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1.
Higher serotonin transporter availability in early‐onset obsessive–compulsive disorder patients undergoing escitalopram treatment: A [11C]DASB PET study
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Junhee Lee Bo‐Hyung Kim Euitae Kim Oliver D. Howes Kang Ik Kevin Cho Youngwoo Bryan Yoon Jun Soo Kwon 《Human psychopharmacology》2018,33(1)
Objective
Early‐onset obsessive–compulsive disorder (EOCD) and late‐onset obsessive–compulsive disorder (LOCD) are distinct subtypes of obsessive–compulsive disorder (OCD). OCD patients are treated with serotonin reuptake inhibitors, but the difference in serotonin transporter (SERT) availability between medicated EOCD and LOCD is unexplored yet.Methods
Six EOCD and 6 LOCD patients were enrolled. They underwent serial [11C]DASB positron emission tomography scans during maintenance therapy with escitalopram, and their plasma concentration of escitalopram was measured simultaneously with the scan. Then, the drug‐free binding potential of SERT was calculated by pharmacokinetic–pharmacodynamic modelling.Results
In comparison with LOCD patients, SERT availability was significantly higher in the putamen of EOCD patients (U = 4, p = .026), but not in the caudate nucleus (U = 14, p = .589), thalamus (U = 16, p = .818), and dorsal raphe nucleus (U = 7, p = .093). Binding potential of putamen showed a negative correlation (r = ?.580, p = .048) with age of onset of the disease, but not with the Yale–Brown Obsessive Compulsive Scale scores.Conclusions
These findings indicate that the earlier the age of onset of OCD, the less serotonergic pathology there is and that this difference remains even after long‐term serotonin reuptake inhibitor treatment. Clinically, it might suggest that nonserotonergic treatments would be a better option for EOCD patients. 相似文献2.
3.
PPARD rs2016520 polymorphism affects repaglinide response in Chinese Han patients with type 2 diabetes mellitus
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Jin‐Fang Song Tao Wang Jing Zhu Xue‐Yan Zhou Qian Lu Hao Guo Fan Zhang Yan Wang Wei Li Dan‐Dan Wang Ya‐Wen Cui Dong‐Mei Lv Xiao‐Xing Yin 《Clinical and experimental pharmacology & physiology》2015,42(1):27-32
Repaglinide is a short‐acting insulin secretagogue, which often results in considerable interindividual variability in therapeutic efficacy when widely used in a clinical setting. Among various reasons under discussion is genetic polymorphism, especially the genes related to insulin secretion and resistance. Recent studies have described the importance of PPARD in regulating the secretion and resistance of insulin. However, little is known about the impacts of PPARD genetic polymorphism on the efficacy of repaglinide. Therefore, the current study was designed to investigate the associations of PPARD rs2016520 polymorphism with type 2 diabetes mellitus (T2DM) susceptibility and repaglinide therapeutic efficacy in Chinese Han T2DM patients. A total of 338 T2DM patients and 200 healthy subjects were genotyped for PPARD rs2016520 polymorphism by polymerase chain reaction–restriction fragment length polymorphism assay. A total of 84 patients with the same genotypes of CYP2C8*3 139Arg and OATP1B1 521TT were randomized to orally take repaglinide for 8 weeks. Then the pharmacodynamic parameters of repaglinide and biochemical indicators were determined before and after repaglinide treatment. No significant difference was found in either allelic frequency (P = 0.298) or genotype distribution (P = 0.151) of PPARD rs2016520 between T2DM patients and healthy subjects. However, T2DM patients carrying genotype TC showed a significantly lower increase in postprandial serum insulin (mU/L) than those with wild‐type TT (P < 0.05). These findings suggest that PPARD rs2016520 polymorphism might influence the therapeutic effect of repaglinide rather than T2DM susceptibility in Chinese Han T2DM patients. 相似文献
4.
