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Nishi-Tokyo-shi, Japan

Sukegawa T.,Tottori Medical Center | Inagaki A.,Aoyama Gakuin University | Yamanouchi Y.,National Institute of Mental Health | Inada T.,Institute of Neuropsychiatry | And 3 more authors.
BMC Psychiatry

Background: In Japan, combination therapy with high doses of antipsychotic drugs is common, but as a consequence, many patients with schizophrenia report extrapyramidal and autonomic nervous system side effects. To resolve this, we proposed a method of safety correction of high dose antipsychotic polypharmacy (the SCAP method), in which the initial total dose of all antipsychotic drugs is calculated and converted to a chlorpromazine equivalent (expressed as milligrams of chlorpromazine, mg CP). The doses of low-potency antipsychotic drugs are then reduced by ≤ 25 mg CP/week, and the doses of high-potency antipsychotics are decreased at a rate of ≤50 mg CP/week. Although a randomized, case-controlled comparative study has demonstrated the safety of this method, the number of participants was relatively small and its results required further validation. In this study of the SCAP method, we aimed to substantially increase the number of participants.Methods/design: The participants were in- or outpatients treated with two or more antipsychotics at doses of 500-1,500 mg CP/day. Consenting participants were randomized into control and dose reduction groups. In the control group, patients continued with their normal regimen for 3 months without a dose change before undergoing the SCAP protocol. The dose reduction group followed the SCAP strategy over 3-6 months with a subsequent 3-month follow-up period. Outcome measures were measured at baseline and then at 3-month intervals, and included clinical symptoms measured on the Manchester scale, the extent of extrapyramidal and autonomic side effects, and quality of life using the Euro QOL scale. We also measured blood drug concentrations and drug efficacy-associated biochemical parameters. The Brief Assessment of Cognition in Schizophrenia, Japanese version, was also undertaken in centers where it was available.Discussion: The safety and efficacy of the SCAP method required further validation in a large randomized trial. The design of this study aimed to address some of the limitations of the previous case-controlled study, to build a more robust evidence base to assist clinicians in their efforts to reduce potentially harmful polypharmacy in this vulnerable group of patients. © 2014 Sukegawa et al.; licensee BioMed Central Ltd. Source

Arinami T.,University of Tsukuba | Inada T.,Institute of Neuropsychiatry
Japanese Journal of Neuropsychopharmacology

Tardive dyskinesia (TD) is characterized by repetitive, involuntary, purposeless movements that develop in patients treated with long-term dopaminergic antagonists, usually antipsychotics. By a genome-wide association screening of TD in 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD (non-TD group) and subsequent confirmation in independent samples of 36 treatment-resistant TD and 136 non-TD subjects, we identified an association of SNPs in the HSPG2 (heparan sulfate proteoglycan 2, perlecan) gene with TD. By canonical pathway-based analyses with Ingenuity Pathway Analysis software, we also found that genes involved in the GABA receptor signaling pathway were significantly enriched among the genes with gene-based corrected association allelic P vales of less than 0.05. The gene expression levels in the postmortem prefrontal brains in those with the risk genotypes for TD were in the opposite direction to those in mouse brains after long-term admiration of haloperidol. These findings indicate that individuals with the susceptibility to TD may have less ability to adapt to long-term exposure of neuroleptics in some gene expression levels. Source

Matsunami K.,Institute of Neuropsychiatry
Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica

The assumption that a core group of depressive disorders is due to a discontinuous change in the function of the brain system, suggests that the symptoms of the core group of depressive disorders should be discerned from those of non-core depression. Core depression is thought to correspond to depression of an endogenous nature, which has recently been disregarded in diagnosing mood disorders. However, in diagnosing endogenous depression, we can identify its characteristic symptoms by referring to a traditional symptomatology. Therefore, the idea of Verstehen (Jaspers, K) becomes essential, but has been neglected in academic journals in English-speaking countries. The depressive mood in endogenous depression may be an inhibition of various kinds of emotion, which can never be experienced within a normal emotional state. Thus, it is thought to be 'unverstaendlich' (incomprehensible) in nature. The "anhedonia hypothesis" of depression from DSM-IV permits the inclusion of the non-core group of depression into major depressive disorder, because patients with the endogenous type suffer not only from a loss of pleasure but also from a loss of sadness. A new type of depression that has recently been debated in Japan is diagnosed as major depressive disorder in DSM-IV, but many suspected cases are thought to be due to a psychogenic state or neurotic condition, because their symptoms are thought to be 'verstaendlich' (comprehensible). Endogenous depression can manifest as manic-depressive disorder in almost all cases, but psychiatric practitioners have taken the necessary precautions against the risk of a shift to a manic state even when treating pure depression which seemingly appears to have no manic component. According to recent studies on bipolar disorder, pure mania is not empirically found. Thus, the manic pole may not exist, and we may be able to think of endogenous depression as manic-depressive disorder based on its genetic entity. Additionally, from the viewpoint of its symptomatology there is one pole of depression modified by manic tendencies based on various intensities. The current study presents the hypothesis that there is one entity for disease, manic-depression, but whether the disorder manifests itself as uni- or bipolar disorder depends upon the regulation of manic manifestations by a meticulous, obsessive-compulsive personality which has been considered to be the premorbid personality for unipolar depression. Source

Yoshida M.,Kobe University | Shiroiwa K.,Kobe University | Mouri K.,Kobe University | Ishiguro H.,Yamanashi University | And 12 more authors.
Schizophrenia Research

Recent genome-wide association study (GWAS) and gene expression analyses have revealed that single nucleotide polymorphisms (SNPs) associated with complex diseases such as schizophrenia are significantly more likely to be associated with expression quantitative trait loci (eQTL). The interleukin-1β (IL1B) gene has been strongly implicated in the susceptibility to schizophrenia. In order to test this association, we selected five tag SNPs in the eQTL of the IL1B gene and conducted a case-control study using two independent samples. The first sample comprised 528 schizophrenic patients and 709 controls and the second sample comprised 576 schizophrenic patients and 768 controls. We identified two SNPs and several haplotypes as being significantly associated with schizophrenia. Previous reports indicated that one major haplotype that was protective against schizophrenia reduced IL1B transcription, while two risk haplotypes for schizophrenia enhanced IL1B transcription. Therefore, we measured IL1B mRNA expression in PAXgene-stabilized whole blood from 40 schizophrenic patients and 40 controls to explore the possibility of using five tag SNPs as schizophrenic trait markers. A multiple regression analysis taking confounding factors into account revealed that the T allele of rs4848306 SNP, which is a protective allele for schizophrenia, predicted reduced change in IL1B mRNA expression, regardless of phenotype. Our results appear to support the previous hypothesis that IL1B contributes to the genetic risk of schizophrenia and warrant further research on the association of eQTL SNPs with schizophrenia. © 2012 Elsevier B.V. Source

Nishizawa D.,Tokyo Metropolitan Institute of Medical Science | Fukuda K.,Orofacial Pain Center Suidoubashi Hospital | Kasai S.,Tokyo Metropolitan Institute of Medical Science | Hasegawa J.,Tokyo Metropolitan Institute of Medical Science | And 27 more authors.
Molecular Psychiatry

Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence. © 2014 Macmillan Publishers Limited. Source

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