金原 信久

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.

Although many studies report various factors related to future employment of schizophrenia patients, few identify the treatable or improvable ones. The responses to the first year of treatment and daily antipsychotic drug doses may be the treatable and improvable factors. We surveyed 235 schizophrenia outpatients in three facilities, of whom 129 and 106 were employed and unemployed, respectively. Through face-to-face interviews and medical record reviews, we investigated symptomatic and social functioning responses to the first year of treatment using the Global Assessment of Psychopathology Scale (GAPS) and the Social and Occupational Functioning Assessment Scale (SOFAS). We investigated daily antipsychotic drug doses and other clinical assessments at the interview time. Finally, we used multivariable logistic regression analysis. SOFAS-measured improvements in the period 6 to 12 months after beginning treatment and daily antipsychotic drug doses equivalent to less than 600 mg of chlorpromazine were identified as an employment-related factor, but GAPS-measure improvements were not. Social functioning improvements in the period 6 to 12 months after beginning treatment and low-to-moderate daily antipsychotic drug doses were detected as employment-related factors, suggesting that early efforts to improve social functioning and optimize antipsychotic drug doses could lead to future employment for schizophrenia patients.

Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and N-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein N-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of WDR3 and ALG1 in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic P = 0.003, genotypic P = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)–W5 (rs379058) also displayed a significant association in the female schizophrenics (P = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the WDR3 gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia.

Dopamine supersensitivity psychosis (DSP) is observed in patients with schizophrenia under antipsychotic treatment, and it is characterized by rebound psychosis, an uncontrollable psychotic episode following a stable state and tardive dyskinesia. DSP, first described in patients taking typical antipsychotics in the late 1970s, sometimes appears even in patients who are treated with current atypical antipsychotics. It was recently demonstrated that DSP can have a negative impact on the long-term prognosis of schizophrenia patients and that DSP could be involved in the etiology of some cases of treatment-resistant schizophrenia. Accumulating evidence suggests that an up-regulation of dopamine D2 receptors (DRD2) in the brain caused by long-term exposure to antipsychotics is related to the DSP phenomenon. The present review describes the clinical characteristics and the etiology of DSP in the era of second-generation antipsychotics for patients with schizophrenia. Based on the mechanism of DSP, several potential treatments for patients presenting with a DSP episode or the dopamine supersensitivity state are also discussed.

The synapse-associated protein 97/discs, large homolog 1 of Drosophila (DLG1) gene encodes synaptic scaffold PDZ proteins interacting with ionotropic glutamate receptors including the N-methyl-D-aspartate type glutamate receptor (NMDAR) that is presumed to be hypoactive in brains of patients with schizophrenia. The DLG1 gene resides in the chromosomal position 3q29, the microdeletion of which confers a 40-fold increase in the risk for schizophrenia. In the present study, we performed genetic association analyses for DLG1 gene using a Japanese cohort with 1808 schizophrenia patients and 2170 controls. We detected an association which remained significant after multiple comparison testing between schizophrenia and the single nucleotide polymorphism (SNP) rs3915512 that is located within the newly identified primate-specific exon (exon 3b) of the DLG1 gene and constitutes the exonic splicing enhancer sequence. When stratified by onset age, although it did not survive multiple comparisons, the association was observed in non-early onset schizophrenia, whose onset-age selectivity is consistent with our recent postmortem study demonstrating a decrease in the expression of the DLG1 variant in early-onset schizophrenia. Although the present study did not demonstrate the previously reported association of the SNP rs9843659 by itself, a meta-analysis revealed a significant association between DLG1 gene and schizophrenia. These findings provide a valuable clue for molecular mechanisms on how genetic variations in the primate-specific exon of the gene in the schizophrenia-associated 3q29 locus affect its regulation in the glutamate system and lead to the disease onset around a specific stage of brain development.

