Hirokazu Tachikawa

Genomewide High-Density SNP Linkage Analysis of 236 Japanese Families Supports the Existence of Schizophrenia Susceptibility Loci on Chromosomes 1p, 14q, and 20p

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

The (CTG)n polymorphism in the NOTCH4 gene is not associated with schizophrenia in Japanese individuals

BackgroundThe human NOTCH4 gene is a candidate gene for schizophrenia due to its chromosomal location and neurobiological roles. In a British linkage study, NOTCH4 gene polymorphisms were highly associated with schizophrenia. In a Japanese case-control association study, however, these polymorphisms did not show significant associations with schizophrenia. We conducted a case-control study with Japanese subjects to explore an association between the triplet repeat polymorphism in the NOTCH4 gene and schizophrenia, including subtypes of schizophrenia, longitudinal disease course characteristics, and a positive family history for psychoses.MethodsWe examined the (CTG)n repeat polymorphism in the NOTCH4 gene among 100 healthy Japanese individuals and 102 patients with schizophrenia (22 paranoid, 38 disorganized, 29 residual, 64 episodic, 31 continuous, 42 with prominent negative symptoms, and 46 with positive family histories) using a polymerase chain reaction-based, single-strand conformational polymorphism analysis.ResultsFive different alleles consisting of 6, 9, 10, 11, and 13 repeats of CTG (Leu) in patients with schizophrenia, and 4 alleles consisting of 6, 9, 10, and 11 repeats in controls were found. No significant differences in genotype or allele frequencies of repeat numbers were found between controls and patients. In addition, there were no associations between the polymorphism and schizophrenia subtypes, longitudinal disease course characteristics, or positive family history of the patients.ConclusionsOur data suggest a lack of association between the NOTCH4 gene triplet repeat polymorphism and schizophrenia in Japanese individuals.

Parental representation in eating disorder patients with suicide

OBJECTIVE We examined parental, personality, and symptomatological characteristics in relation to suicide attempts among eating disorder patients. METHODS Fifty-one eating disorder inpatients, divided into two groups according to lifetime suicide attempts, and 107 non-psychiatric subjects were compared on the following variables: Parental Bonding Instrument (PBI), Global Clinical Score (GCS), Eating Disorder Inventory-91 (EDI-91), Eating Attitudes Test-26 (EAT), clinical and personality characteristics, and family backgrounds. RESULTS Suicidal patients reported significantly higher overprotection by both parents than non-suicidal patients and non-psychiatric subjects. Suicidal patients had a more prevalent history of child abuse, affective instability, unstable self-image, avoidance of abandonment, maladaptive perfectionism, personality disorder, and mood disorder. There were no differences in symptomatological factors or the severity of the eating disorders. CONCLUSION The results suggest that high overprotection is associated with suicidal behaviour in eating disorder patients. The association between overprotective parenting and personality characteristics, and methods of suicide prevention are discussed briefly.

Pharmacogenomics and schizophrenia

Although antipsychotic drugs are effective in alleviating schizophrenic symptoms, individual differences in patient response suggest that genetic components play a major role, and pharmacogenetic studies have indicated the possibility for a more individually based pharmacotherapy. The new field of pharmacogenomics, which focuses on genetic determinants of drug response at the level of the entire human genome, is important for development and prescription of safer and more effective individually tailored drugs. DNA microarray (DNA chip) analysis enables genome-wide scanning, using the high-density single nucleotide polymorphisms map. Pharmacogenomics will aid in understanding how genetics influence disease development and drug response, and contribute to discovery of new treatments. The rate of discovery of those polymorphisms will depend on the quality of the drug response phenotype. Prospective genotyping of schizophrenic patients for the many genes at the level of the drug target, drug metabolism, and disease pathways will contribute to individualized therapy matching the patients unique genetic make-up with an optimally effective drug.