Pharmacogenetics of Risperidone‐Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder
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Chonlaphat Sukasem Natchaya Vanwong Pornpen Srisawasdi Nattawat Ngamsamut Nopphadol Nuntamool Yaowaluck Hongkaew Apichaya Puangpetch Bhunnada Chamkrachangpada Penkhae Limsila 《Basic & clinical pharmacology & toxicology》2018,123(1):42-50
The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body‐weight and height. Genotyping was performed by TaqMan real‐time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852) and *41 (rs28371725), ATP‐binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642) and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag‐SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) ‐2548G>A (rs7799039), ghrelin gene (GHRL) ‐604G>A (rs27647) and brain‐derived neurotrophic factor (BDNF) 196G>A (rs6265)). Drug levels were analysed by liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The results revealed that 5 (5.62%) patients presented with hyperglycaemia. Insulin resistance was detected in 15 (16.85%) patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (p = 0.051 and p = 0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (p = 0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results. 相似文献
5.
Polymorphisms in the promoter region of the dimethylarginine dimethylaminohydrolase 2 gene are associated with prevalence of hypertension 总被引:1,自引:0,他引:1
Renke Maas Jeanette Erdmann Nicole Lüneburg Jan Stritzke Edzard Schwedhelm Christa Meisinger Annette Peters Joachim Weil Heribert Schunkert Rainer H. Bger Wolfgang Lieb 《Pharmacological research》2009,60(6):488
Infusion of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) causes an elevation of blood pressure and depression of cardiac output. Polymorphisms in the promoter region of the ADMA-degrading enzyme dimethylarginine dimethylaminohydrolase 2 (DDAH2) gene have been associated with elevated ADMA concentrations and adverse outcomes in critically ill patients. We hypothesized that two DDAH2 promoter -1151 A/C and -449 G/C polymorphisms (rs805304 and rs805305) will be associated with blood pressure levels, hypertension prevalence and measures of cardiac structure and function in the general population.
Methods and results
We genotyped rs805304 and rs805305 in 783 participants of the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg S3 study. Plasma ADMA concentrations did not differ by rs805304 and rs805305 genotypes. Both polymorphisms were associated with a higher prevalence of hypertension. The odds ratio (adjusted for age, gender and body mass index) for hypertension was 1.70 (95%CI: 1.22–2.36: p = 0.002) for those homozygous (n = 348) for the -1151A allele and 1.80 (95%CI: 1.29–2.49, p < 0.001) for individuals homozygous for the -449G allele (n = 350). However, both polymorphisms were not related to measures of cardiac structure and function (left ventricular [LV] mass, LV wall thickness, LV end-diastolic diameter, ejection fraction, E/A ratio, isovolumetric relaxation time) in multivariable-adjusted models.Conclusion
The present study indicates that the -1151 A/C and -449 G/C polymorphisms in the DDAH2 promoter region are not related to plasma ADMA levels or measures of cardiac structure and function but are associated with an increased prevalence of hypertension. The mechanisms of this association need further investigation. 相似文献6.
Ram Lakhan Ritu Kumari Usha K. Misra Jayanti Kalita Sunil Pradhan & Balraj Mittal 《British journal of clinical pharmacology》2009,68(2):214-220
AIMS
To evaluate sodium channel genes as candidates for epilepsy susceptibility and their role in therapeutic efficacy, we screened coding single-nucleotide polymorphism of SCN1A p. Thr 1067 Ala or c.3184 A→G (rs2298771) and SCN2A p.Arg19Lys or c.56 G→A (rs17183814) in north Indian epilepsy patients.METHODS
The genotyping was performed in 160 control subjects and 336 patients with epilepsy, of whom 117 were drug resistant and 219 were drug responsive. Therapeutic drug monitoring for phenytoin, carbamazepine, phenobarbital and valproate was also performed in 20% of the patients to confirm compliance.RESULTS
AG genotype of SCN1A 3184 A→G polymorphism was significantly higher and associated in epilepsy patients [P= 0.005; odds ratio (OR) 1.76, 95% confidence interval (CI) 1.19, 2.61], whereas A variant of SCN2A c.56 G→A was associated with multiple drug resistance in north Indian patients with epilepsy (P= 0.03; OR 1.62, 95% CI 1.03, 2.56).CONCLUSIONS
Overall, results indicate a differential role of genetic polymorphisms of sodium channels SCN1A and SCN2A in epilepsy susceptibility and drug response. 相似文献7.
Rationale Aripiprazole acts as a partial agonist at dopamine D2 and D3 and serotonin 1A receptors and as an antagonist at serotonin
2A receptors (HTR2A). Since aripiprazole acts as an antagonist at HTR2A, genetic variants of HTR2A may be important in explaining
variability in response to aripiprazole.