The long-term administration of antipsychotics is known to induce dopamine supersensitivity psychosis (DSP). Although the mechanism of DSP involves mainly a compensatory upregulation of dopamine D2 receptors, the precise mechanisms underlying DSP are unknown. It is known that glutamatergic signaling plays a key role in psychosis. We thus conducted this study to investigate whether glutamatergic signaling plays a role in the development of DSP. Haloperidol (0.75 mg/kg/day for 14 days) or vehicle was administered to rats via osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSP rats and non-DSP rats based on locomotion data. Tissue levels of glutamate, glutamine, glycine, L-serine, D-serine, and GABA and the protein expressions of N-methyl-D-aspartate receptors (NMDAR), glutamic acid decarboxylase (GAD), and serine hydroxymethyltransferase (SHMT) in the rat brain regions were examined. In the DSP rats, the ratio of GABA to glutamate was significantly increased. In addition, the ratio of L-serine to glycine was increased. The striatal expressions of GAD and SHMT2 in the DSP rats were significantly increased. In contrast, the striatal expression of NMDAR2B in the non-DSP rats was significantly decreased. The present study suggests that glutamatergic signaling is relatively decreased to GABA in DSP rats. Our results also showed that excessive doses of haloperidol can induce striatal NMDAR hypofunction in non-DSP rats, which could prevent the formation of tardive dyskinesia but cause treatment resistance. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, further research exploring our present findings is necessary.

Involvement of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia pathogenesis through disrupted neurodevelopment has been highlighted in numerous studies. However, the function of common genetic variants of this system in determining schizophrenia risk is unknown. We therefore tested the association of 375 Lagged SNPs in genes derived from the GABAergic system such as GABA(A) receptor subunit genes, and GABA related genes (glutamate decarboxylase genes, GABAergic-marker gene, genes involved in GABA receptor trafficking and scaffolding) in Japanese schizophrenia case-control samples (n = 2926; 1415 cases and 1511 controls). We observed nominal association of SNPs in nine GABAA receptor subunit genes and the GPHN gene with schizophrenia, although none survived correction for study-wide multiple testing. Two SNPs located in the GABRA1 gene, rs4263535 (P-allele = 0.002; uncollected) and rs1157122 (P-allele = 0.006; uncorrected) showed top hits, followed by rs723432 (P-allele = 0.007; uncorrected) in the GPHN gene. All three were significantly associated with schizophrenia and survived gene-wide multiple testing. Haplotypes containing associated variants in GABRA1 but not GPHN were significantly associated with schizophrenia. To conclude, we provided substantiating genetic evidence for the involvement of the GABAergic system in schizophrenia susceptibility. These results warrant further investigations to replicate the association of GABRA1 and GPHN with schizophrenia and to discern the precise mechanisms of disease pathophysiology. (C) 2017 Elsevier B.V. All rights reserved.

Although the effectiveness of clozapine (CLZ) for patients with treatment-resistant schizophrenia (TRS) has been well established, its active mechanism has not been completely clarified. Several clinical studies showed that neuroleptic-induced dopamine supersensitivity psychosis (DSP) could be involved in the etiology of TRS. We preliminarily explored the possible beneficial effect of CLZ for dopamine supersensitivity schizophrenia. The present study is a case series. We followed 15 patients with DSP for about 2.5 years from the introduction of CLZ and compared the prevalence of episodes (particularly, rebound psychosis, tolerance to antipsychotic effects, or tardive dyskinesia) between the period before and during CLZ treatment. Our observation over 2.5 years following the introduction of CLZ showed that 13 of the 15 DSP patients presented no further DSP episodes. One patient showed continued tardive dyskinesia, which had already existed in the preperiod, and the other patient presented with rebound psychosis that appeared immediately after discontinuation of CLZ. The results of the present study indicated that DSP in schizophrenic patients treated with general antipsychotics disappeared over the subsequent 2.5 years under CLZ treatment, suggesting that the agent ameliorates the dopamine supersensitivity state induced by previous antipsychotic treatment.

