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author:("inyo, masami")
1.  Defining outcome measures of hospitalization for assessment in the Japanese forensic mental health scheme: a Delphi study 
A new legislation concerning forensic mental health was established by the Japanese Government in 2005, the “Act on Medical Care and Treatment for the Persons Who Had Caused Serious Cases under the Condition of Insanity,” or the Medical Treatment and Supervision (MTS) Act. Since it was passed, however, there has been broad controversy over Hospitalization for Assessment (HfA), the first stage of the MTS scheme.
Following a comprehensive literature search to assemble a list of candidates, we conducted a Delphi study to establish standard outcome measures for HfA.
Five Delphi rounds were conducted by 19 panelists including medical practitioners and lawyers. A total of 139 items were accepted as outcome measures for HfA based on panel agreement.
The Delphi study established a list of HfA outcome measures for the MTS act, which will contribute to the optimization of the new forensic mental health system in Japan.
Electronic supplementary material
The online version of this article (doi:10.1186/1752-4458-9-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4328080
Forensic mental health; Delphi study; the Medical Treatment and Supervision Act; Hospitalization for Assessment; Outcome measure
2.  Yokukan-san: a review of the evidence for use of this Kampo herbal formula in dementia and psychiatric conditions 
Japanese traditional herbal medicine (Kampo) has its origins in traditional Chinese medicine (TCM). It was introduced to Japan in the middle of the sixth century and has evolved over the past 1,400 years after combining with Japan’s original folk remedies. While it retains some similarities to TCM, Kampo has evolved in Japan, resulting in a system of medicine that has many differences from TCM. Kampo medicine is considered to be very safe; in Japan, Kampo herbal formulas are manufactured by licensed pharmaceutical companies, prescribed by Western-trained medical doctors (usually as a freeze-dried extract), and have quality control standards similar to those of prescription drugs. The present study examined Yokukan-san (Yi-Gan San in TCM), a Kampo formula that has been used empirically in Japan for more than 400 years. Accumulating clinical trials have demonstrated Yokukan-san’s efficacy in treating patients with behavioral and psychological symptoms of dementia, which has resulted in the Japanese Society of Neurology listing it in the Japanese Guidelines for the Management of Dementia 2010. Efficacy in other diseases and conditions, such as sleep disorders, tardive dyskinesia, aggression, and impulsivity has also been reported. This article reviews both clinical and basic studies of Yokukan-san, with the goal of clarifying its clinical indications.
PMCID: PMC4168872  PMID: 25246794
Yokukan-san-ka-chimpi-hange; Japanese traditional medicine; Asian medicine; dementia with Lewy bodies (DLB); Alzheimer’s disease; BPSD; Parkinson’s disease
3.  Evidence for Shared Genetic Risk Between Methamphetamine-Induced Psychosis and Schizophrenia 
Neuropsychopharmacology  2013;38(10):1864-1870.
Methamphetamine (METH) use can provoke psychotic reactions requiring immediate treatment, namely METH-induced psychosis. Although the distinction between METH-induced and primary psychosis is important for understanding their clinical courses, we do not have clear diagnostic procedure by their symptoms. Not only are there similarities between the clinical features of METH-induced psychosis and schizophrenia (SCZ), but there is also epidemiological evidence of a shared genetic risk between ‘METH-related' disorders and SCZ, which makes the differentiation of these two conditions difficult. In this study, we conducted a genome-wide association study (GWAS) targeting METH-dependent patients. The METH sample group, used in the METH-dependence GWAS, included 236 METH-dependent patients and 864 healthy controls. We also included a ‘within-case' comparison between 194 METH-induced psychosis patients and 42 METH-dependent patients without psychosis in a METH-induced psychosis GWAS. To investigate the shared genetic components between METH dependence, METH-induced psychosis, and SCZ, data from our previous SCZ GWAS (total N=1108) were re-analyzed. In the SNP-based analysis, none of the SNPs showed genome-wide significance in either data set. By performing a polygenic component analysis, however, we found that a large number of ‘risk' alleles for METH-induced psychosis are over-represented in individuals with SCZ (Pbest=0.0090). Conversely, we did not detect enrichment either between METH dependence and METH-induced psychosis or between METH dependence and SCZ. The results support previous epidemiological and neurobiological evidence for a relationship between METH-induced psychosis and SCZ. These also suggest that the overlap between genes scored as positive in these data sets can have higher probability as susceptibility genes for psychosis.