Objectives This study investigated whether the efficacy of aripiprazole can be predicted by functional HTR2A A-1438G/T102C polymorphisms
(rs63311/rs6313) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia.
Materials and methods After hospitalization, the patients (n = 128) were given a 4-week course of aripiprazole. Patients were genotyped for HTR2A A-1438G/T102C polymorphisms via the
restriction fragment length polymorphism method. Clinical factors such as gender, age, duration of illness, education level,
diagnostic subtype, and medication dosage were noted as well. The researchers measured psychopathology biweekly, using the
Positive and Negative Syndrome Scale (PANSS). A mixed model regression approach (SAS Proc MIXED) was used to analyze the effects
of genetic and clinical factors on PANSS performance after aripiprazole treatment.
Results We found that the GG/CC genotype group of HTR2A A-1438G/T102C polymorphisms predicts poor aripiprazole response specifically
for negative symptoms. In addition, the clinical factors, including dosage of aripiprazole, age, duration of illness, and
diagnostic subtype, were found to influence PANSS performance after aripiprazole treatment.
Conclusions The data suggest HTR2A A-1438G/T102C polymorphisms may predict negative symptoms performance upon aripiprazole treatment in
schizophrenic patients as modified by clinical factors. 相似文献
8.
Xiao-long WANG Ou LIU Yan-wen QIN Hong-jia ZHANG Yi LV 《Acta pharmacologica Sinica》2014,35(3):351-355
Aim: Thoracic aortic dissection (TAD) is the most common life-threatening disorder, and a shifted balance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is involved in TAD pathogenesis. The aim of this study was to evaluate the association of 4 single-nucleotide polymorphisms (SNPs) in MMP-9 and TIMP-3 genes with TAD risk in Chinese Han population. Methods: A total of 206 Chinese patients with TAD and 180 controls were included in this study. Four SNPs (rs3918249, rs2274756, rs9609643 and rs8136803) were genotyped using high-throughput MALDI-TOF mass spectrometry. Allele and genotype association analyses were conducted using PLINK. Results: All the 4 SNPs resulted in Hardy-Weinbergl equilibrium in patients and controls. The G allele frequency for the MMP-9 SNP rs2274756 was significantly higher in female TAD patients than in female controls (P=0.0099). Moreover, after adjusting for traditional cardiovascular risk factors (sex, age, hypertension, dyslipidemia, diabetes and smoking habit), the rs2274756 polymorphism (odds ratio: 0.30; 95% confidence interval: 0.11 to 0.79, P--0.015) resulted in an independent susceptibility factor for TAD in females. No associations were found between the other SNPs and TAD. Conclusion: The results provide strong evidence for an association between MMP-9 SNP rs2274756 and female TAD risk in Chinese Han population. 相似文献
9.
ABCB1 and CYP2D6 polymorphisms and treatment response of psychotic patients in a naturalistic setting
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Georgios Papazisis Antonios Goulas Alexios Sarrigiannidis Stavroula Bargiota Diomidis Antoniadis Nikolaos Raikos Emmanouela Basgiouraki Vasileios P. Bozikas Georgios Garyfallos 《Human psychopharmacology》2018,33(1)
Objectives
The aim of our study was to examine the association between ABCB1 polymorphisms G2677T/A (rs2032582) and C3435T (rs1045642) and common CYP2D6 variants, with the response to antipsychotic treatment of psychotic patients, in a naturalistic setting, in Greece.Methods
One hundred patients suffering from schizophrenia and other psychotic disorders were included in the study. Dosages were normalized to chlorpromazine equivalents. Response following 1 month of treatment was assessed as either a continuous variable, using the distribution of the corrected Positive and Negative Syndrome Scale percent change, or as a dichotomous variable defined as the number of patients scoring ≥30% from the corrected baseline Positive and Negative Syndrome Scale score. Genotyping was achieved with established polymerase chain reaction–restriction fragment length polymorphism methods.Results
With response treated as a continuous variable, the homozygous recessive rs2032582 genotypes (TT) who were simultaneously carriers of a loss‐of‐function CYP2D6 allele (*4 or *5) responded significantly worse than the rest of the patients. Comparison of genotype frequencies revealed a statistically significant association of the above combination. No significant association between chlorpromazine equivalents and the tested genotypes was detected.Conclusion
We have detected a possible interaction between ABCB1 and CYP2D6 in affecting response of psychotic patients to drug treatment, in a naturalistic setting. 相似文献10.