Aim: The aims of this study were to determine whether the serum levels of precursor brain-derived neurotrophic factor (proBDNF), mature BDNF (mBDNF), and matrix metalloproteinase-9 (MMP-9) are altered in patients with eating disorders (ED), including anorexia nervosa (AN) and bulimia nervosa (BN), and to explore whether those levels are associated with decision-making abilities. Methods: Nineteen women with AN, 28 women with BN, and 22 age-matched healthy control women (HC) were enrolled in the current study. All participants had their decision-making abilities assessed using the Iowa Gambling Task (IGT). Their eating-related pathophysiology and depressive/anxiety symptoms were also evaluated. Results: The MMP-9 level in AN was significantly lower than that in either BN or HC, but the serum levels of proBDNF and mBDNF did not differ among the three groups. Investigation of the serum levels of proBDNF and MMP-9 in patients with ED and controls revealed a significant correlation between them. In the BN, there were positive correlations between mBDNF level and IGT performance and also between MMP-9 level and IGT performance, but these correlations did not occur in AN. The MMP-9 level was positively associated with the Symptom Scale, one of the subscales of the Bulimic Investigatory Test, Edinburgh, only in AN. Conclusion: These results suggest that the serum level of MMP-9 plays a role in the pathophysiology of AN, and both the serum levels of mBDNF and MMP-9 may be associated with decision-making abilities in patients with BN.

Dopamine supersensitivity psychosis (DSP) is a type of acute exacerbation of recurrent psychosis caused by long term treatment with antipsychotics in schizophrenic patients. Although DSP is exceedingly troublesome for clinicians, effective treatment has not yet been established, Based on clinical research and our animal study, we hypothesize that aripiprazole, an atypical anti psychotic, may reduce the exacerbation of recurrent psychotic episodes. We report the case of a 46 year old female who suffered from schizophrenia with DSP. In this case, sustained treatment with a high dose of aripiprazole gradually reduced the severity of her recurrent psychotic episodes. In conclusion, sustained treatment with aripiprazole may reduce the exacerbation of recurrent psychotic episodes in schizophrenic Patients with DSP, and may be an effective treatment of DSP.

The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D-2 like dopamine receptors. However, long-term administration of antipsychotics can upregulate D-2 receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dosereduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics ( risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D-2 receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP. (C) 2017 S. Karger AG, Basel.

Objective Dopamine supersensitivity psychosis (DSP) is one of the key factors contributing to the development of antipsychotic treatment-resistant schizophrenia (TRS). We investigated the efficacy of blonanserin, an atypical antipsychotic, for patients with TRS and DSP. Methods In this 12-month retrospective follow-up study, we investigated the cases of eight consecutive patients with unstable TRS and DSP treated with blonanserin as an add-on therapy. We examined changes in scores for the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression-Severity of Illness (CGI-S) scale and the Global Assessment of Functioning scale (GAF) during the 12 months after the administration of blonanserin. Results The patients’ total scores on the BPRS and GAF scores were significantly improved by 3 months at the latest. Positive BPRS and CGI-S scores were also improved by 6 months at the latest. The total chlorpromazine-equivalent doses of antipsychotics were significantly reduced from 1462.3 ± 499.6 mg to 794.1 ± 642.8 mg (p = 0.001) after 12 months of blonanserin treatment, with a favorable safety and tolerability profile. Conclusions Blonanserin may be a promising antipsychotic for the treatment of TRS and DSP.

BACKGROUND: Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. METHODS: To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. RESULTS: We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 x 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 x 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 x 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3 similar to 15.8) was approximately double that in CIG (OR: 4.4 similar to 7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) similar to 50% of CIG subjects would be non-CIA; and 2) similar to 60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. CONCLUSIONS: Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated.

