Taq1A polymorphism in the dopamine D2 receptor gene as a predictor of clinical response to aripiprazole

We investigated whether the clinical response to aripiprazole differed according to the Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene.In this 26-week, prospective, open-label, double-blind, parallel-group study, 90 patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder were recruited and divided into two groups according to their DRD2 genotype (A1A1, n = 14; A1A2+A2A2, n = 76). The efficacy assessment included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression (CGI) scores. Extrapyramidal symptoms were assessed using the Simpson–Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BAS). Plasma prolactin levels were also measured.Patients with the A1A1 genotype showed a more favorable therapeutic response to aripiprazole when assessed using the PANSS ratio. The changes in the SAS score from baseline to week 4 also differed according to the genotype group. There were no significant differences in the changes in the CGI, AIMS, and BAS scores or plasma prolactin level between the two genotype groups.The results suggest an association between the DRD2 Taq1A polymorphism status and the variation in the clinical response to aripiprazole.     

Taq1A polymorphism in the dopamine D2 receptor gene predicts brain metabolic response to aripiprazole in healthy male volunteers

OBJECTIVE: The Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene has been reported to be associated with the pharmacodynamics of antipsychotic drugs. We investigated the metabolic response of glucose in the brain to aripiprazole in relation to the DRD2 Taq1A polymorphism. METHODS: Twenty healthy male volunteers were recruited and were divided into two groups of 10 participants, according to their DRD2 genotypes (A1A1, n=10; A2A2, n=10). The volunteers received single oral doses of aripiprazole (10 mg) and a placebo, following a single-blind, placebo-controlled, randomized, two-way crossover study design. Brain glucose metabolism was assessed using positron emission tomography, scanned with 18F-fluorodeoxyglucose 12 h after the administration of the drug or placebo. RESULTS: In voxel-based analysis using SPM2, volunteers with the A2A2 genotype showed decreased metabolism in the right middle frontal gyrus, the left middle and inferior frontal gyrus, the right and left inferior temporal gyrus, and the right cingulate gyrus, and increased metabolism in the pons. In contrast, volunteers with the A1A1 genotype exhibited increased metabolism in the right caudate head, and no brain region showed decreased metabolism. In a region-of-interest analysis, significant interactions between drug and genotype were observed in the right medial orbitofrontal gyrus and the left caudate nucleus. CONCLUSIONS: This suggests that DRD2 Taq1A polymorphism status may be associated with the clinical response to aripiprazole.     

Dopaminergic drug response and the genotype (Taq IA polymorphism) of the dopamine D2 receptor

The genotype of the receptor with which a particular drug interacts may be a between- subject factor that modifies the pharmacodynamic and consequently the therapeutic response to drugs. Subjects with A1 allele (Taq IA restriction fragment length polymorphism) of the gene encoding for the dopamine D2 receptor (DRD2) seem to express lower number of DRD2 compared to subjects who do not have this allele. We investigated whether subjects homozygous for the A1 allele of the DRD2 gene have decreased response to DRD2 stimulation by apomorphine when compared with those homozygous for the A2 allele. Two hundred and two Caucasian subjects were genotyped for DRD2 Taq IA polymorphism, 6.9 % had the genotype A1A1 and 65% A2A2. Nine homozygous subjects/group were selected for the apomorphine study. Five, 10 and 20 &mgr;g/kg of apomorphine were administered subcutaneously according to a randomized crossover design. The main pharmacodynamic criterion was the plasma growth hormone increase induced by apomorphine. Secondarily, we measured oral temperature responses and yawns in response to apomorphine. Plasma apomorphine concentrations were similar for the two matched and only genotypically different groups. Apomorphine dose-dependently increased serum growth hormone concentration, and significant effect of time, dose by time interaction but no effect of genotype or genotype by dose interaction was shown. Apomorphine decreased body temperature, significant effect of dose, time, dose by time interaction but no effect of genotype or genotype by dose interaction were observed. The number of apomorphine-induced yawns increased dose-dependently but no significant difference between groups occurred. Thus, in this study apomorphine-induced responses were not modified by DRD2 Taq IA polymorphism although the power of the study could be insufficient to detect subtle differences.     