11.
Qiong Huang Ji-Ye Yin Xing-Ping Dai Jing Wu Xiang Chen Cai-Shu Deng Min Yu Zhi-Cheng Gong Hong-Hao Zhou Zhao-Qian Liu 《European journal of clinical pharmacology》2010,66(12):1207-1215
Objective
Genome-wide association studies (GWASs) identified that SLC30A8 genetic polymorphism was a risk of type 2 diabetes mellitus (T2DM) in several populations. This study aimed to investigate whether the SLC30A8 rs13266634 and rs16889462 polymorphisms were associated with T2DM susceptibility and repaglinide therapeutic efficacy in Chinese T2DM patients. 相似文献12.
Abnormal phospholipid metabolism in the brain plays an important role in neuropsychiatric diseases. Phospholipase A2 (PLA2)
is a crucial element for normal neuro-physiological function. This study aims to investigate the genetic association between
the polymorphism of cytosolic phospholipase A2 (cPLA2) family genes and schizophrenia among Han Chinese in the northern part
of China. The polymerase chain reaction-based ligase detection reaction (PCR-LDR) was applied to detect the genotype ten single
nucleotide polymorphisms (SNPs) of cPLA2 family genes among 201 pedigrees consisting of fathers, mothers and affected offsprings
with schizophrenia. The pedigrees were collected from 2000 to 2006. Haplotype relative risk (HRR) test, transmission disequilibrium
test (TDT), haplotype transmission analysis and multiple locus analysis were conducted to analyze the genotyping data. The
genotypic frequency of cPLA2 gene did not deviate from Hardy-Weinberg equilibrium either in case or control group. HRR and
TDT showed that the ten SNPs were not associated with schizophrenia (P > 0.05). Analysis for haplotype transmission showed that no haplotype system was associated with schizophrenia (P > 0.05). The conditioning on allele (COA) and conditioning on gene (COG) tests showed disease associations with the haplotype
of rs2162886-rs1668589, rs891014-rs1668589 and rs2307279-rs7542180 (χ2 = 6.913, P = 0.032; χ2 = 8.393, P = 0.015; χ2= 8.447, P = 0.038). Our data suggest that many loci in the cPLA2 family genes may be associated with schizophrenia. 相似文献
13.
《Human psychopharmacology》2017,32(2)
A recent genome‐wide pharmacogenomics study showed that the rs 7968606 single‐nucleotide polymorphism (SNP) of the ankyrin repeat and sterile alpha motif domain‐containing protein 1B (ANKS1B ) gene approached the threshold of statistical significance. The aim of this study was to determine the association between the rs 7968606 SNP of ANKS1B and the treatment response to amisulpride in schizophrenia patients. In total, 154 participants were enrolled from six university hospitals in Korea. All the subjects were interviewed before and after 6 weeks of amisulpride treatment with the aid of the positive and negative syndrome scale and the clinical global impression–severity scale. Genotyping for the rs 7968606 SNP of ANKS1B was performed in 101 subjects. Both the decrease (t = −2.067, p = 0.041) and improvement rate (t = −1.990, p = 0.049) in the positive and negative syndrome scale general score differed significantly between T‐allele carriers and noncarriers of this polymorphism after 6 weeks of amisulpride treatment. To the best of our knowledge, this is the first genetic association study of the relationship between the rs 7968606 SNP of ANKS1B and the response of schizophrenia patients to treatment with amisulpride. Future larger‐scale studies involving more SNPs of ANKS1B will improve the understanding of the pharmacogenetics underlying the treatment responses to amisulpride. 相似文献
14.