PMCID: PMC3746703  PMID: 23594818
addiction & substance abuse; biological psychiatry; genome-wide association study; methamphetamine; Neurogenetics; polygenic component; schizophrenia; schizophrenia/Antipsychotics; substance-induced psychosis; substance-induced psychosis; genome-wide association study; schizophrenia; methamphetamine; substance use disorder; polygenic component analysis
5.  Recognition of change in the reform of forensic mental health by clinical practitioners: a questionnaire survey in Japan 
In Japan, new legislation regarding forensic mental health, namely, the Act on Medical Care and Treatment for Persons Who Have Caused Serious Cases under the Condition of Insanity (Medical Treatment and Supervision Act (MTS Act)) was enforced in 2005, although community mental health care remains largely unchanged. We surveyed local clinical psychiatrists by questionnaire to gather information on the influence of the MTS Act on clinical mental health practice. We sent a paper questionnaire to almost all the psychiatrists in the Chiba prefecture, 56% of whom (N = 306) responded. The participants felt that the MTS Act had minimal direct impact on community mental health care. However, some relatively new schemes such as a multiple disciplinary team approach or supervised outpatient care are given more attention than before. These results suggest that this new forensic mental health legislation may assist in the spread of new paradigms into clinical practice.
PMCID: PMC3974740  PMID: 24678884
Forensic mental health; Offenders with mental disorders; Medical Treatment and Supervision (MTS) Act; Mental Health and Welfare (MHW) Law; Questionnaire survey; Community mental health
6.  Tipepidine in children with attention deficit/hyperactivity disorder: a 4-week, open-label, preliminary study 
Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) has been used solely as a nonnarcotic antitussive in Japan since 1959. The safety of tipepidine in children and adults has already been established. It is reported that tipepidine inhibits G-protein-coupled inwardly rectifying potassium (GIRK)-channel currents. The inhibition of GIRK channels by tipepidine is expected to modulate the level of monoamines in the brain. We put forward the hypothesis that tipepidine can improve attention deficit/hyperactivity disorder (ADHD) symptoms by modulating monoaminergic neurotransmission through the inhibition of GIRK channels. The purpose of this open-label trial was to confirm whether treatment with tipepidine can improve symptoms in pediatric patients with ADHD.
Subjects and methods
This was a 4-week, open-label, proof-of-efficacy pilot study for pediatric subjects with ADHD. Ten pediatric ADHD subjects (70% male; mean age, 9.9 years; combined [inattentive and hyperactive/impulsive] subtype, n=7; inattentive subtype, n=3; hyperimpulsive subtype, n=0) received tipepidine hibenzate taken orally at 30 mg/day for 4 weeks. All subjects were assessed using the ADHD Rating Scale IV (ADHD-RS), Japanese version, and the Das–Naglieri Cognitive Assessment System (DN-CAS), Japanese version.
A comparison of baseline scores and 4-week end-point scores showed that all the ADHD-RS scores (total scores, hyperimpulsive subscores, and inattentive subscores) improved significantly (P<0.001). Furthermore, a comparison of baseline DN-CAS total scores and 4-week end-point scores showed a mild trend of improvement (P=0.093). Tipepidine was well tolerated, with no patients discontinuing medication because of side effects.
Our pilot study suggests that tipepidine therapy may prove to be an effective alternative treatment for pediatric patients with ADHD. Nonetheless, more detailed randomized, double-blind trials are needed to confirm tipepidine’s efficacy.
PMCID: PMC3908907  PMID: 24493927
attention deficit/hyperactivity disorder; tipepidine; GIRK channel; pediatric; antitussive; nucleus accumbens
7.  Onset Pattern and Long-Term Prognosis in Schizophrenia: 10-Year Longitudinal Follow-Up Study 
PLoS ONE  2013;8(6):e67273.