The relationship between dopamine D2 receptor polymorphism at the Taq1 A locus and therapeutic response to nemonapride, a selective dopamine antagonist, in schizophrenic patients

Previous studies have demonstrated that subjects with one or two A1 alleles of dopamine D2 receptor (DRD2) polymorphism at the Taq1 A locus have lower DRD2 density than those with no A1 allele. The present study aimed to examine whether the Taq1 A DRD2 genotypes are related to therapeutic response to nemonapride, a selective dopamine antagonist, in schizophrenic patients. The subjects were 25 acutely exacerbated schizophrenic inpatients who had received no medication for at least 1 month before the study. The fixed dose (18 mg/day) of nemonapride was administered to each patient for 3 weeks. The clinical status was prospectively monitored by the Brief Psychiatric Rating Scale (BPRS) before, and 3 weeks after, the treatment. The Taq1 A genotypes (A1 and A2 alleles) were determined by the polymerase chain reaction method. Three patients were homozygous for the A1 allele, 11 were heterozygous for the A1 and A2 alleles, and 11 were homozygous for the A2 allele. The patients with one or two A1 alleles (n = 14) showed significantly higher percentage improvement in total BPRS and positive symptoms than those with no A1 allele (n = 11) after 3-week treatment while the percentage improvement in other subgrouped symptoms (negative, anxiety-depression, excitement and cognitive symptoms) was similar between the two genotype groups. The present results suggest that the Taq1 A DRD2 polymorphism is related to early therapeutic response to nemonapride in schizophrenic patients, possibly by modifying the efficiency of DRD2 antagonism of the drug in the central nervous system.     

The relationship between the therapeutic response to risperidone and the dopamine D2 receptor polymorphism in Chinese schizophrenia patients

Antipsychotic drugs exert both therapeutic and adverse effects through dopamine D2 receptor (DRD2) antagonism. Genetic variants of this receptor may be responsible for individual variations in neuroleptic response and may therefore be useful in predicting response. In this study we evaluated the role of six polymorphisms of the DRD2 gene in 125 risperidone-treated Chinese schizophrenia patients following the hypothesis that variation in the DRD2 gene could affect drug response. Response was categorized as a change of >40% on the Brief Psychiatric Rating Scale (BPRS). Our results show that genotyping A-241G may help to predict the efficacy of risperidone treatment on the basis that patients with the A allele showed greater improvement than those with the G allele on the overall BPRS (chi2=7.19, p=0.007, p=0.031 after correction by the program SNPSpD), while other polymorphisms, including -141C Ins/Del, TaqIB, rs1076562, T939C and TaqIA, did not show any association with the response to risperidone. These data suggest that the DRD2 A-241G polymorphism or, alternatively, another genetic variation that is in linkage disequilibrium, may influence response to risperidone in schizophrenia patients.     

多巴胺D2受体基因多态性与利培酮致高泌乳素血症的相关性

目的:探讨多巴胺D2受体基因多态性与利培酮致高泌乳素血症的相关性.方法:纳入115例接受单一利培酮治疗的精神分裂症患者为研究对象,于治疗前后测定血清泌乳素水平,根据泌乳素水平＞25 ng·mL-1和≤25 ng· mL-1,分为高泌乳素血症(hyperprolactinemia,HPRL)组和泌乳素水平正常(norma...     

Prolactin response to nemonapride, a selective antagonist for D2 like dopamine receptors, in schizophrenic patients in relation to Taq1A polymorphism of DRD2 gene

