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Purpose: There is little evidence regarding the effects of dental status on body mass index (BMI) in inpatients with schizophrenia. Thus, we performed a cross-sectional study to explore the associations between the number of remaining teeth and BMI in Japanese inpatients with schizophrenia. Patients and Methods: We performed multiple regression analysis to assess the effects of potential predictors (age, sex, number of remaining teeth, number of antipsychotics prescribed, chlorpromazine equivalent dose, and antipsychotic type) on BMI in 212 inpatients with schizophrenia. We then compared the number of remaining teeth between inpatients with schizophrenia and the Japanese general population (3283 individuals) from the Japan Dental Diseases Survey 2016, using an analysis of covariance with age and sex as covariates. Results: Multiple regression analysis showed that the number of remaining teeth and the number of antipsychotics prescribed were significantly correlated with BMI (standardized regression coefficient = 0.201 and 0.235, respectively). In the analysis of covariance, inpatients with schizophrenia had significantly fewer remaining teeth compared with the Japanese general population (mean 14.8 [standard deviation: 10.9] vs mean 23.0 [standard deviation: 8.1]). Conclusion: These results suggested that tooth loss and antipsychotic polypharmacy affect BMI in inpatients with schizophrenia, and that inpatients with schizophrenia lose more teeth compared with the general population.
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The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this model such as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination.
Assuntos
Córtex Auditivo , Esquizofrenia , Animais , Córtex Auditivo/metabolismo , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Fator de Crescimento Epidérmico , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , RatosRESUMO
Aim: There is little evidence on the effects of antipsychotic polypharmacy on metabolic parameters in patients with schizophrenia. Thus, this cross-sectional study explored the associations between the number of antipsychotics prescribed and metabolic parameters in Japanese patients with schizophrenia. Methods: We obtained metabolic parameter data from 19,675 patients with schizophrenia. Of these, 1380 (7.0%), 8422 (42.8%), 6326 (32.2%), and 3547 (18.0%) were treated with none, one, two, and three or more antipsychotics, respectively. We compared eight metabolic parameters among the four groups using univariate analyses. We then performed multiple regression analysis to assess the effect of the number of antipsychotics prescribed on metabolic parameters after controlling for the effects of age, sex, type of care (outpatient/inpatient), chlorpromazine-equivalent dose, and antipsychotic type (aripiprazole, olanzapine, and risperidone). Results: There were significant differences in body mass index (BMI), systolic and diastolic blood pressure (dBP), total cholesterol, low-density lipoprotein cholesterol, and triglycerides among the four groups. The multiple regression analysis showed that the number of antipsychotics prescribed was significantly correlated with BMI and dBP (standardized regression coefficient = 0.031 and 0.026, respectively). Conclusion: Our results suggested that the number of antipsychotics prescribed adversely affects BMI and dBP. Clinicians should avoid inappropriate antipsychotic polypharmacy, especially polypharmacy involving three or more antipsychotics.
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BACKGROUND: Hyperprolactinemia is a troublesome adverse effect of antipsychotics. Aripiprazole (ARP), which is one of second-generation antipsychotics, has been reported to lower serum prolactin (PRL) levels. However, few studies have compared the effect of ARP on plasma PRL levels between monopharmacy and polypharmacy with antipsychotics. METHODS: We conducted a large-scale investigation of the physical risk for inpatients with schizophrenia using a questionnaire covering demographic data, the number, dose and type of antipsychotics, and serum PRL levels. RESULTS: Sufficient data to conduct an assessment of the effect on PRL levels between antipsychotic monopharmacy and polypharmacy were obtained from 316 of the inpatients. Serum PRL levels in ARP combination group were lower than non-ARP combination group, regardless of antipsychotic monopharmacy or polypharmacy. CONCLUSIONS: The present study suggests that ARP lowers serum PRL levels regardless of monopharamacy or polypharmacy with antipsychotics.