Although the duration of untreated psychosis (DUP) plays an important role in the short-term prognosis of patients with schizophrenia, their long-term prognosis generally is not determined by DUP alone. It is important to explore how other clinical factors in the early stage are related to DUP and consequent disease courses.
A total of 664 patients with untreated psychosis were surveyed for this study. At the first examination, we divided them into the severe positive symptoms cases (SC) or the less severe cases (NonSC) and compared the prognosis among the two groups after a 10-year follow-up. In all, 113 patients in the SC group and 43 patients in the NonSC group were follow-up completers.
Whereas DUP was not different between the two groups, patients with nonacute onset in both groups had significantly longer DUP than those in patients with acute onset. For all clinical measures, there was no difference in prognosis between the two groups or among the four groups classified by mode of onset (MoO) and initial severity of positive symptoms. However, the degree of improvement of global assessment of functioning (GAF) was significantly smaller in the NonSC-nonacute group than in the SC-acute and SC-nonacute groups.
These results suggest that neither DUP nor MoO alone necessarily affects the initial severity of positive symptoms. Moreover, it is possible that patients with low impetus of positive symptoms onset within long DUP experience profound pathologic processes. Therefore, the current study results indicated that long DUP and nonacute onset were related to poor long-term prognosis, regardless of initial positive symptoms.
PMCID: PMC3693949  PMID: 23840649
8.  Neonatal Disruption of Serine Racemase Causes Schizophrenia-Like Behavioral Abnormalities in Adulthood: Clinical Rescue by D-Serine 
PLoS ONE  2013;8(4):e62438.
D-Serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, is synthesized from L-serine by serine racemase (SRR). Given the role of D-serine in both neurodevelopment and the pathophysiology of schizophrenia, we examined whether neonatal disruption of D-serine synthesis by SRR inhibition could induce behavioral abnormalities relevant to schizophrenia, in later life.
Methodology/Principal Findings
Neonatal mice (7–9 days) were injected with vehicle or phenazine methosulfate (Met-Phen: 3 mg/kg/day), an SRR inhibitor. Behavioral evaluations, such as spontaneous locomotion, novel object recognition test (NORT), and prepulse inhibition (PPI) were performed at juvenile (5–6 weeks old) and adult (10–12 weeks old) stages. In addition, we tested the effects of D-serine on PPI deficits in adult mice after neonatal Met-Phen exposure. Finally, we assessed whether D-serine could prevent the onset of schizophrenia-like behavior in these mice. Neonatal Met-Phen treatment reduced D-serine levels in the brain, 24 hours after the final dose. Additionally, this treatment caused behavioral abnormalities relevant to prodromal symptoms in juveniles and to schizophrenia in adults. A single dose of D-serine improved PPI deficits in adult mice. Interestingly, chronic administration of D-serine (900 mg/kg/day from P35 to P70) significantly prevented the onset of PPI deficits after neonatal Met-Phen exposure.
This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life. Furthermore, early pharmacological intervention with D-serine may prevent the onset of psychosis in adult.
PMCID: PMC3632541  PMID: 23630632
9.  Changes in Self-Regulation-Related Prefrontal Activities in Eating Disorders: A Near Infrared Spectroscopy Study 
PLoS ONE  2013;8(3):e59324.
The aim of this study is to clarify the symptomatology of the eating disorders examining the prefrontal function and activity associated with self-regulation among participants with or without eating disorders.
Ten patients with anorexia nervosa, fourteen with bulimia nervosa, and fourteen healthy control participants performed two cognitive tasks assessing self-regulatory functions, an auditorily distracted word fluency task and a rock-paper-scissors task under the measurements on prefrontal oxyhemoglobin concentration with near infrared spectroscopy. The psychiatric symptoms of patient groups were assessed with several questionnaires.