The dopamine D₂ receptor (DRD2) gene has a Taq1A restriction fragment length polymorphism yielding two alleles, A1 and A2. It has been shown that the subjects with less frequent allele, the A1 allele, have lower density and diminished function of DRD2 in the striatum, compared to those with no A1 allele. In the present study, the relationship between this polymorphism and prolactin response to nemonapride, an antipsychotic drug with selective and potent DRD2 antagonistic property, was investigated in 25 Japanese schizophrenic inpatients (13 males, 12 females). The daily dose of nemonapride was fixed at 18 mg, and the duration of treatment was 3 weeks. Taq1A genotypes were determined by the polymerase chain reaction method. Plasma prolactin concentrations were measured by enzyme immunoassay. The subjects were divided into four subgroups by gender and Taq1A genotypes, i.e., six males and eight females with the A1 allele, seven males and four females with no A1 allele. The Δprolactin (change from the pretreatment concentration) at 1 week was significantly (P<0.05) higher in females with the A1 allele (78.0±47.1 ng/ml) than in males with the A1 allele (33.4±14.0 ng/ml) or with no A1 allele (29.5±24.8 ng/ml). In addition, Δprolactin at 3 weeks was significantly (P<0.05) higher in females with the A1 allele (98.1±67.9 ng/ml) than in females with no A1 allele (33.4±24.6 ng/ml), males with the A1 allele (29.1±17.3 ng/ml) or males with no A1 allele (28.6±22.0 ng/ml). The present study thus suggests that female patients with the A1 allele show a greater prolactin response to nemonapride, who may have a high risk for adverse effects associated with neuroleptic-induced hyperprolactinemia. Received: 27 July 1999 / Final version: 9 December 1999     

Role of silent polymorphisms within the dopamine D1 receptor associated with schizophrenia on D1–D2 receptor hetero-dimerization

Within the coding region of the dopamine D₁ receptor (D₁R), two synonymous polymorphisms, D₁R^G198A and D₁R^G1263A, have been identified and postulated to correlate with the schizophrenia phenotype. Binding studies revealed that the density of these genetic variants was much lower than the density of wild type D₁R in the human embryonic kidney (HEK) 293 cell line, used as a model system. From the data obtained using MFOLD software it is apparent that the G198A mutation has a greater impact on the secondary structure of the mRNA, which may affect its translation. However, the G1263A mutation is localized within the serine 421 codon of D₁R, which is predicted to be a potential site of phosphorylation according to the PHOSIDA database.In order to determine whether the studied synonymous polymorphisms influence the process of dopamine D₁–D₂ receptors hetero-dimerization, we employed fluorescence resonance energy transfer (FRET) technology. The dopamine D₂ receptor (D₂R) was tagged with cyan fluorescence protein and the D₁R and its genetic variants were tagged with yellow fluorescence protein. The degree of D₁–D₂ receptor hetero-dimerization was significantly decreased when genetic variants of D₁R were co-expressed with D₂R. Since the D₁R mutations affected the expression levels of the proteins in the cell membrane without affecting the cellular localization of the receptor proteins, we postulated that the D₁R polymorphisms altered the translation rate and protein structure of the receptor. The altered hetero-dimerization that likely results from the lower expression of these genetic variants of D₁R with D₂R may be partially responsible for the association of both G198A and G1263A polymorphisms with the schizophrenia phenotype.     

Effects of dopamine D1 and dopamine D2 receptor agonists on coronary and peripheral hemodynamics

This study evaluated the coronary dopamine receptors by using the dopamine D1 receptor agonist fenoldopam, dopamine D2 receptor agonist propylbutyldopamine, and their selective antagonists SCH23390 and domperidone. Left circumflex coronary flow (CF), coronary perfusion pressure at constant flow, left ventricular hemodynamics, and total peripheral vascular resistance (TPR) were measured in pentobarbital-anesthetized dogs at constant arterial pressures. At doses of 200, 500 and 5000 nM, both fenoldopam and propylbutyldopamine induced dose-related inotropic effects, as evidenced by maximal dp/dt and cardiac output, an increase in CF, decrease in coronary vascular resistance and a decrease in TPR. Fenoldopam was more potent in its cardiac and coronary effects while propylbutyldopamine was more potent peripherally. On the basis of dosage used, the positive inotropic effects of fenoldopam and propylbutyldopamine were much weaker than dopamine. After beta-receptor blockade, the inotropic and coronary effects of fenoldopam and propylbutyldopamine were extremely attenuated. Domperidone could largely antagonize the propylbutyldopamine-induced inotropic and coronary effects while SCH23390 showed no significant effect. In addition, under our experimental conditions, the fenoldopam- and propylbutyldopamine-induced decreases in TPR were markedly reduced by SCH23390 and domperidone, respectively. The results indicate that the coronary effects of fenoldopam and propylbutyldopamine result not from a primary coronary vasodilating action, but from vasodilation secondary to positive inotropic effects. Both dopamine D1 and dopamine D2 receptors are involved in the peripheral vascular hemodynamics.     