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Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Prolactina/sangue , Esquizofrenia/tratamento farmacológico , Adulto , Idoso , Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Estudos Transversais , Regulação para Baixo , Quimioterapia Combinada , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Polimedicação , Esquizofrenia/sangue , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Resultado do TratamentoRESUMO
Clozapine is an antipsychotic agent prescribed to psychotic patients exhibiting tolerance and/or resistance to the conventional antipsychotic medications that mainly drive monoamine antagonism. As the pharmacological fundamentals of its unique antipsychotic profile have been unrevealed, here, we attempted to obtain hints at this question. Here, we found that clozapine directly acts on ErbB kinases to downregulate epidermal growth factor (EGF)/neuregulin signaling. In cultured cell lines and cortical neurons, EGF-triggered ErbB1 phosphorylation was diminished by 30 µM clozapine, but not haloperidol, risperidone, or olanzapine. The neuregulin-1-triggered ErbB4 phosphorylation was attenuated by 10 µM clozapine and 30 µM haloperidol. We assumed that clozapine may directly interact with the ErbB tyrosine kinases and affect their enzyme activity. To test this assumption, we performed in vitro kinase assays using recombinant truncated ErbB kinases. Clozapine (3-30 µM) significantly decreased the enzyme activity of the truncated ErbB1, B2, and B4 kinases. Acute in vivo administration of clozapine (20 mg/kg) to adult rats significantly suppressed the basal phosphorylation levels of ErbB4 in the brain, although we failed to detect effects on basal ErbB1 phosphorylation. Altogether with the previous findings that quinazoline inhibitors for ErbB kinases harbor antipsychotic potential in animal models for schizophrenia, our present observations suggest the possibility that the micromolar concentrations of clozapine can attenuate the activity of ErbB receptor kinases, which might illustrate a part of its unique antipsychotic psychopharmacology.
Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Clozapina/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Neurregulinas/metabolismo , Proteínas Oncogênicas v-erbB/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: Patients with schizophrenia have a higher prevalence of metabolic syndrome (MetS) than the general population. Minimizing weight gain and metabolic abnormalities in a population with an already high prevalence of obesity is of clinical and social importance. This randomized controlled trial investigated the effect of monthly nutritional education on weight change and metabolic abnormalities among patients with schizophrenia in Japan. METHODS: From July 2014 to December 2014, we recruited 265 obese patients who had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder. Participants were randomly assigned to a standard care (A), doctor's weight loss advice (B), or an individual nutritional education group (C) for 12 months. The prevalence of MetS and body weight were measured at baseline and 12 months. RESULTS: After the 12-month treatment, 189 patients were evaluated, and the prevalence of MetS based on the ATP III-A definition in groups A, B, and C was 68.9%, 67.2%, and 47.5%, respectively. Group C showed increased weight loss (3.2 ± 4.5 kg) over the 12-month study period, and the change in weight differed significantly from that of group A; additionally, 26.2% of the participants in group C lost 7% or more of their initial weight, compared with 8.2% of those in group A. CONCLUSION: Individual nutrition education provided by a dietitian was highly successful in reducing obesity in patients with schizophrenia and could be the first choice to address both weight gain and metabolic abnormalities induced by antipsychotic medications.
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Antipsicóticos/uso terapêutico , Síndrome Metabólica/dietoterapia , Obesidade/dietoterapia , Avaliação de Resultados em Cuidados de Saúde , Educação de Pacientes como Assunto/métodos , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Redução de Peso , Adulto , Antipsicóticos/efeitos adversos , Feminino , Humanos , Japão , Masculino , Síndrome Metabólica/induzido quimicamente , Pessoa de Meia-Idade , Obesidade/induzido quimicamenteRESUMO
BACKGROUND: Olanzapine (OLZ) treatment is associated with a high risk of weight gain, and may cause abnormalities in glycolipid metabolism. Therefore, the underlying mechanism of OLZ-related weight gain is needed to clarify but not yet been adequately determined. In recent years, adipocytokines such as leptin, adiponectin, and tumor necrosis factor (TNF)-α, which play important roles in energy homeostasis, have been suggested as biomarkers of weight gain. Here, we determined if baseline plasma concentrations of leptin, adiponectin, and TNF-α predict weight gain following OLZ treatment. METHODS: We recruited 31 schizophrenia outpatients (12 men and 19 women, 28.8 ± 10.2 years old) that were unmedicated or on another antipsychotic monotherapy medication. Baseline body mass index (BMI) and plasma levels of leptin, adiponectin, and TNF-α were obtained. All patients started or were switched to OLZ monotherapy for a maximum of 1 year. BMI was also obtained at the endpoint. RESULTS: Mean BMI change following OLZ treatment was 2.1 ± 2.7 kg/m2. BMI change from baseline to endpoint negatively-correlated with baseline leptin levels in female patients (r = -0.514, P = 0.024), but not male patients. Baseline adiponectin or TNF-α levels were not correlated with BMI change. CONCLUSION: Baseline plasma leptin can have an effect on subsequent weight gain following OLZ treatment in female patients with schizophrenia.
