predict subsequent response. It looks like there is significant response to olanzapine that doesn't occur until 4 weeks. Thus, clinicians may want to switch to another drug earlier when risperidone is the first drug, and later when olanzapine is the first drug.

Clinical analyses of sighted patients with non-24-hour sleep-wake syndrome: a study of 57 consecutively diagnosed cases.

STUDY OBJECTIVES: The objective of this study was to clarify the clinical features of sighted patients with non-24-hour sleep-wake syndrome. DESIGN: Clinical analyses of consecutive patients suffering from non-24-hour sleep-wake syndrome. SETTING: The sleep disorders clinic at Kohnodai Hospital, National Center of Neurology and Psychiatry, Japan. PATIENTS: Fifty-seven patients who were diagnosed consecutively as having non-24-hour sleep-wake syndrome between 1991 and 2001 were included in the study. MEASUREMENTS AND RESULTS: The clinical features and sleep characteristics of the patients were analyzed. A semistructured psychiatric interview that included the criteria for Axis I or II disorders of Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised was conducted, and relationships between psychiatric problems and non-24-hour sleep-wake syndrome were analyzed. The patient cohort included 41 (72%) men and 16 (28%) women. The onset of non-24-hour sleep-wake syndrome had occurred during the teenage years in 63% of the cohort, and the mean ( +/-SD) period of the sleep-wake cycle was 24.9 +/- 0.4 hours (range 24.4-26.5 hours). The mean sleep length of the patients was 9.3 +/- 1.3 hours, and 44% of them had a sleep length of between 9 and 10 hours. Psychiatric disorders had preceded the onset of non-24-hour sleep-wake syndrome in 16 patients (28%); of the remaining 41 patients, 14 (34%) developed major depression after the onset of non-24-hour sleep-wake syndrome. CONCLUSIONS: These results represent the first detailed clinical review of a relatively large number of sighted patients with non-24-hour sleep-wake syndrome.

Larger phase angle between sleep propensity and melatonin rhythms in sighted humans with non-24-hour sleep-wake syndrome.

STUDY OBJECTIVES: This study was aimed to clarify phase angle between sleep propensity and the circadian pacemaker in patients with non-24-hour sleep-wake syndrome (Non-24). DESIGN AND SETTING: A case-control study was underaken. PARTICIPANTS: Sighted patient with Non-24 (4 males and 1 female, aged 16 to 39 y), and sex- and age-matched healthy controls (12 males and 3 females, aged 19 to 35 y) participated the study. MEASUREMENT AND INTERVENTION: Following an actigraphic assessment of the sleep-wake cycle in their homes, the participants entered an ultra-short sleep-wake schedule together with simultaneous measurement of dim light melatonin rhythm after 24-hour sleep deprivation. RESULTS: The period of the sleep-wake cycle observed at home was longer in the Non-24 patients (25.12 hours) than in the controls (24.02 hours, p<0.0001). The interval from sleep propensity (SP) onset to the melatonin midpoint (MLmid) was significantly shorter in the Non-24 patients than in the controls. The interval from the MLmid to the SP offset was significantly longer in the Non-24 patients than in the controls. CONCLUSIONS: It was postulated that Non-24 sufferers' delayed SP onset relative to the circadian pacemaker may accelerate the light-induced phase-delay, leading to sleep-wake cycle that is longer than 24 hours.