High-dose of multiple antipsychotics and cognitive function in schizophrenia: The effect of dose-reduction

We evaluated the effect of antipsychotic dose-reduction on the neurocognitive function of 17 schizophrenic patients (11 male and 6 female, mean age=42.4+/-11.3) who have been taking high-doses of multiple conventional antipsychotics. The mean (+/-SD) of total daily antipsychotic doses (in mg/day, chlorpromazine-equivalent) was 2,253 (+/-668) at baseline, which was reduced to 1,315 (+/-276). Possible changes in neurocognitive function were assessed using Wisconsin card sorting test (WCST) and continuous performance test (CPT). As controls, we examined WCST and CPT in 6 schizophrenic patients (4 male and 2 female, mean age=47.7+/-14.2) who had been taking high-doses of multiple antipsychotics (mean daily antipsychotic dose=1,753+/-165 mg) and declined to change their antipsychotic regimen. In WCST, the mean number of total correct answers significantly increased (53.2+/-16.3 vs. 63.8+/-19.6, P=0.035, Wilcoxon signed rank test); perseverative errors significantly decreased (54.4+/-27.3 vs. 35.4+/-20.1, P=0.013, Wilcoxon signed rank test) after the antipsychotic dose-reduction. In contrast, the control group showed no significant difference between the two WCST performances conducted with a three-month interval. The improvements in WCST performance significantly correlated with the decreases in PANSS negative syndrome score in the subject patients. No significant change was observed in CPT performances in either group. Our preliminary data shows that, in schizophrenic patients taking high-doses of multiple conventional antipsychotics, dose-reduction might lead to improvements in cognitive functions.

Interventions to prevent repeat suicidal behavior in patients admitted to an emergency department for a suicide attempt: a meta-analysis

BACKGROUND A huge number of patients with self-harm and suicide attempt visit emergency departments (EDs). We systematically reviewed studies and examined the effect of interventions to prevent repeat suicidal behavior in patients admitted to EDs for a suicidal attempt. METHOD We searched the databases of MEDLINE, PsychoINFO, CINAHL, and EMBASE through August 2013. Eligible studies were randomized controlled trials assessing the effects on repeat suicidal behavior of interventions initiated in suicidal patients admitted to EDs. Interventions in each trial were classified into groups by consensus. Meta-analyses were performed to determine pooled relative risks (RRs) and 95% confidence intervals (CIs) of repetition of suicide attempt for interventions in each group. RESULTS Out of 5390 retrieved articles, 24 trials were included and classified into four groups (11 trials in the Active contact and follow-up, nine in the Psychotherapy, one in the Pharmacotherapy, and three in the Miscellaneous). Active contact and follow-up type interventions were effective in preventing a repeat suicide within 12 months (n=5319; pooled RR=0.83; 95% CI: 0.71 to 0.97). However, the effect at 24 months was not confirmed (n=925; pooled RR=0.98; 95% CI: 0.76-1.22). The effects of the other interventions on preventing a repetition of suicidal behavior remain unclear. LIMITATION Caution is needed regarding the heterogeneity of the effects. CONCLUSION Interventions of active contact and follow-up are recommended to reduce the risk of a repeat suicide attempt at 12 months in patients admitted to EDs with a suicide attempt. However, the long-term effect was not confirmed.

Novel variants in the promoter region of the CREB gene in schizophrenic patients

AbstractCyclic AMP-responsive element-binding protein (CREB) is one of the messenger molecules involved in intracellular signal transduction pathways used by most dopamine and serotonin receptor subtypes. In addition, CREB stimulates the expression of a number of genes, alterations in the expression of which may be associated with schizophrenia. The promoter region of the human CREB gene was therefore analyzed to identify genetic variants that may lead to the modification of CREB expression and contribute to schizophrenia. Eighty unrelated schizophrenics and 100 healthy controls were screened for genetic variants of the CREB gene by SSCP analysis, followed by direct sequencing of PCR products. Two novel variants (−933T→C and −413G→A) were found only in schizophrenics. A patient with the −933T→C variant had unusual clinical characteristics in addition to typical schizophrenic symptoms.