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Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Leptina/sangue , Esquizofrenia/tratamento farmacológico , Aumento de Peso/efeitos dos fármacos , Adiponectina/sangue , Adolescente , Adulto , Antipsicóticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Índice de Massa Corporal , Feminino , Humanos , Masculino , Olanzapina , Esquizofrenia/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto JovemRESUMO
Among the most important adverse effects of antipsychotics is abnormal glucose metabolism, which includes not only hyperglycemia but hyperinsulinemia and hypoglycemia. We have previously described five patients who experienced hypoglycemia during treatment with antipsychotics. Thus, an anamnesis of gastric surgery, which often causes dumping syndrome, and treatment with antipsychotics may synergistically induce hypoglycemia. We describe here a patient with schizophrenia under treatment of olanzapine and an anamnesis of gastric surgery, who experienced late dumping syndrome, hyperinsulinemia and overactivation of glucose-dependent insulinotropic polypeptide. Dumping syndrome, however, was improved after the patient was switched from olanzapine to quetiapine.
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Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Síndrome de Esvaziamento Rápido/etiologia , Gastrectomia/efeitos adversos , Polipeptídeo Inibidor Gástrico/metabolismo , Fumarato de Quetiapina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Substituição de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Olanzapina , Esquizofrenia/complicações , Neoplasias Gástricas/complicaçõesRESUMO
Association between gastric inhibitory polypeptide receptor polymorphism, rs10423928, and body mass index in olanzapine-treated schizophrenia was examined. Body mass index change for the A/T+A/A genotypes was significantly higher than that for the T/T genotype. rs10423928 may predict weight gain in schizophrenia.
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Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Peso Corporal/genética , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Receptores dos Hormônios Gastrointestinais/genética , Esquizofrenia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN) have been implicated in the pathogenesis of schizophrenia because they function as molecular integrators of dopamine and glutamate signaling. DARPP-32 and CaN are mainly expressed in the caudate nucleus and putamen; however, a few postmortem brain studies have focused on DARPP-32 expression in striatum from patients with schizophrenia. METHODS: We used immunoblotting techniques and postmortem tissue samples from patients with schizophrenia and from normal control individuals to examine the expression of two major DARPP-32 isoforms, full-length (FL-DARPP) and truncated (t-DARPP), and of CaN in the striatum. We also assessed whether there was any significant correlation between the expression levels of either protein and the A1 allele of Taq1A genotype in the dopamine D2 receptor (DRD2) gene/ankyrin-repeat containing kinase 1 (ANKK1) gene. RESULTS: We found that the mean t-DARPP expression level in the caudate was higher in patients with schizophrenia than in control individuals (P<0.05) and the A1 allele of Taq1A genotype in DRD2/ANKK1 was significantly associated with elevated expression of t-DARPP in the caudate. Also, the A1 allele was significantly correlated with the total score of antemortem psychiatric symptoms. CONCLUSION: These results may reflect potential molecular mechanisms important to the pathogenesis of schizophrenia.