Qi Pei Qiong Huang Guo-ping Yang Ying-chun Zhao Ji-ye Yin Min Song Yi Zheng Zhao-hui Mo Hong-hao Zhou Zhao-qian Liu 《Acta pharmacologica Sinica》2013,34(2):255-261
Aim:
To investigate the influence of peroxisome proliferator-activated receptor γ2 (PPAR-γ2) gene polymorphism rs1801282 and protein tyrosine phosphatase receptor type D (PTPRD) gene polymorphism rs17584499 on the occurrence of type 2 diabetes and pioglitazone efficacy in a Chinese Han population.Methods:
One hundred ninety seven type 2 diabetes patients and 212 healthy controls were enrolled. Among them, 67 type 2 diabetes patients were administered pioglitazone (30 mg/d, po) for 3 months. All the subjects were genotyped for genetic variants in PPAR-γ2 and PTPRD using MALDI-TOF mass spectrometry. Fasting plasma glucose, postprandial plasma glucose, glycated hemoglobin, serum triglyceride, total cholesterol, low-density and high-density lipoprotein-cholesterol were determined.Results:
The PPAR-γ2 gene rs1801282 polymorphism was significantly associated with type 2 diabetes susceptibility (OR=0.515, 95% CI 0.268–0.990) and the PTPRD gene rs17584499 polymorphism was also significantly associated with type 2 diabetes (OR=1.984, 95% CI 1.135–3.469) in a dominant model adjusted for age, gender and BMI. After pioglitazone treatment for 3 months, the type 2 diabetes patients with PPAR-γ2 rs1801282 CG genotypes significantly showed higher differential values of postprandial plasma glucose and serum triglyceride compared with those with rs1801282 CC genotype. The patients with PTPRD rs17584499 CT+TT genotypes showed significantly lower differential value of postprandial plasma glucose compared to those with rs17584499 CC genotype.Conclusion:
Diabetes risk alleles in PPAR-γ2 (rs1801282) and PTPRD (rs17584499) are associated with pioglitazone therapeutic efficacy. 相似文献15.
Case‐control pharmacogenetic study of HCN1/HCN2 variants and genetic generalized epilepsies
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Shu‐Zhi Wu Hua Ye Xiao‐Guo Yang Zhi‐Li Lu Qiang Qu Jian Qu 《Clinical and experimental pharmacology & physiology》2018,45(3):226-233
Epilepsy is a common complex neurological disorder, and some forms are resistant to drug treatment. The HCN1/HCN2 genes encode hyperpolarization‐activated cyclic nucleotide‐gated channels, which play important roles in the electrophysiology of neurons. We investigated the association between HCN1/HCN2 variants and drug resistance or the risk of genetic generalized epilepsies (GGEs). We used matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry to assess nine variants of HCN1/HCN2 in 284 healthy participants and 483 GGEs (279 drug‐responsive, 204 drug‐resistant). Frequencies of HCN2 rs7255568 and rs3752158 G alleles differed in GGEs and in controls (P = .039, P = .027, respectively). The frequency of HCN2 haplotype (CAC) was higher in patients than controls (P = .046). The frequency of the HCN1 rs10462087 CC+CT genotype was lower in patients with childhood absence epilepsy (CAE) than controls (P = .047). Rs7255568 was associated with the risk of CAE (P = .028) and juvenile myoclonic epilepsy (JME) (P = .02). Rs3752158 was associated with the risk of generalized tonic‐clonic seizures, JME, and febrile seizures (all P < .05). The frequency of the HCN2 haplotype (CAC) was higher in patients with JME (P = .015) and in those with febrile seizures (P = .024) than in controls. No significant association was found between HCN1/HCN2 alleles, genotypes or haplotypes, and drug resistance in patients. After Bonferroni's multiple comparisons correction, only the HCN2 rs3752158 C allele and GC+CC genotype frequencies in patients with JME were higher than those in controls (19.2% vs 11.6%, odds ratio (OR) = 1.71, 95% CI = 1.18‐2.32), P = .004 < 0.05/9; 36% vs 22.2%, OR = 1.62(1.18‐2.23), P = .003 < 0.05/9). Our study suggests that HCN2 rs3752158 is involved in the susceptibility to JME. 相似文献
16.
Merenäkk L Mäestu J Nordquist N Parik J Oreland L Loit HM Harro J 《Psychopharmacology》2011,215(1):13-22
Rationale and objective
Twin studies suggest that substance use initiation in children and adolescents is determined primarily by environmental influences, whereas the establishment of use patterns is strongly controlled by genetic factors. The present study analysed the effects of the serotonin transporter promoter polymorphism [5-HT transporter gene-linked polymorphic region (5-HTTLPR)] and the α2A-adrenoceptor C-1291G genotype (ADRA2A C-1291G) as well as their interaction effects on alcohol, tobacco and drug use from preadolescence to the late adolescence. 相似文献17.