Dopamine supersensitivity psychosis (DSP) resulting from antipsychotic treatment is related to treatment-resistant schizophrenia (TRS), and its treatment has not been established to date. Maintaining thoroughly stable occupancy of the dopamine D2 receptor by risperidone long-acting injectable (RLAI) is one strategy for treatment. In this study, RLAI was given as an adjunctive medication to oral antipsychotic(s), which were switched partially and gradually to RLAI in 108 treatment-resistant patients for an additional 1-year follow-up in a 2-year study, and to compare the effects in 72 patients with a DSP history (DSP group) and 36 patients without this history (NonDSP group). Although both groups showed significant improvements in the total Brief Psychotic Rating Scale (BPRS) score during the follow-up period, greater improvement was observed for the DSP group than the NonDSP group. High doses (> 850 mg chlorpromazine-dose combined of oral antipsychotics and RLAI) did not significantly change in both groups throughout the study period; however, extrapyramidal symptoms, including tardive dyskinesia, were significantly improved only in the patients with DSP. This study strongly suggested that the RLAI treatment, even with only partial switching, provides relief from refractory symptoms, particularly for patients with a history of DSP.

Objective 'Treatment-resistant depression' is depression that does not respond to an adequate regimen of evidence-based treatment. Treatment-resistant depression frequently becomes chronic. Children with treatment-resistant depression might also develop bipolar disorder (BD). The objective of this study was to determine whether serum levels of oxytocin (OXT) in treatment-resistant depression in adolescents (TRDIA) differ from non-treatment-resistant depression in adolescents (non-TRDIA) or controls. We also investigated the relationships between serum OXT levels and the clinical symptoms, severity, and familial histories of adolescent depressive patients. Methods We measured serum OXT levels: TRDIA (n = 10), non-TRDIA (n = 27), and age-and sex-matched, neurotypical controls (n = 25). Patients were evaluated using the Children's Depression Rating Scale-Revised (CDRS-R) and the Depression Self-Rating Scale for Children-Japanese Version (DSRS-C-J). The patients were also assessed retrospectively using the following variables: familial history of major depressive disorder and BD (1st degree or 2nd degree), history of disruptive mood dysregulation disorder, recurrent depressive disorder (RDD), history of antidepressant activation. Results Serum levels of OXT among the TRDIA and non-TRDIA patients and controls differed significantly. Interestingly, the rates of a family history of BD (1st or 2nd degree), RDD and a history of antidepressant activation in our TRDIA group were significantly higher than those of the non-TRDIA group. Conclusions Serum levels of OXT may play a role in the pathophysiology of TRDIA.

Chronic auditory verbal hallucinations (AVHs) in patients with schizophrenia are sometimes resistant to standard pharmacotherapy. Repetitive transcranial magnetic stimulation (rTMS) may be a promising treatment modality for AVHs, but the best protocol has yet to be identified. We used a double-blind randomized sham-controlled design aimed at 30 patients (active group N=16 vs. sham group N=14) with chronic AVHs that persisted regardless of adequate pharmacotherapy. The protocol was a total of four sessions of high-frequency (20-Hz) rTMS targeting the left temporoparietal cortex over 2 days (total 10,400 stimulations) administered to each patient. After the rTMS session the patients were followed for 4 weeks and evaluated with the Auditory Hallucination Rating Scale (AHRS). The mean changes of AHRS score were 22.9 (baseline) to 18.4 (4th week) in the Active group and 24.2 (baseline) to 21.8 (4th week) in the Sham group, indicating no significant difference by mix model analysis. As regards other secondary end points (each subscore of AHRS, BPRS, GAF and CGI-S), none of these parameters showed a significant between-group difference. The present study's rTMS protocol was ineffective for our patients. However, several previous studies demonstrated that high-frequency rTMS is a possible strategy to ameliorate pharmacotherapy-resistant AVH. It is important to establish a high-frequency rTMS protocol with more reliability. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Objective: Glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. Method: We measured the serum levels of D-serine, L-serine, glycine, glutamate and glutamine in patients with depression (n = 70), and age-matched healthy subjects (n = 78). Results: Serum levels of D-serine and L-serine in patients with depression were significantly higher than those of healthy controls (p < 0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of L-serine to glycine in patients was significantly higher than that of healthy controls (p < 0.001). Conclusion: This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the D-serine-L-serine-glycine cycle plays a role in the pathophysiology of depression.