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Corpo Estriado/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Esquizofrenia/genética , Esquizofrenia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Calcineurina/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mudanças Depois da MorteRESUMO
9-Hydroxyrisperidone (9-OH-RIS) is an active metabolite of the antipsychotic drug risperidone (RIS). The total active moiety level, in other words the sum of the RIS and 9-OH-RIS serum levels, may be important for estimating the clinical effects of RIS treatment. However, there have been no consistent results reported regarding the relationship between cytochrome P450 (CYP) 2D6 or adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) variant alleles and 9-OH-RIS or total active moiety plasma levels. Seventy-four Japanese patients treated with RIS were examined in the present study. Steady-state plasma RIS and 9-OH-RIS were measured. The CYP2D6*5, CYP2D6*10, ABCB1 3435C>T, and ABCB1 2677G>T/A genotypes were detected. Multiple regression analysis showed that the dose-corrected plasma RIS levels were significantly correlated with the number of CYP2D6 variant alleles and ABCB1 3435C>T genotypes, whereas the 9-OH-RIS and total active moiety levels were significantly correlated with the ABCB1 3435C>T genotypes and with age. On the other hand, the ABCB1 2677G>T/A genotypes did not affect plasma RIS, 9-OH-RIS, or total active moiety levels. The ABCB1 3435C>T genetic polymorphism may predict plasma 9-OH-RIS and total active moiety levels.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Isoxazóis/farmacocinética , Pirimidinas/farmacocinética , Risperidona/farmacocinética , Esquizofrenia/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Fatores Etários , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Citocromo P-450 CYP2D6/genética , Feminino , Genótipo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona , Polimorfismo Genético , Análise de Regressão , Risperidona/uso terapêutico , Adulto JovemRESUMO
OBJECTIVE: The underlying mechanism for second-generation antipsychotic (SGA)-related glucose-lipid metabolic dysfunction is not fully understood. Recent studies have suggested a possible impact of SGAs on endocrine regulation, especially on adipocytokines. We examined the effect of each SGA on various adipocytokines in normal fasting glucose (NFG) subjects. METHOD: The study population comprised 113 Japanese inpatients with schizophrenia who were treated with olanzapine, risperidone, or quetiapine, and 123 healthy control (CONT) volunteers. All of the subjects were diagnosed with NFG. Plasma concentration of adiponectin, leptin, tumor necrosis factor α, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were compared between the SGA and CONT groups. RESULTS: Second-generation antipsychotic subjects had significantly higher leptin levels in comparison to the CONT subjects. The plasma concentration of adiponectin, total cholesterol, and high-density lipoprotein cholesterol in the SGA subjects were significantly lower than those in the CONT subjects. There were no significant differences in tumor necrosis factor α, triglyceride, and low-density lipoprotein cholesterol levels between the 2 groups. In a stepwise multiple regression analysis, olanzapine was found to be a factor that contributed to decreased adiponectin levels, and the CONT subjects were detected to be a factor associated with lower leptin levels. CONCLUSIONS: The present study indicates the possibility that the administration of SGAs may affect adipocytokines in the NFG stage, excluding the impaired fasting glucose group, which is in the transition stage into diabetes mellitus.
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Antipsicóticos/efeitos adversos , Leptina/sangue , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Adiponectina/sangue , Adolescente , Adulto , Antipsicóticos/uso terapêutico , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Glicemia/análise , Estudos Transversais , Manual Diagnóstico e Estatístico de Transtornos Mentais , Dibenzotiazepinas/efeitos adversos , Dibenzotiazepinas/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Olanzapina , Fumarato de Quetiapina , Risperidona/efeitos adversos , Risperidona/uso terapêutico , Esquizofrenia/imunologia , Adulto JovemRESUMO
OBJECTIVE: Antipsychotic-treated schizophrenia patients are susceptible to dyslipidemia. However, the results of previous studies of North American and UK populations including various races have been contradictory with regard to which lipid measure was the most affected in patients with schizophrenia taking antipsychotic agents. The aim of this study was to investigate the effect of schizophrenia patients receiving antipsychotic agents on each lipid measure in a Japanese population. METHODS: The samples included 136 control individuals and 157 patients with schizophrenia treated with antipsychotic agents. Age, gender distribution and body mass index (BMI) of the controls were matched with the patients. RESULTS: The high-density lipoprotein cholesterol (HDL-cholesterol) levels were significantly lower in patients than in the control subjects (P<.001). However, there were no significant differences in either the low-density lipoprotein cholesterol (LDL-cholesterol) or triglyceride levels between the patient and control groups. We performed a multiple linear regression analysis, and schizophrenia receiving antipsychotics was an independent predictor of decreased HDL-cholesterol. An increased BMI, male gender and cigarette smoking were also major predictors of a decreased HDL-cholesterol level (r(2)=0.42, P<.001). CONCLUSION: At least in Japanese with schizophrenia receiving antipsychotic agents, the HDL-cholesterol levels should be closely monitored in all patients, even those who are not obese or do not smoke, to decrease their risk of cardiovascular disease.