Effects of repeated treatment with the dopamine D2/D3 receptor partial agonist aripiprazole on striatal D2/D3 receptor availability in monkeys

Rationale

Chronic treatment with dopamine (DA) receptor agonists and antagonists can differentially affect measures of DA D2/D3 receptor number and function, but the effects of chronic treatment with a partial D2/D3 receptor agonist are not clear.

Objective

We used a within-subjects design in male cynomolgus monkeys to determine the effects of repeated (17-day) treatment with the D2/D3 receptor partial agonist aripiprazole (ARI; 0.03 mg/kg and 0.1 mg/kg i.m.) on food-reinforced behavior (n?=?5) and on D2/D3 receptor availability as measured with positron emission tomography (PET; n?=?9).

Methods

Five monkeys responded under a fixed-ratio 50 schedule of food reinforcement and D2/D3 receptor availability was measured before and 4 days after ARI treatment using PET and the D2/D3 receptor-selective radioligand [¹⁸F]fluoroclebopride (FCP). Four additional monkeys were studied using [¹¹C]raclopride and treated sequentially with each dose of ARI for 17 days.

Results

ARI decreased food-maintained responding with minimal evidence of tolerance. Repeated ARI administration increased FCP and raclopride distribution volume ratios (DVRs) in the caudate nucleus and putamen in most monkeys, but decreases were observed in monkeys with the highest baseline DVRs.

Conclusions

The results indicate that repeated treatment with a low-efficacy DA receptor partial agonist produces effects on brain D2/D3 receptor availability that are qualitatively different from those of both high-efficacy receptor agonists and antagonists, and suggest that the observed individual differences in response to ARI treatment may reflect its partial agonist activity.     

Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia.

In 112 schizophrenic patients previously treated with typical neuroleptics, we investigated the putative role of the dopamine D3 receptor gene (DRD3) in tardive dyskinesia (TD). Patients were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS) and were subsequently genotyped for the MscI polymorphism that identifies a serine to glycine substitution in DRD3. A modified analysis of covariance model, which incorporated several clinical risk factors for TD, was utilized to detect differences in TD severity among the various genotypic groups. The glycine allele of DRD3 was found to be associated with typical neuroleptic-induced TD (F[2,95] = 8.25, p < .0005). Higher mean AIMS scores were found in patients homozygous for the glycine variant of the DRD3 gene, as compared to both heterozygous and serine homozygous patients. Although replication is necessary, this finding supports a role for the dopamine D3 receptor in the pathogenesis of TD.     

5-羟色胺2A受体基因多态性与帕罗西汀临床疗效的关联研究

目的 研究中国汉族重性抑郁症(MDD)患者5-羟色胺2A受体基因多态性与帕罗西汀抗抑郁临床疗效之间的关系.方法 117例抑郁症患者给予帕罗西汀(20～50 mg·d-1)治疗8周,用汉密尔顿抑郁量表(HAMD-17)评估临床疗效,聚合酶链式反应(PCR)和限制酶切的方法检测A1438G基因型.结果 有效率、缓解率及不良反应发生率在A1438G不同基因型及等位基因间分布差异无统计学意义(P>0.05);G等位基因携带者睡眠症状改善好.结论 A1438G多态性与帕罗西汀对睡眠症状的改善有关.     

Association between three functional polymorphisms of the dopamine D2 receptor gene and polydipsia in schizophrenia