Patients with bulimia nervosa showed decreased performances and prefrontal hyper activation patterns. Prefrontal activities showed a moderate negative correlation with task performances not in the patient groups but only in the healthy participants. The prefrontal activities of the patient groups showed positive correlations with some symptom scale aspects.
The decreased cognitive abilities and characteristic prefrontal activation patterns associated with self-regulatory functions were shown in patients with bulimia nervosa, which correlated with their symptoms. These findings suggest inefficient prefrontal self-regulatory function of bulimia nervosa that associate with its symptoms.
PMCID: PMC3602060  PMID: 23527162
10.  Tandospirone, a 5-HT1A partial agonist is effective in treating anorexia nervosa: a case series 
This case report details the therapeutic effects of tandospirone on two patients with anorexia nervosa, one with the restricting subtype (ANR), and another with the binge-eating/purging subtype (ANBP). A 22-year-old female patient with ANR and a 23-year-old female patient with ANBP were treated successfully with the 5-HT1A partial agonist tandospirone. After treatment, not only did both patients gain weight, they also showed improved scores on the Eating Disorder Examination Questionnaire. In addition, a 6-month follow-up showed maintenance of these effects. In this disorder, tandospirone may be an effective drug for long-term use with good patient compliance.
PMCID: PMC3606595  PMID: 23497393
Anorexia nervosa; Pharmacotherapy; Treatment; Serotonin 1A receptor; Tandospirone
11.  A preliminary study of individual cognitive behavior therapy for social anxiety disorder in Japanese clinical settings: a single-arm, uncontrolled trial 
BMC Research Notes  2013;6:74.
Cognitive behavior therapy (CBT) is regarded as an effective treatment for social anxiety disorder (SAD) in Europe and North America. Individual CBT might be acceptable and effective for patients with SAD even in non-Western cultures; therefore, we conducted a feasibility study of individual CBT for SAD in Japanese clinical settings. We also examined the baseline predictors of outcomes associated with receiving CBT.
This single-arm trial employed a 14-week individual CBT intervention. The primary outcome was the self-rated Liebowitz Social Anxiety Scale, with secondary measurements of other social anxiety and depressive severity. Assessments were conducted at baseline, after a waiting period before CBT, during CBT, and after CBT.
Of the 19 subjects screened, 15 were eligible for the study and completed the outcome measures at all assessment points. Receiving CBT led to significant improvements in primary and secondary SAD severity (ps < .001). The mean total score on the Liebowitz Social Anxiety Scale improved from 91.8 to 51.7 (before CBT to after CBT), and the within-group effect size at the end-point assessment was large (Cohen’s d = 1.71). After CBT, 73% of participants were judged to be treatment responders, and 40% met the criteria for remission. We found no significant baseline predictors of those outcomes.
Despite several limitations, our treatment—which comprises a 14-week, individual CBT program—seems feasible and may achieve favorable treatment outcomes for SAD in Japanese clinical settings. Further controlled trials are required in order to address the limitations of this study.
Trial registration
UMIN-CTR UMIN000005897
PMCID: PMC3602169  PMID: 23448435
Cognitive behavioral therapy; CBT; Social anxiety disorder; Social phobia; SAD; Japanese
13.  Strategy for treating selective serotonin reuptake inhibitor-resistant social anxiety disorder in the clinical setting: a randomised controlled trial protocol of cognitive behavioural therapy in combination with conventional treatment 
BMJ Open  2013;3(2):e002242.
Pharmacotherapy and cognitive behavioural therapy (CBT) are consistently effective as first-line treatments for social anxiety disorders (SADs). Nevertheless, pharmacotherapy is often the first choice in clinical practice. In many countries, the first line of pharmacotherapy involves the administration of a selective serotonin reuptake inhibitor (SSRI). Although a significant proportion of patients with SAD fail to respond to the initial SSRI administration, there is no standard approach to the management of SSRI-resistant SAD. This paper describes the study protocol for a randomised controlled trial to evaluate the clinical effectiveness of CBT as a next-step strategy, concomitant with conventional treatment, for patients with SSRI-resistant SAD.