The Eating Disorder Inventory-2 in Japanese clinical and non-clinical samples: Psychometric properties and cross-cultural implications

Objective: To determine the usefulness of and cross-cultural differences in the Japanese version of the eating disorder inventory-2 (EDI-2). Method: A Japanese version of the EDI-2 was administered to a consecutive series (1995–2001) of 91 Japanese eating disordered inpatients and 119 matched non-clinical controls. Scores were compared with each other and with those of Canadian data previously reported. Internal consistencies were also examined. Results: All subscales (except Ascetism) reached sufficient internal consistencies. The patients’ mean scores were significantly higher than controls on most subscales. Restricting anorexics (AN-R) scored higher than controls on body dissatisfaction (BD) and Social Insecurity (SI) subscales. Purging bulimics (BN-P) scored higher than controls on most subscales, except for maturity fears (MF) and SI subscales. Scores of binge-eating/purging type anorexics (AN-B/P) were higher than controls on all subscales. AN-B/P and BN-P scored higher than AN-R on bulimia (B) subscale. Comparison with Canadian subjects showed that Japanese control subjects scored significantly higher on the MF, ineffectiveness (I), impulse regulation (IR), SI subscales, and lower on the perfectionism (P) subscale. Discussion: The EDI-2 is useful and reliable in understanding Japanese clinical and non-clinical samples. High MF and low P subscales in our samples confirm previous findings in Chinese samples suggesting meaningful cultural differences in the emphasis placed on family bonds and individual accomplishments. In addition, high I, IR, and SI scores in Japanese non-clinical samples may reflect recent problems in Japanese culture.

Persistence Criteria for Susceptibility Genes for Schizophrenia: a Discussion from an Evolutionary Viewpoint

Background The central paradox of schizophrenia genetics is that susceptibility genes are preserved in the human gene-pool against a strong negative selection pressure. Substantial evidence of epidemiology suggests that nuclear susceptibility genes, if present, should be sustained by mutation-selection balance without heterozygote advantage. Therefore, putative nuclear susceptibility genes for schizophrenia should meet special conditions for the persistence of the disease as well as the condition of bearing a positive association with the disease. Methodology/Principal Findings We deduced two criteria that every nuclear susceptibility gene for schizophrenia should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. The first criterion demands an upper limit of the case-control difference of the allele frequencies, which is determined by the mutation rate at the locus, and the prevalence and the selection coefficient of the disease. The second criterion demands an upper limit of odds ratio for a given allele frequency in the unaffected population. When we examined the top 30 genes at SZGene and the recently reported common variants on chromosome 6p with the criteria using the epidemiological data in a large-sampled Finnish cohort study, it was suggested that most of these are unlikely to confer susceptibility to schizophrenia. The criteria predict that the common disease/common variant hypothesis is unlikely to fit schizophrenia and that nuclear susceptibility genes of moderate effects for schizophrenia, if present, are limited to ‘rare variants’, ‘very common variants’, or variants with exceptionally high mutation rates. Conclusions/Significance If we assume the nuclear DNA model for schizophrenia, it should have many susceptibility genes of exceptionally high mutation rates; alternatively, it should have many disease-associated resistance genes of standard mutation rates on different chromosomes. On the other hand, the epidemiological data show that pathogenic genes, if located in the mitochondrial DNA, could persist through sex-related mechanisms.

Quality of Internet information referring to mental health and mental disorders in Japan

Abstract  Although the Internet has been widely used in Japan, the quality of information on mental health‐related issues has not been evaluated so far. The purpose of the present study was to investigate the current status of Japanese websites that deal with mental health, mental disorders, and their associated matters. Using a search engine, Google, 37 websites were identified that exclusively contain information on mental health or mental disorders. The characteristics of the sites were then examined, along with variety of mental disorders mentioned, and quality of contents for each of the 37 websites. More than half of the websites were set up, at least in part, for commercial purposes and only 27% of sites were owned by professionals. Mood disorder, panic disorder, and schizophrenia were the three most commonly referred disorders on websites. Aside from some exceptions, the quality of information was inadequate, especially that regarding treatment. Most of the websites on mental health and mental disorders examined in the present study have scope for improvement. The challenge is to establish a system to evaluate the sites and to motivate each webmaster to improve the sites.