Taro Kishi Tomoko Tsunoka Tsuyoshi Kitajima Tomo Okochi Yoshio Yamanouchi Hiroshi Ujike Toshiya Inada Mitsuhiko Yamada Naohisa Uchimura Ichiro Sora Masaomi Iyo Norio Ozaki Nakao Iwata 《Neuropharmacology》2010,58(2):452-456
Background
Several investigations have reported associations the serotonin 1A (5-HT1A) receptor to schizophrenia and psychotic disorders, making 5-HT1A receptor gene (HTR1A) an adequate candidate gene for the pathophysiology of schizophrenia and methamphetamine (METH)-induced psychosis. Huang and colleagues reported that rs6295 in HTR1A was associated with schizophrenia. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. It may indicate that METH-induced psychosis and schizophrenia have common susceptibility genes. In support of this hypothesis, we reported that the V-act murine thymoma viral oncogene homologue 1 (AKT1) gene was associated with METH-induced psychosis and schizophrenia in the Japanese population. Furthermore, we conducted an analysis of the association of HTR1A with METH-induced psychosis.Method
Using one functional SNP (rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients.Results
Rs878567 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this significance remained after Bonferroni correction. In addition, we detected an association between rs6295 and rs878567 in HTR1A and METH-induced psychosis patients in the haplotype-wise analysis. Although we detected an association between rs6295 and METH-induced psychosis patients, this significance disappeared after Bonferroni correction.Conclusion
HTR1A may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population. However, because we did not perform a mutation scan of HTR1A, a replication study using a larger sample may be required for conclusive results. 相似文献18.
A. P. Rajkumar B. Poonkuzhali A. Kuruvilla A. Srivastava M. Jacob K. S. Jacob 《Psychopharmacology》2012,224(3):441-449
Rationale
Pharmacogenetics of schizophrenia has not yet delivered anticipated clinical dividends. Clinical heterogeneity of schizophrenia contributes to the poor replication of the findings of pharmacogenetic association studies. Functionally important HTR3A gene single-nucleotide polymorphisms (SNPs) were reported to be associated with response to clozapine.Objective
The aim of this study was to investigate how the association between HTR3A gene SNP and response to clozapine is influenced by various clinical predictors and by differing outcome definitions in patients with treatment-resistant schizophrenia (TRS).Methods
We recruited 101 consecutive patients with TRS, on stable doses of clozapine, and evaluated their HTR3A gene SNP (rs1062613 and rs2276302), psychopathology, and serum clozapine levels. We assessed their socio-demographic and clinical profiles, premorbid adjustment, traumatic events, cognition, and disability using standard assessment schedules. We evaluated their response to clozapine, by employing six differing outcome definitions. We employed appropriate multivariate statistics to calculate allelic and genotypic association, accounting for the effects of various clinical variables.Results
T allele of rs1062613 and G allele of rs2276302 were significantly associated with good clinical response to clozapine (p?=?0.02). However, varying outcome definitions make these associations inconsistent. rs1062613 and rs2276302 could explain only 13.8?% variability in the responses to clozapine, while combined clinical predictors and HTR3A pharmacogenetic association model could explain 38?% variability.Conclusions
We demonstrated that the results of pharmacogenetic studies in schizophrenia depend heavily on their outcome definitions and that combined clinical and pharmacogenetic models have better predictive values. Future pharmacogenetic studies should employ multiple outcome definitions and should evaluate associated clinical variables. 相似文献19.
Andrea M. Dlugos Ajna Hamidovic Abraham A. Palmer Harriet de Wit 《Psychopharmacology》2009,206(3):501-511
Background and rationale
We previously found that the intronic norepinephrine transporter gene (SLC6A2) polymorphism rs36017 modulates feelings of elation after administration of 20 mg d-amphetamine in healthy volunteers. 相似文献20.
Wonodi I Gopinath HV Liu J Adami H Hong LE Allen-Emerson R McMahon RP Thaker GK 《Psychopharmacology》2011,218(2):341-345