The underlying pathophysiology of polydipsia in schizophrenia is poorly understood. However, several studies suggest there may be a genetic predisposition to polydipsia, including our previous study demonstrating familial concordance of polydipsia among first-degree relatives with schizophrenia. Antipsychotic medications may contribute to the development of polydipsia and studies show that dopamine D2 receptors are involved in drinking behaviour pathophysiology. Our hypothesis is that polymorphisms in the dopamine D2 receptor gene (DRD2) may confer susceptibility to polydipsia in schizophrenia. We tested for an association between polydipsia in schizophrenia and three functional polymorphisms of DRD2. The three polymorphisms, -141C Ins/Del, Ser311Cys, and TaqIA, were genotyped in patients with polydipsia (n = 64) and in those without polydipsia (n = 91). Of the three polymorphisms, TaqIA was significantly associated with polydipsia [genotype: chi2 = 6.59, df = 2, p = 0.037; allele: chi2 = 6.52, df = 1, p = 0.011, OR 1.81, 95% CI 1.15-2.86]. Haplotype analysis of the three markers found increased significance of the association (global, p = 0.00091). Although based on a relatively small portion of the sample, individual comparison of the common haplotypes showed that haplotype Ins-Cys-A1 was significantly less frequent in patients with polydipsia (p = 0.00082). The present data suggests polymorphisms in DRD2 may confer susceptibility to polydipsia in schizophrenia. To confirm our findings, further studies are warranted on larger samples using more extensive biological measures for diagnosing the polydipsia phenotype.     

抗精神病药物所致体重增加与多巴胺D2受体基因多态性和治疗效应的关联分析

目的　探讨抗精神病药物 (APS)所致体重增加与多巴胺D2 受体 (DRD2 )基因TaqIA多态性和治疗效应之间有无相关。方法　采用PCR RFLP方法分析 117例首发精神分裂症患者DRD2 基因TaqIA多态性 ,APS(氯丙嗪或利培酮 )单药治疗 10周 ,测定患者治疗前后体重和体重指数 (BMI) ,用阳性和阴性症状量表 (PANSS)评定患者治疗前后精神症状 ,并分析BMI变化值与基因型和PANSS减分率的相关性。结果　治疗后患者平均体重变化 (3 15± 3 47)kg或基础体重的(5 6 9± 6 15 ) % ,体重变化的范围为 - 7kg～ 12kg或 - 7 78%～ 32 43% ;患者年龄和基础BMI明显影响BMI变化值 ,差异有显著性 (P =0 0 3)和非常显著性 (P =0 0 0 0 1) ;A1等位基因和PANSS减分率对BMI变化值的影响差异均无显著性 (P >0 0 5 )。结论　DRD2 基因TaqIA多态性不可能是APS所致精神分裂症体重增加的主要遗传因素 ;体重增加不是APS临床治疗效果的指标。     

Effects of dopamine D1 and D2 receptor agonists and antagonists on bombesin-induced behaviors

Central administration of bombesin elicits excessive grooming and locomotor activity in rats. This grooming activity is one characterised by vigorous scratching of the face, nape and body flanks. Pretreatment with the D1 receptor antagonist SCH 23390 inhibited the expression of bombesin-induced activity with grooming being more inhibited than locomotion. Blockade of D2 receptors with eticlopride significantly attenuated the behavioral responses to bombesin. When SCH 23390 and eticlopride were administered concurrently, it was apparent that D1 blockade had a greater effect on grooming and D2 blockade a larger effect on locomotion. Stimulation of D1 receptors by SKF 38393 elicited non-stereotyped locomotor activity and a form of grooming behavior characterised by vigorous washing of the face and ventral body surfaces. Co-administration of bombesin and SKF 38393 resulted in a form of grooming which resembled that elicited by SKF 38393 alone. The specific D2 agonist PPHT elicited a form of locomotion characterised by a downward oriented head posture and slow ambulatory activity around the cage perimeter. Co-administration of PPHT and bombesin resulted in a complete suppression of bombesin-induced behaviors and was largely indistinguishable from activity observed under PPHT alone conditions. These data implicate both D1 and D2 receptor based mechanisms in the modulation/mediation of the behavioral effects of bombesin. Part of the bombesin-induced behavioral effects may be explained by (indirect) activation of (a) dopamine system(s).     