Methods and analysis
This Prospective Randomized Open Blinded End-point study is designed with two parallel groups, with dynamic allocation at the individual level. The interventions for the two groups are conventional treatment, alone, and CBT combined with conventional treatment, for 16 weeks. The primary end-point of SAD severity will be assessed by an independent assessor using the Liebowitz Social Anxiety Scale, and secondary end-points include severity of other social anxieties, depressive severity and functional impairment. All measures will be assessed at weeks 0 (baseline), 8 (halfway point) and 16 (postintervention) and the outcomes will be analysed based on the intent-to-treat. Statistical analyses are planned for the study design stage so that field materials can be appropriately designed.
Ethics and dissemination
This study will be conducted at the academic outpatient clinic of Chiba University Hospital. Ethics approval was granted by the Institutional Review Board of Chiba University Hospital. All participants will be required to provide written informed consent. The trial will be implemented and reported in accordance with the recommendations of CONSORT.
Clinical Trial Registration Number
PMCID: PMC3586054  PMID: 23408078
Mental Health
14.  Orengedoku-to augmentation in cases showing partial response to yokukan-san treatment: a case report and literature review of the evidence for use of these Kampo herbal formulae 
Yokukan-san, a Japanese traditional herbal (Kampo) prescription, has recently gathered increasing attention due to accumulating reports showing its remarkable efficacy in treating a wide variety of diseases refractory to conventional medicine as well as the behavioral and psychological symptoms of dementia. As yokukan-san has become broadly integrated with conventional medicine, augmentation therapy with other Kampo prescriptions has become necessary when the yokukan-san has been only partially efficacious. In this paper, we report three cases in which the addition of orengedoku-to, another Kampo formula, to yokukan-san was remarkably effective.
Case 1 was an 85-year-old man with Alzheimer-type dementia who had become aggressive during the past 2 years. Three milligrams of aripiprazole completely suppressed his problematic behaviors but had to be stopped because of extrapyramidal symptoms. In the second case, a 44-year-old man with methamphetamine-induced psychosis had suffered from serious tardive dystonia for 2 years. No conventional approach had improved his tardive dystonia. The third case was a 29-year-old engineer who often failed to resist aggressive impulses and was diagnosed with intermittent explosive disorder. He was prescribed 5 mg of olanzapine, which did not suppress his extraordinary anger and caused somnolence even though the dose was low.
Interventions and outcomes
Yokukan-san was complementarily added to the patients’ regular medication and exerted a definitive but partial effect in all cases. The addition of orengedoku-to to yokukan-san exerted the same efficacy as aripiprazole in controlling aggressiveness in Case 1, improved the tardive dystonia by 80% in Case 2, and was completely effective in controlling the patient’s aggressive impulses in Case 3.
Together with empirical evidence demonstrating the effectiveness of both yokukansan and orengedoku-to in reducing irritability, impulsivity, and aggression, these three cases suggest that orengedoku-to augmentation can be an effective option in cases that are partially responsive to yokukan-san treatment.
PMCID: PMC3554226  PMID: 23378767
traditional medicine; aggressiveness; tardive dystonia; intermittent explosive disorder
15.  Decreased Serum Levels of Mature Brain-Derived Neurotrophic Factor (BDNF), but Not Its Precursor proBDNF, in Patients with Major Depressive Disorder 
PLoS ONE  2012;7(8):e42676.
Meta-analyses have identified serum levels of brain-derived neurotrophic factor (BDNF) as a potential biomarker for major depressive disorder (MDD). However, at the time, commercially available human ELISA kits are unable to distinguish between proBDNF (precursor of BDNF) and mature BDNF because of limited BDNF antibody specificity. In this study, we examined whether serum levels of proBDNF, mature BDNF, and matrix metalloproteinase-9 (MMP-9), which converts proBDNF to mature BDNF, are altered in patients with MDD.