Objective Glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. Method We measured the serum levels of d-serine, l-serine, glycine, glutamate and glutamine in patients with depression (n=70), and age-matched healthy subjects (n=78). Results Serum levels of d-serine and l-serine in patients with depression were significantly higher than those of healthy controls (p&lt 0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of l-serine to glycine in patients was significantly higher than that of healthy controls (p&lt 0.001). Conclusion This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the d-serine-l-serine-glycine cycle plays a role in the pathophysiology of depression.

Background: Although a variety of factors are known to be significantly related to poor prognosis in schizophrenia, their interactions remain unclear. Dopamine supersensitivity psychosis (DSP) is a clinical concept related to long-term pharmacotherapy and could be one of the key factors contributing to the development of treatment-resistant schizophrenia (TRS). The present study aims to explore the effect of DSP on progression to TRS. Methods: Two-hundreds and sixty-five patients were classified into either a TRS or Non-TRS group based on retrospective survey and direct interview. The key factors related to prognosis, including the presence or absence of DSP episodes, were extracted, and each factor was compared between the two groups. Results: All parameters except for the duration of untreated psychosis (DUP) were significantly worse in the TRS group compared to the Non-TRS group. In particular, the TRS group presented with a significantly higher rate of DSP episodes than the Non-TRS group. Regression analysis supported the notion that DSP plays a pivotal role in the development of TRS. In addition, deficit syndrome was suggested to be a diagnostic subcategory of TRS. Conclusions: Our data confirmed that the key predicting factors of poor prognosis which have been established would actually affect somehow the development of TRS. In addition, the occurrence of a DSP episode during pharmacotherapy was shown to promote treatment refractoriness. (c) 2016 Elsevier B.V. All rights reserved.

Previous studies showed that food craving in eating disorders can be weakened with high-frequency repetitive transcranial magnetic stimulation (rTMS) on the left dorsolateral prefrontal cortex (DLPFC). The aims of this study were to assess cerebral oxygenation change induced with rTMS and to assess the short-term impact of rTMS on food craving and other bulimic symptoms in patients with bulimia nervosa (BN). Eight women diagnosed with BN according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria participated in this study. We measured haemoglobin concentration changes in the DLPFC with near-infrared spectroscopy during cognitive tasks measuring self-regulatory control in response to food photo stimuli, both at baseline and after a single session of rTMS. Subjective ratings for food cravings demonstrated significant reduction. A significant decrease in cerebral oxygenation of the left DLPFC was also observed after a single session of rTMS. Measurement with NIRS after rTMS intervention may be applicable for discussing the mechanisms underlying rTMS modulation in patients with BN. Copyright (c) 2015 John Wiley & Sons, Ltd and Eating Disorders Association.

Background: We assessed the effect of switching patients with major depressive disorder to milnacipran following an initial selective serotonin reuptake inhibitor treatment failure, and explored potential biomarkers in their blood. Methods: We conducted a prospective, open-label, 24-week trial. Depression was assessed with the 17-item Hamilton Depression Rating Scale. Patients showing a $50% reduction in Hamilton Depression Rating Scale scores from baseline to final visit were considered responders. Regarding adverse effects (AEs), moderate-to-severe AEs were specifically identified as effects that required any medical treatment or that induced treatment withdrawals. We also measured blood levels of various molecules including inflammatory cytokines. Results: Of the 30 participants who enrolled, 17 completed this study. The responder rate was 30% (n=10). Baseline serum levels of interleukin-6 (Z=-2.155 P=0.031) and interleukin-8 (Z=-2.616 P=0.009) were significantly higher when moderate-to-severe AEs were present (n=13 patients with moderate-to-severe AEs). Serum levels of macrophage inflammatory protein-1β showed a significant continuous decrease from the baseline level (Friedman’s test: χ2=23.9, df=4, P&lt 0.001) only in non-responders. Conclusion: These results demonstrate that serum levels of interleukin-6, interleukin-8, and macrophage inflammatory protein-1β as potential blood biomarkers could be utilized to identify the responsiveness of patients to serotonin and norepinephrine reuptake inhibitor like milnacipran, or to identify those patients who may experience AEs strong enough to warrant discontinuation of treatment.