阿立哌唑与奥氮平对首发精神分裂症急性期疗效及对催乳素的影响

目的:研究奥氮平和阿立哌唑对首发精神分裂症患者急性期疗效及对血中催乳素(PRL)水平的影响。方法:65例首发精神分裂症患者分为奥氮平组42例[男21例,女21例;年龄(23.9±6.6)岁]和阿立哌唑组23例[男11例,女12例;年龄(23.7±7.2)岁]。分别给予奥氮平和阿立哌唑单药治疗4周。在基线和4周末,分别用阳性症状与阴性症状量表(PANSS)、临床总体印象量表-疗效总评(CGI-I)评定疗效。放射免疫法测定血清催乳素水平。结果:治疗4周末,奥氮平组PANSS总分(59±13)较基线(103±15)明显下降;阿立哌唑组PANSS总分(60±18)较基线(101±13)明显下降,差异具有统计学意义(P<0.01);治疗后,两组间CGI-I评分比较差异无统计学意义(P>0.05);治疗前后奥氮平组和阿立哌唑组之间PANSS量表阴性因子和一般精神病理因子分量表分的变化有统计学意义的差异(P<0.01)。奥氮平组治疗后催乳素(418±362)uIu/mL和基线(547±382)uIu/mL比较虽有所下降,但差异无统计学意义(P>0.05);阿立哌唑组治疗后催乳素(123±114)uIu/mL较基线(351±299)uIu/mL下降,差异具有统计学意义(P<0.01)。结论:阿立哌唑治疗首发精神分裂症患者急性期总体疗效和奥氮平相当。奥氮平对一般精神病理症状的改善优于阿立哌唑,阿立哌唑对阴性症状的改善优于奥氮平。阿立哌唑可能降低首发精神分裂症患者血催乳素水平。     

Effects of dopamine D1 and D2 receptor antagonists on oral activity in rats

Two experiments were performed to investigate the actions of the selective D1 blocker SCH 23390 and the selective D2 blocker sulpiride, on oral movements in rats; these were quantified by a human observer scoring vacuous chewing movements (VCMs), jaw tremor and head movements, as well as a computer analysis system which measured the amplitude and slope of each movement. In the first experiment it was found that both SCH 23390 and sulpiride decreased VCMs and head movements in a dose-dependent manner, with SCH 23390 more effectively decreasing head movements and sulpiride more effectively decreasing VCMs. In a second experiment, the effectiveness of these two drugs in blocking the actions of selective D1 (SKF 38393) and D2 (LY 171555) agonists was studied. The SKF 38393-induced increase in computer-scored movement was attenuated by both sulpiride and SCH 23390, whereas the LY 171555-induced decrease in VCMs was attenuated by sulpiride, while SCH 23390 exacerbated it. These findings, together with our earlier results, suggest a simple relationship of D1 receptors to oral movement, with increased activation resulting in increased oral movement and decreased activation resulting in decreased oral movement. The relationship of D2 receptors to oral movement shows a more complex pattern, with both stimulation and blockade decreasing oral movement. One possibility may be the existence of more than one subpopulation of D2 receptors mediating these effects.     

Association study of four dopamine D1 receptor gene polymorphisms and clozapine treatment response

Dopamine D1 receptors (D1) in the prefrontal cortex have been implicated in the modulation of cognitive processes as well as both positive and negative symptoms of schizophrenia. Therefore pharmacologic agents with potent D1 effects such as clozapine may influence the symptoms of schizophrenia (SCZ). Genetic variation in the D1 receptor gene (DRD1) may help to explain some of the variability in patient response to antipsychotics (APs). This study investigates the effect of four single nucleotide polymorphisms (SNPs) in DRD1 on clozapine response in two distinct SCZ populations (Caucasian and African American) refractory or intolerant to conventional APs. This study included 183 Caucasian and 49 African American schizophrenics diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (revised third or fourth edition). Genotyping was determined by 5'-exonuclease fluorescence assays. Within each population genotype, allele, allele +/- and haplotype frequencies were compared against dichotomous and quantitative measures of treatment response. Linkage disequilibrium analysis was also performed. In the Caucasian sample, no associations were observed for individual SNP tests. However, a rare three-marker haplotype predicted poor response. In the African American sample, the rs265976 variant and another three-marker haplotype were associated with cLozapine response. Although we did not find an association between the rs4532 SNP (-48 A/G, recognized by a DdeI restriction cut site) and cLozapine response as reported by Potkin et al. (2003), a trend in the same direction was observed as well. Our findings suggest that the rs4532 SNP may have a small effect if any. Further studies in larger, independent samples are required to validate these findings.