Methodology/Principal Findings
Sixty-nine patients with MDD and 78 age- and gender-matched healthy subjects were enrolled. Patients were evaluated using 17 items on the Structured Interview Guide for the Hamilton Depression Rating Scale. Cognitive impairment was evaluated using the CogState battery. Serum levels of proBDNF, mature BDNF, and MMP-9 were measured using ELISA kits. Serum levels of mature BDNF in patients with MDD were significantly lower than those of normal controls. In contrast, there was no difference in the serum levels of proBDNF and MMP-9 between patients and normal controls. While neither proBDNF nor mature BDNF serum levels was associated with clinical variables, there were significant correlations between MMP-9 serum levels and the severity of depression, quality of life scores, and social function scores in patients.
These findings suggest that mature BDNF may serve as a biomarker for MDD, and that MMP-9 may play a role in the pathophysiology of MDD. Further studies using larger sample sizes will be needed to investigate these results.
PMCID: PMC3411809  PMID: 22880079
16.  Treatment of refractory catatonic schizophrenia with low dose aripiprazole 
This case is of 54-year-old female with catatonic schizophrenia, characterized by treatment resistance to the pharmacotherapy with olanzapine, risperidone, flunitrazepam, and ECT. Olanzapine and risperidone and flunitrazepam did not improve her catatonic and psychotic symptoms, and induced the extrapyramidal symptoms. The effects of ECT did not continue even for a month. However, the treatment with low-dose aripiprazole dramatically improved the patient’s psychotic symptoms and extrapyramidal symptoms. The mechanisms underlying the effects of low-dose aripiprazole in this case remain unclear, but unlike other antipsychotics, aripiprazole is a dopamine D2 partial agonist. In this regard, our results suggest that aripiprazole has numerous advantages, especially in cases of stuporous catatonia and a defective general status.
PMCID: PMC3473267  PMID: 22553911
17.  Occupancy of α7 Nicotinic Acetylcholine Receptors in the Brain by Tropisetron: A Positron Emission Tomography Study Using [11C]CHIBA-1001 in Healthy Human Subjects 
Agonists of α7-nicotinic acetylcholine receptors (nAChRs) have been developed as potential therapeutic drugs for neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. Positron emission tomography (PET) is a noninvasive brain imaging technique to measure receptor occupancy in the living human brain. Although much effort has been expended to create specific PET radioligands for α7-nAChRs in the brain, only 4-[11C]methylphenyl-1,4-diazabicyclo[3.2.2.]nonane-4-carboxylate ([11C]CHIBA-1001) is currently available for clinical studies. In contrast, two 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, tropisetron and ondansetron, have been used to treat patients with chemotherapy-induced or postoperative nausea and vomiting. Furthermore, tropisetron, but not ondansetron, possesses high affinity for α7-nAChRs. In the present study, we evaluated the receptor occupancy in the human brain after a single oral administration of tropisetron and ondansetron using [11C]CHIBA-1001 and PET.
Two serial dynamic PET scans using [11C]CHIBA-1001 in healthy non-smoking male subjects were performed before and after receiving an oral administration of these medications.
A single oral administration of tropisetron, but not ondansetron, decreased the total distribution volume of [11C]CHIBA-1001 in the human brain.
This study shows that tropisetron, but not ondansetron, could bind to α7-nAChRs in the human brain after a single oral administration. Therefore, [11C]CHIBA-1001 may be a useful PET radioligand to measure the occupancy of α7-nAChRs in the human brain.
PMCID: PMC3569118  PMID: 23430308
α7-nicotinic acetylcholine receptor; Positron-emission tomography; Tropisetron; Ondansetron; [11C]CHIBA-1001
18.  Association Analysis of Nuclear Receptor Rev-erb Alpha Gene (NR1D1) and Japanese Methamphetamine Dependence 
Current Neuropharmacology  2011;9(1):129-132.
Several investigations suggested abnormalities in circadian rhythms are related to the pathophysiology of psychiatric disorders, including drug addiction. Recently, orphan nuclear receptor rev-erb alpha and glycogen synthase kinase-3 β (GSK-3β) were shown to be important circadian components. In addition, the orphan nuclear receptor rev-erb alpha is a key negative feedback regulator of the circadian clock. These evidences indicate that rev-erb alpha gene (NR1D1) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between NR1D1 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with three tagging SNPs selected by HapMap database. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between NR1D1 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that NR1D1 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population.