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Antipsicóticos/uso terapêutico , Dislipidemias/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Esquizofrenia/sangue , Adulto JovemRESUMO
The CYP2D6 enzyme is a capacity-limited high-affinity drug elimination pathway that metabolizes numerous psychiatric medicines. The capacity-limited nature of this enzyme suggests that drug dose may serve as an important factor that influence genotype-phenotype associations. However, dose dependency of CYP2D6 genotype contributions to drug elimination, and its interaction with environmental factors (e.g., smoking) did not receive adequate attention in translational study designs. Fluvoxamine is a selective serotonin reuptake inhibitor antidepressant. Fluvoxamine concentration is one of the factors previously linked to clinical remission in moderate to severe depression. We investigated the joint effect of smoking (an inducer of CYP1A2) and CYP2D6 genotype on interindividual variability in fluvoxamine steady-state concentration. Fluvoxamine concentration was measured in 87 patients treated with 50, 100, 150 or 200 mg/d. While CYP2D6 genotype significantly influenced fluvoxamine concentration in all four dose groups (p < 0.05), the percentage variance explained (R²) by CYP2D6 decreased as the dose of fluvoxamine increased. Smoking status (nonsmokers vs. smoking 20 or more cigarettes/d) significantly affected fluvoxamine concentration in the 50 mg/d group only (p = 0.005). Together, CYP2D6 genotype and smoking status explained 23% of the variance in fluvoxamine concentration but only at the low 50 mg/d dose group. These findings contribute to evidence-based and personalized choice of fluvoxamine dose using smoking status and CYP2D6 genetic variation. Additionally, these data lend evidence for drug dose as an important variable in translational pharmacogenetic study design and pharmaceutical phenotype associations with capacity-limited drug metabolism pathways such as CYP2D6.
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Povo Asiático/genética , Citocromo P-450 CYP2D6/genética , Fluvoxamina/farmacocinética , Transtornos Mentais/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Fumar/etnologia , Fumar/metabolismo , Adulto , Distribuição de Qui-Quadrado , Citocromo P-450 CYP1A2/biossíntese , Citocromo P-450 CYP2D6/metabolismo , Feminino , Fluvoxamina/sangue , Estudos de Associação Genética , Genótipo , Humanos , Japão , Masculino , Transtornos Mentais/enzimologia , Transtornos Mentais/etnologia , Transtornos Mentais/genética , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Farmacogenética , Fenótipo , Análise de Regressão , Inibidores Seletivos de Recaptação de Serotonina/sangue , Pesquisa Translacional BiomédicaRESUMO
The adenylate cyclase-activating polypeptide 1 (ADCYAP1) gene encodes a neuropeptide with neurotransmission activity, which is known as the pituitary adenylate cyclase-activating polypeptide. Associations of two polymorphisms, rs1893154 and rs2856966 (Asp54Gly), in the ADCYAP1 gene with schizophrenia were reported earlier by a Japanese case-control study. In this study, we tried to confirm the association in 2027 Japanese patients with schizophrenia and 2058 controls. The power to detect an association was more than 0.9. However, we did not detect allelic associations of rs1893154 with schizophrenia (P=0.36). Although rs2856966 was nominally significant (P=0.045), the association was in the opposite direction from that reported earlier. Combined data and meta-analysis of the two studies comprising nearly 6000 Japanese case-control patients did not show significant associations (P=0.53-0.86). It is concluded that single-nucleotide polymorphisms, including Asp54Gly, of the ADCYAP1 gene are unlikely to play a sizeable role in the genetic susceptibility to schizophrenia.