Although the dopamine D2 receptor (DRD2) has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%-30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s) could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP) is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s), is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed.

There is consistent data from European cohorts suggesting a genetic contribution from the major histocompatibility complex (MHC) to the pathogenesis of schizophrenia. However, the genomic complexity and ethnicity-specific diversity found in the MHC cause difficulties in identifying causal variants or genes, and there is a need for studies encompassing the entire MHC region in multiple ethnic populations. Here, we report on association signals in the MHC region, with schizophrenia in the Japanese population. We genotyped and imputed a total of 10,131 single nucleotide polymorphisms (SNPs), spanning the entire MHC interval. The analysis included 3302 participants (1518 schizophrenics and 1784 healthy controls) from the Japanese population. In this study, we present evidence for association at rs494620, located in the SLC44A4 gene. The association survived after correction for multiple testing (unadjusted P = 7.78 x 10(-5), empirical P = 0.0357). The imputation results detected the highest association at rs707937 in the MSH5-SAPCD1 gene (imputed P = 8.40 x 10(-5)). In expression analysis using postmortem brains from schizophrenia and control samples, MSH5-SAPCD1 showed marginally significant expression differences in Brodmann's area 46 (P = 0.044 by unpaired t test with Welch's correction, P = 0.099 by Mann-Whitney U test). Our study further strengthens evidence for the involvement of the MHC in schizophrenia across populations, and provides insight into population-specific mechanisms for the MHC region in schizophrenia susceptibility. (C) 2015 Elsevier B.V. All rights reserved.

Attention Deficit/Hyperactivity Disorder (ADHD) and autism spectrum disorder (ASD) are highly comorbid, and both disorders share executive function deficits. Accumulating evidence suggests that ASD patients have significantly lower peripheral oxytocin (OXT) levels compared with their normal counterparts, and that the repetitive behavior seen in ASD is related to abnormalities in the OXT system. In this study, we investigated whether serum levels of OXT are altered in pediatric patients with ADHD. We measured serum OXT levels: drug naive ADHD (n=23), medicated ADHD (n=13), and age- and sex- matched, neurotypical controls (n=22). Patients were evaluated using the ADHD-RS. Serum levels of OXT in total subjects with ADHD were significantly decreased compared with those of neurotypical controls, and serum levels of OXT in drug naive ADHD patients were significantly lower than those in medicated ADHD patients. Interestingly, there was a significant negative correlation between serum OXT levels and ADHD-RS total scores, as well as ADHD-RS inattentive scores in all ADHD patients. In conclusion, this study suggests that decreased levels of OXT may play a role in the pathophysiology of patients with ADHD and its inherent inattentiveness. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

Recent reports suggest that carbonyl stress might affect a subset of schizophrenia patients suffering from severe symptoms. Carbonyl stress protection is achieved by the glyoxalase system consisting of two enzymes, glyoxalase 1 and 2, which in humans are encoded by the genes GLO1 and HAGH, respectively. Glyoxalase 1 and 2 catalyze the detoxification of reactive alpha-oxoaldehydes such as glyoxal and methylglyoxal, which are particularly damaging components of carbonyl stress. Here, we investigated the role of the glyoxalase system in schizophrenia by performing association analyses of common genetic variants (n=12) in GLO1 and HAGH in a Japanese sample consisting of 2012 schizophrenia patients and 2170 healthy controls. We detected a nominally significant association with schizophrenia (p=0.020) of rs11859266, a SNP in the intronic region of HAGH. However, rs11859266 did not survive multiple testing (empirical p=0.091). The variants in HAGH, rs11859266 and rs3743852, showed significant associations with schizophrenia in males at allelic and genotype levels, which remained persistent after multiple testing with the exception of rs3743852 for the genotype model. We further measured the mRNA expression of both genes in postmortem brain, but did not detect any changes in transcript expression levels between case and control samples or in sex-specific comparisons. Therefore, our findings suggest that an explanation of elevated carbonyl stress in a substantial part (reported as ~20%) of patients with schizophrenia will require the examination of a much larger cohort to detect risk alleles with weak effect size and/or other risk factors.