PMCID: PMC3137167  PMID: 21886577
Orphan nuclear receptor Rev-erb alpha gene (NR1D1); methamphetamine dependence; tagging SNPs; linkage disequilibrium.
19.  Lack of Association Between Prokineticin 2 Gene and Japanese Methamphetamine Dependence  
Current Neuropharmacology  2011;9(1):133-136.
Disruption of circadian rhythms may be involved in the pathophysiology of psychiatric disorders, including drug addiction. Recently, we detected the significant association between prokineticin 2 receptor gene (PROKR2) and Japanese methamphetamine dependence patients. Also, prokineticin 2 (PK2) gene deficient mice showed reduced physiological and behavioral parameters, including circadian locomotor activity, circulating glucocorticoid, glucose levels and the expression of peripheral clock genes compared with WT mice. These evidences indicate that PK2 gene (PROK2) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between PROK2 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with four tagging SNPs selected by HapMap database. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between PROK2 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that PROK2 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population.
PMCID: PMC3137168  PMID: 21886578
Prokineticin 2 gene (PROK2); methamphetamine dependence; tagging SNPs; linkage disequilibrium.
20.  Association Analysis of the Adenosine A1 Receptor Gene Polymorphisms in Patients with Methamphetamine Dependence/Psychosis 
Current Neuropharmacology  2011;9(1):137-142.
Several lines of evidence suggest that the dopaminergic nervous system contributes to methamphetamine (METH) dependence, and there is increasing evidence of antagonistic interactions between dopamine and adenosine receptors in METH abusers. We therefore hypothesized that variations in the A1 adenosine receptor (ADORA1) gene modify genetic susceptibility to METH dependence/psychosis. In this study, we identified 7 single nucleotide polymorphisms (SNPs) in exons and exon-intron boundaries of the ADORA1 gene in a Japanese population. A total of 171 patients and 229 controls were used for an association analysis between these SNPs and METH dependence/psychosis. No significant differences were observed in either the genotypic or allelic frequencies between METH dependent/psychotic patients and controls. A global test of differentiation among samples based on haplotype frequencies showed no significant association. In the clinical feature analyses, no significant associations were observed among latency of psychosis, prognosis of psychosis, and spontaneous relapse. These results suggest that the ADORA1 gene variants may make little or no contribution to vulnerability to METH dependence/psychosis.
PMCID: PMC3137169  PMID: 21886579
Single nucleotide polymorphism; SNP; variation; human; Japanese; MAP; abuse; dopamine.
21.  Genetic Association Analysis of NOS1 and Methamphetamine-Induced Psychosis Among Japanese 
Current Neuropharmacology  2011;9(1):155-159.
The neuronal nitric oxide synthase gene (NOS1) is located at 12q24, a susceptibility region for schizophrenia, and produces nitric oxide (NO). NO has been reported to play important roles as a gaseous neurotransmitter in brain. NO is a second messenger for the N-methyl-D aspartate (NMDA) receptor and is related to the dopaminergic system. Because the symptomatology of methamphetamine (METH) use disorder patients with psychosis is similar to that of patients with schizophrenia, NOS1 is a good candidate gene for METH-induced psychosis. Therefore, we conducted a case-control association study between NOS1 and METH-induced psychosis with Japanese subjects (183 with METH-induced psychosis patients and 519 controls). We selected seven SNPs (rs41279104, rs3782221, rs3782219, rs561712, rs3782206, rs6490121, rs2682826) in NOS1 from previous reports. Written informed consent was obtained from each subject. This study was approved by the Ethics Committee at Fujita Health University School of Medicine and each participating institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). No significant association was found between NOS1 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS1 might not contribute to the risk of METH-induced psychosis in the Japanese population.
PMCID: PMC3137172  PMID: 21886582
Methamphetamine-induced psychosis; neuronal nitric oxide synthase 1 gene (NOS1); case-control association study.