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Predisposição Genética para Doença , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Alelos , Povo Asiático/genética , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Neural endocannabinoid function appears to be involved in schizophrenia. Two endocannabinoid receptors, CB1 and CB2, are found in the brain and elsewhere in the body. We investigated roles of CB2 in schizophrenia. MATERIALS AND METHODS: An association study was performed between tag single nucleotide polymorphisms (SNPs) in the CNR2 gene encoding the CB2 receptor and schizophrenia in two independent case-control populations. Allelic differences of associated SNPs were analyzed in human postmortem brain tissues and in cultured cells. Prepulse inhibition and locomotor activity in C57BL/6JJmsSlc mice with CB2 receptor antagonist AM630 administration was examined. RESULTS: The analysis in the first population revealed nominally significant associations between schizophrenia and two SNPs, and the associations were replicated in the second population. The R63 allele of rs2501432 (R63Q) (p = .001), the C allele of rs12744386 (p = .005) and the haplotype of the R63-C allele (p = 5 x 10(-6)) were significantly increased among 1920 patients with schizophrenia compared with 1920 control subjects in the combined population. A significantly lower response to CB2 ligands in cultured CHO cells transfected with the R63 allele compared with those with Q63, and significantly lower CB2 receptor mRNA and protein levels found in human brain with the CC and CT genotypes of rs12744386 compared with TT genotype were observed. AM630 exacerbated MK-801- or methamphetamine-induced disturbance of prepulse inhibition and hyperactivity in C57BL/6JJmsSlc mice. CONCLUSIONS: These findings indicate an increased risk of schizophrenia for people with low CB2 receptor function.
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Encéfalo/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Animais , Células CHO , Estudos de Casos e Controles , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Indóis/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Receptor CB2 de Canabinoide/antagonistas & inibidores , Reflexo de Sobressalto/efeitos dos fármacosRESUMO
Tumor necrosis factor-alpha (TNF-alpha) is a pleiotrophic cytokine and exerts neuroprotective and neurodegenerative effects in brain. Several studies have indicated that TNF-alpha is likely related to the pathogenesis of schizophrenia. Recent genetic investigations have revealed that a TNF-alpha gene promoter polymorphism (-G308A) is associated with schizophrenia, although negative findings have also been reported. To assess whether the TNF-alpha gene promoter variants including -G308A could be implicated in vulnerability to schizophrenia, we conducted a case-control association analysis (265 cases and 424 controls) and the transmission disequilibrium test (TDT) analysis (83 trios) for four polymorphisms (-G238A, -G308A, -C857T and -T1031C) in Japanese subjects. In a case-control analysis, there was no significant association between the promoter polymorphisms or haplotypes in the TNF-alpha gene and schizophrenia. In the TDT analysis, we also did not observe transmission distortion. Our results suggest that the above four polymorphisms in the promoter region of the TNF-alpha gene appear not to confer increased susceptibility for schizophrenia in a Japanese population.
Assuntos
Povo Asiático/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Esquizofrenia/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Alelos , Povo Asiático/psicologia , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnósticoRESUMO
OBJECTIVE: To compare long-term survival rates and causes of death in community-dwelling elderly with and without depression using the International Research Diagnostic Criteria administered by a psychiatrist. METHOD: From 1985 to 2000, we prospectively examined Japanese persons (N = 920) aged 65 years or older. Cases with depression (n = 158) and a control sample without depression (N = 762) were evaluated. The main outcome variables were survival rates and causes of mortality. RESULTS: By 2000, 61% of the subjects with depression had died. By contrast, 48% had died in the control group at the completion of the 15-year follow-up. Using age-adjusted Kaplan-Meier survival analysis, we found a hazard ratio (HR) of 1.49 (95% confidence interval [CI] 1.16-1.89) for mortality in the depressed group compared with controls (p = .0009). Importantly, in female subjects with depression, the HR was 1.55 (95% CI 1.16-2.07; p = .002). In males with depression, by contrast, the HR (1.34) was not significant (95% CI 0.84-2.13; p = .19). Significantly more subjects died of cerebrovascular disorders, malignant tumors, respiratory disorders, or suicide after the onset of depression compared with controls (p < .05). CONCLUSIONS: Depression appears to be associated with a significant increase in the risk of mortality among elderly Japanese subjects, particularly in females. The elderly with a diagnosis of depression may be at an elevated risk of mortality owing to cerebrovascular disorder, malignant tumors, respiratory disorders, or suicide. These prospective data provide a new quantitative insight on gender differences and the long-term public health significance of depression among the community-dwelling elderly.