It is widely accepted that malfunction of the N-methyl-d-aspartate (NMDA)-type glutamate receptor may be involved in the pathophysiology of schizophrenia. Several recent microRNA (miRNA) studies have demonstrated that the expression of the glutamate system-related miR-132 and miR-212 is changed in postmortem schizophrenic brains. Here we attempted to obtain further insight into the relationships among schizophrenia, the NMDA receptor, the molecular cascades controlled by these miRNAs and commonly predicted target genes of the two miRNAs. We focused on the H2AFZ (encoding H2A histone family, member Z) gene, whose expression was shown in our screening study to be modified by a schizophrenomimetic NMDA antagonist, phencyclidine. By performing polymerase chain reaction with fluorescent signal detention using the TaqMan system, we examined four tag single nucleotide polymorphisms (SNPs; SNP01-04) located around and within the H2AFZ gene for their genetic association with schizophrenia. The subjects were a Japanese cohort (2,012 patients with schizophrenia and 2,170 control subjects). We did not detect any significant genetic association of these SNPs with schizophrenia in this cohort. However, we observed a significant association of SNP02 (rs2276939) in the male patients with schizophrenia (allelic P = 0.003, genotypic P = 0.008). A haplotype analysis revealed that haplotypes consisting of SNP02-SNP03 (rs10014424)-SNP04 (rs6854536) also showed a significant association in the male patients with schizophrenia (P = 0.018). These associations remained significant even after correction for multiple testing. The present findings suggest that the H2AFZ gene may be a susceptibility factor in male subjects with schizophrenia, and that modification of the H2AFZ signaling pathway warrants further study in terms of the pathophysiology of schizophrenia.

There may be subtypes in treatment-resistant schizophrenia (TRS), and one of the subtypes may be related to dopamine supersensitivity psychosis (DSP). In developing strategies for prevention and treatment TRS, it is important to clarify the role of DSP in TRS. TRS patients were recruited from 3 hospitals for the present study. Through chart reviews, all patients were judged as either TRS or not, and then possible TRS patients were investigated about their past/present histories of DSP episode(s) by direct interviews. We then compared each factor between the groups with and without DSP episode(s). Out of 611 patients screened, 147 patients met the criteria for TRS and were included in the present analysis. These were divided into groups with and without DSP, comprising 106 (72.1%) and 41 patients (27.9%), respectively. Clinical characteristics in the two groups were similar, except for drug-induced movement disorders (DIMDs), which were significantly more important in DSP patients. Of the DSP patients, 42% and 56% experienced rebound psychosis and tolerance to antipsychotic effects, respectively. The present study revealed that approximately 70% of TRS patients experienced one or more DSP episodes, which may have a strong impact on the long-term prognosis of patients with schizophrenia. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

The administration of aripiprazole (ARI), a dopamine partial agonist, could provoke abrupt psychotic worsening in patients with schizophrenia. We explored the relationship between this psychotic worsening and dopamine supersensitivity psychosis (DSP), which is a clinically vulnerable state. We conducted a retrospective investigation for 264 patients whose treatment medication was switched to ARI from other antipsychotics. We divided the patients into the DSP(+) group with a history of DSP episode(s) (N = 70) and the DSP(-) group without such a history (N = 194), and then compared the clinical factors relevant to the success or failure of the switch to ARI between them. The results revealed that patients in the DSP(+) group experienced psychotic worsening following the switch to ARI with a significant higher rate compared to the DSP(-) group (23% vs. 8%, P < 0.01). Moreover, the dosages of the drugs before the ARI introduction in the patients experiencing the psychotic worsening in the DSP (-) group were higher than those in other patients of the group. Our findings suggest that patients who receive high dosages of antipsychotic drugs form overt or covert DSP and such state is highly associated with psychotic worsening following ARI treatment.