22.  No Association Between GRM3 and Japanese Methamphetamine-Induced Psychosis 
Current Neuropharmacology  2011;9(1):160-162.
Several investigations have suggested that abnormalities in glutamate neural transmission play a role in the pathophysiology of psychiatric disorders, including schizophrenia. The metabotropic glutamate 3 receptor (mGluR3) gene was reported to be associated with schizophrenia, and paranoid type schizophrenia has symptoms that are similar to those of methamphetamine-induced psychosis. This suggests that mGluR3 gene (GRM3) is a good candidate gene for the pathogenesis of methamphetamine-induced psychosis. To evaluate the association between GRM3 and methamphetamine-induced psychosis, we conducted a case-control study of Japanese samples (181 methamphetamine-induced psychosis and 232 controls).
We selected one functional SNP (rs6465084), reported to be associated with prefrontal brain functioning, for an association analysis. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA).
We did not detect an association between rs6465084 in GRM3 and Japanese methamphetamine-induced psychosis.
Our findings suggest that rs6465084 in GRM3 does not play a major role in the pathophysiology of methamphetamine-induced psychosis in the Japanese population. However, because we did not perform an association analysis based on linkage disequilibrium (LD) or a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results.
PMCID: PMC3137173  PMID: 21886583
GRM3; Methamphetamine-Induced Psychosis; case-control study.
23.  Association Analysis of the Tryptophan Hydroxylase 2 Gene Polymorphisms in Patients with Methamphetamine Dependence/Psychosis 
Current Neuropharmacology  2011;9(1):176-182.
There is a growing evidence that serotoninergic systems modulate dopaminergic neurotransmission. We analyzed the association between the variations in the brain tryptophan hydroxylase 2 (TPH2) gene, a rate limiting enzyme for serotonin biosynthesis, and methamphetamine (METH) dependence/psychosis in a Japanese population. We found ten single nucleotide polymorphisms (SNPs) and two polynucleotide polymorphisms in TPH2 gene exons and exon-intron boundaries. A total of 162 patients and 243 controls were used for the association analysis between these polymorphisms and METH dependence/psychosis. No significant differences were observed in either genotypic or allelic frequencies between METH dependent/psychotic patients and controls. A global test of differentiation among samples based on haplotype frequencies showed no significant association. With respect to latency of psychosis, prognosis of psychosis, and spontaneous relapse, we found no significant association with these SNPs. These results suggest that the TPH2 gene variants may not be a factor in vulnerability to METH dependence/psychosis.
PMCID: PMC3137177  PMID: 21886586
Single nucleotide polymorphism; SNP; variation; serotonin; human; Japanese; MAP; abuse.
24.  Criterion and Construct Validity of the CogState Schizophrenia Battery in Japanese Patients with Schizophrenia 
PLoS ONE  2011;6(5):e20469.
The CogState Schizophrenia Battery (CSB), a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J) in Japanese patients with schizophrenia.
Methodology/Principal Findings
Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors.
This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia.
PMCID: PMC3102733  PMID: 21637776
25.  Expert consensus on hospitalization for assessment: a survey in Japan for a new forensic mental health system 
In Japan, hospitalization for the assessment of mentally disordered offenders under the Act on Medical Care and Treatment for the Persons Who Had Caused Serious Cases under the Condition of Insanity (the Medical Treatment and Supervision Act, or the MTS Act) has yet to be standardized.
We conducted a written survey that included a questionnaire regarding hospitalization for assessment; the questionnaire consisted of 335 options with 9 grades of validity for 60 clinical situations. The survey was mailed to 50 Japanese forensic mental health experts, and 42 responses were received.
An expert consensus was established for 299 of the options. Regarding subjects requiring hospitalization for assessment, no consensus was reached on the indications for electroconvulsive therapy (ECT) or for confronting the offenders regarding their offensive behaviors.
The consensus regarding hospitalization for assessment and its associated problems were clarified. The consensus should be widely publicized among practitioners to ensure better management during the hospitalization of mentally disordered offenders for assessment.
PMCID: PMC3080841  PMID: 21473787

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