Assuntos
Transtorno Depressivo/complicações , Transtorno Depressivo/mortalidade , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/mortalidade , Transtorno Depressivo/epidemiologia , Feminino , Cardiopatias/complicações , Cardiopatias/mortalidade , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Neoplasias/complicações , Neoplasias/mortalidade , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Doenças Respiratórias/complicações , Doenças Respiratórias/mortalidade , Fatores Sexuais , Suicídio/estatística & dados numéricos , Taxa de SobrevidaRESUMO
UNLABELLED: This study investigated effects of the 3435 C>T genotype of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1, MDR1) gene on the steady-state plasma concentration of fluvoxamine (FLV). METHODS: Sixty-two psychiatric patients were treated with different doses (50, 100, 150, and 200 mg/d) of FLV. Blood samples were collected after at least 2 weeks of treatment with the same daily dose to obtain steady-state concentrations of FLV, and 3435 C>T genotype was determined by polymerase chain reaction. RESULTS: FLV concentration-to-dose ratio was significantly different among 3435 C>T genotype groups at the 200 mg/d dose (P = 0.019). A post-hoc analysis revealed that FLV concentration-to-dose ratio was significantly higher in the TT genotype group as compared with the CC genotype group at the 200 mg/d dose (median value of concentration-to-dose ratio (ng/mL)/(mg/d), 0.861 vs 0.434, P = 0.026). FLV concentration-to-dose ratio was significantly higher in the CT + TT genotype group than the CC genotype group at the 200 mg/d dose (median value of concentration-to-dose ratio (ng/mL)/(mg/d), 0.618 vs 0.434, P = 0.031). At 50, 100, and 150 mg/d dose, FLV concentration-to-dose ratios were not significantly different among 3435 C>T genotype groups. At 50, 100, and 150 mg/d dose, no significant differences were found in FLV concentration-to-dose ratios between the CT + TT genotype group and CC genotype group. CONCLUSIONS: This study suggests that pharmacokinetics of FLV depend on ABCB1 gene polymorphism only at the 200 mg/d dose.
Assuntos
Fluvoxamina/sangue , Transtornos Mentais/tratamento farmacológico , Transportadores de Ânions Orgânicos/genética , Inibidores Seletivos de Recaptação de Serotonina/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Adulto , Relação Dose-Resposta a Droga , Feminino , Fluvoxamina/uso terapêutico , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Fasciculation and elongation of protein zeta-1 (FEZ1) is a binding partner of Disrupted-In-Schizophrenia 1 (DISC1). Because the DISC1 gene is shown to be a causative gene for psychosis in a Scottish family, the FEZ1 gene may well have importance in mental disease. A previous association study that analyzed polymorphisms of the FEZ1 gene in Japanese patients with schizophrenia and control subjects found significant association of the Asp123Glu polymorphism with schizophrenia. In the present study, we examined two polymorphic markers, rs559668 and rs597570 (Asp123Glu), in the FEZ1 gene to confirm the association in 1920 Japanese patients with schizophrenia and 1920 control subjects. The power to detect an association was more than 0.98. However, we did not detect genotypic associations of either of these two single nucleotide polymorphisms with schizophrenia (p=1 and 0.79, respectively). We concluded that the missense mutation Asp123Glu of the FEZ1 gene is unlikely to play a substantial role in the genetic susceptibility to schizophrenia.