5-HT2c受体基因多态性与抗精神病药物疗效的关联分析

目的探讨5-HT2c受体基因-759C／T、-697G／C多态性与非典型抗精神病药物治疗首发精神分裂症患者疗效的关系。方法179例首发精神分裂症患者接受利培酮或氯氮平治疗8周,以PANSS量表评定患者的症状改善,以聚合酶链式反应（PCR）扩增及限制性片段长度多态性（RFLP）技术,检测5-HT2C受体基因-759C／T及-697G／C多态性。结果女性患者携带-759C等位基因的总疗效较-759T好,C／C基因型的阴性症状改善及总疗效优于C／T及T／T基因型,没有发现男性组和女性组697C／G各基因型与疗效存在关联。结论5-HT2。受体基因-759C／T基因多态性可能与非典型抗精神病药的疗效相关,C／C基因型和等位基因C可能是总体疗效好和阴性症状疗效好的预测因子。5-HT孙受体基因_1597G／C基因多态性可能与非典型抗精神病药的疗效无关。     

5—羟色胺2A受体基因多态性与精神分裂症阳性症状相关性研究

目的:探讨中国汉族人群精神分裂症阳性症状患者与5-羟色胺2A受体基因T102C多态性之间的关系.方法:采用AmP-RFLP方法,检测精神分裂症患者对照组的5-HT2A受体基因频率分布.结果:精神分裂症阳性症状患者5-HT2A受体基因型频率,等位基因频率与对照组无明显差异,但有精神病家族史精神分裂症患者A1A1基因型频率,A1等位基因频率明显高于对照组.结论:实验结果提示,5-HT2A受体基因多态性与有精神病家庭史的精神分裂症阳性症状患者密切相关.A1等位基因可能是精神分裂症发病的风险基因之一.     

5-羟色胺2A、2C受体基因多态性与难治性抑郁症的关联分析

目的：探讨中国汉族人群难治性抑郁症患者5-羟色胺2C（5-HT2C）受体基因与5-HT2A受体基因之间的关联性。方法：应用聚合酶链式反应（PCR）扩增技术及限制性片段长度多态性（RFLP）分别测定77例难治性抑郁症患者及90名正常人5-HT2C受体基因和5-HT2A受体基因的基因型和等位基因。结果：难治性抑郁症组-759野生型频率明显低于对照组。-759野生型／-697野生型频率也显著低于正常;患者组5-HT2A受体基因型杂合子组的-759野生型、-697野生型以及-759野生型／-697野生型均明显高于纯合子组。结论：-759野生型可能与难治性抑郁症的发病存在一定的相关性;5-HT2A受体基因与5-HT2C受体基因相互之间对难治性抑郁症易患性可能存在一定的关系。     

5-羟色胺2A受体基因多态性与利培酮治疗中国首发精神分裂症患者疗效关联

背景5-羟色胺2A受体基因已经证实为精神分裂症的候选易感基因,因为阐明其作为非典型抗精神病药物重要作用靶点减轻阴性症状已引起业界倍加关注.本研究试图探讨(1)5-HT2A受体基因T102C多态性在不同临床亚型之间等位基因和基因型频率的关系,(2)5-HT2A受体基因T102C在利培酮高剂量组和低剂量组之间基因型和等位基因分布频率的关系,(3)5-HT2A受体基因T102C多态性在治疗有效组与无效组之间的基因型和等位基因分布频率的关系,(4)5-羟色胺2A受体T102C基因多态性是否与中国首发精神分裂症患者利培酮疗效有关.方法对201例精神分裂症初发期患者分别进行利培酮治疗[3～5 mg/d,平均(3.2±1.3)mg/d],疗程8周.采用聚合酶链式反应扩增与限制性片段长度多态性(PCR-RFLP)技术检测5-HT2A受体基因T102C多态性.以临床亚型将精神分裂症患者划分为偏执型、瓦解型、未定型和其他型,分析不同临床亚型等位基因和基因型频率的差异;按服用利培酮剂量划分低剂量组(＜4 mg/d)和高剂量组(≥4 mg/d),经比较利培酮高剂量组和低剂量组的5-HT2A受体基因T102C基因型和等位基因分布频率差异性;同时以阴性和阳性症状量表(PANSS)总减分率＞50%有效,≤50%为无效以分析治疗有效组与无效组之间的基因型和等位基因分布频率差异有无显著性;以PANSS评定患者治疗前及治疗后2周、4周、6周和第8周末的精神症状,比较5-HT2A受体T102C各基因亚型与年龄、发病年龄、PANSS总分值、阳性症状基线分、阴性症状基线分、一般病理症状基线分、PANSS总减分率、阳性症状减分率、阴性症状减分率和一般病理症状减分率的差异.结果5-HT2A受体T102C基因型在患者组分布频率均符合H-W平衡定律(P＞0.05);不同临床诊断亚型精神分裂症患者等位基因和基因型频率无显著性差异(χ2=0.415,P=0.937;χ2=1.705,P=0.941);高剂量组与低剂量组之间的基因型和等位基因分布频率差异均无显著性(χ2=2.402,P=0.301;χ2=2.465,P=0.116);治疗有效和无效组的基因型和等位基因分布频率的差异无显著性(χ2=1.995,P=0.369;χ2=1.939,P=0.164);各基因型亚组的年龄、发病年龄及其病程差异均无显著性(P均大于0.05);但基因亚组A1/A1的治疗前PANSS总分(χ2=4.076,P=0.018)和阴性症状分(χ2=3.946,P=0.021)以及治疗结束PANSS总分减分率(χ2=4.036,P=0.019)和阴性症状减分率(χ2=3.876,P=0.022)均显著高于A1/A2及A2/A2基因型.结论(1)首发精神分裂症患者不同临床亚型5-HT2A受体基因T102C基因型和等位基因频率无显著差异.(2)利培酮高剂量组和低剂量组5-HT2A受体基因T102C基因型和等位基因分布频率没有显著性差异.(3)治疗有效组与无效组之间5-HT2A受体基因T102C基因型和等位基因分布频率也无显著性差异.(4)5-HT2A受体T102C Ai/A1基因亚型可能影响中国首发精神分裂症患者对利培酮的治疗效应.     