Objective: Schizophrenia is a mental disorder characterized by severe cognitive impairment. Accumulating evidence suggests a role for oxidative stress in the pathophysiology of schizophrenia. Sulforaphane (SFN) extracted from broccoli sprout is an agent with potent anti oxidant and anti inflammatory activity. In this study, we attempted to evaluate the effect of SFN on cognitive impairment in medicated patients with schizophrenia. Methods: We recruited a total of 10 outpatients with schizophrenia, all of whom gave informed consent. Participants took 3 tablets of SFN, consisting of 30 mg of SFN glucosinolate per day, for 8 weeks. Clinical symptoms using the Positive and Negative. Syndrome Scale (PANSS) and cognitive function using the Japanese version of CogState battery were evaluated at the beginning of the study and at week 8. Results: A total of 7 patients completed the trial. The mean score in the Accuracy component of the One Card Learning Task increased significantly after the trial. However, we detected no other significant changes in participants. Conclusion: This result suggests that SFN has the potential to improve cognitive function in patients with schizophrenia,

Disruption of synaptic networks has been advocated in the pathogenesis of psychiatric diseases like schizophrenia. The majority of synaptic proteins involved in neuronal communications are localized in lipid rafts. These rafts form the platform for coordinating neuronal signal transduction, by clustering interacting partners. The PAG1 protein is a transmembrane adaptor protein in the lipid raft signaling cluster that regulates Src family kinases (SFKs), a convergent point for multiple pathways regulating N-methyl-D-aspartate (NMDA) receptors. Reports of de novo missense mutations in PAG1 and SFK mediated reductions in tyrosine phosphorylation of NMDA receptor subunit proteins in schizophrenia patients, point to a putative role in schizophrenia pathogenesis. To evaluate this, we resequenced the entire coding region of PAG1 in Japanese schizophrenia patients (n = 1,140) and controls (n = 1,140). We identified eight missense variants, of which four were previously unreported. Case-control genetic association analysis of these variants in a larger cohort (n = 4,182) showed neither a statistically significant association of the individual variants with schizophrenia, nor any increased burden of the rare alleles in the patient group. Expression levels of PAG1 in post-mortem brain samples from schizophrenia patients and controls also showed no significant differences. To assess the precise role of PAG1 in schizophrenia, future studies with larger sample sizes are needed.

Background/aim: Dopamine supersensitivity psychosis (DSP), clinically characterized by unstable and severe psychosis or tardive dyskinesia and often categorized as treatment-resistant schizophrenia, is promoted by long-term antipsychotic treatment. An upregulation of the dopamine D-2 receptor caused by antipsychotic(s) is involved in the development of DSP. The present study explored the potential roles of G protein-coupled receptor kinase 6 (GRK6) and beta-arrestin 2 (ARRB2) that are involved in the trafficking of DRD2 in patients with DSP. Methods: We conducted a genetic association study of GRK6/ARRB2 between the patients with DSP episodes [DSP(+) group: N=108] and the patients without DSP(-) episodes [DSP(-) group: N= 169] from the total group of patients (N=333). Based on the patients' treatment history, a DSP episode was defined as withdrawal psychosis, developed tolerance to antipsychotic effect, and tardive dyskinesia (the remaining 56 patients were excluded due to insufficient information). Results: The results revealed that none of the allelic or genotyping distributions of five single nucleotide polymorphisms (SNPs) of GRK6 and three SNPs of ARRB2 showed any significant difference between the DSP(+) and DSP(-) groups. Conclusion: The results suggest that the SNP analyses of these two molecules fail to classify patients into the potential clinical subtype of DSP(+) or DSP(-) group. However, since GRK6 and ARRB2 are surely involved in dopamine D2 receptor metabolism, further studies based on prospective observations of the onset of DSP under specific antipsychotic treatments are needed.