精神分裂症攻击行为与5-HT2A受体基因多态性的关联研究

目的探讨精神分裂症患者的攻击行为与5-HT2A受体基因T102C和A1438G多态性的相关性。方法采用《修订版外显攻击行为量表》(MOAS)对精神分裂症患者进行评定,MAOS评分≥5分为研究组,MOAS≤4为对照组。并采用聚合酶链反应(PCR)和限制性片断长度多态性(RFLP)技术,检测103例伴发攻击行为精神分裂症(研究组)和99例非攻击行为精神分裂症患者(对照组)5-HT2A基因型,并分别比较两组5-HT2A受体基因T102C位点多态性和A1438G位点多态性差异。结果研究组和对照组T102C位点多态性的等位基因频率和基因型频率分布统计学均具有显著性差异(P0.01),研究组基因型T/T频率和等位基因T频率均高于对照组(χ2=10.126,P=0.006),(χ2=8.176,P=0.004);A1438G位点多态性基因型频率分布差异无统计学意义(P0.05),而等位基因频率分布差异具有统计学意义(P0.05),研究组等位基因A频率高于对照组。结论 5-HT2A受体基因T102C位点和A1438G位点的多态性与精神分裂症的攻击行为均具有相关性,其等位基因T和A可能增加患者攻击行为的风险。     

五羟色胺2C受体基因多态性与抗精神病药急性期治疗精神分裂症疗效关系初探

目的 研究五羟色胺2C受体(5HTR2C)基因启动子区功能多态性与首次治疗的精神分裂症患者精神症状严重程度及抗精神病药物(APS)急性期治疗疗效相关性。方法 采用PCR-RFLP方法分析109例首次治疗精神分裂症患者(男53例,女56例)5HTR2C基因启动区-759C/T单核酸置换多态性;临床用阳性和阴性症状量表(PANSS)评定患者治疗前后精神症状,分析单体型(男性)或暴因型(女性)和其他临床指标与治疗前PANSS分值和治疗后PANSS减分率的相关性。结果5HTR2C基因-759C/T基因型在女性患者组的分布频率符合H-W定律(P>0.05);-759T单体型(男性)或携带-759T的基因型(女性)在治疗显效组和治疗未显著进步组分布频率无显著性差异;单体型或基因型亚组的临床指标均无显著性差异;-759C/T对首次治疗精神分裂症患者PANSS分值无显著影响,但对治疗10周后PANSS总减分率和阴性症状减分率有显著影响。结论 5HTR2C基因启动子区-759C/T单核酸置换多态性在APS急性期治疗疗效中,可能主要影响对阴性症状的控制。     

5-羟色胺2A受体基因多态性与精神分裂症患者迟发性运动障碍的关联分析

目的　探讨5- 羟色胺2A( 5- HT2A)受体基因A 1 4 38G、T1 0 2C多态性与精神分裂症伴迟发性运动障碍(TD)的相关性。方法　先用异常不自主运动量表(AIMS)评定精神分裂症男性患者有无TD及其严重程度,有4 2例符合TD(AIMS总分≥3分)者和51例与TD组严格相匹配的非TD者入组,采用简明精神病评定量表(BPRS)评定精神症状,应用聚合酶链反应 限制性片段长度多态性方法分析5 HT2A受体基因的A 1 4 38G、T1 0 2C多态性位点的多态性。结果　①5- HT2A受体基因A 1 4 38G和T1 0 2C两位点多态性呈完全连锁不平衡,TD组与非TD组的两多态性位点的基因型总体分布无显著性差异( χ2 =4 37,v =2 ,P >0 . 0 5) ,在TD组有更高的C/A等位基因频率,与非TD组有显著性差异( χ2 =4 . 36 ,v =1 ,P <0. 0 5)。②不同基因型间的人口学和临床学资料(如:病程、服药总时间、日服抗精神病药物剂量、AIMS和BPRS的评分)间无显著性差异(P >0. 0 5)。结论　5 -HT2A受体基因的A 1 4 38G、T1 0 2C多态性可能与男性精神分裂症患者的TD相关联。     

5-羟色胺2C受体基因启动子区多态性与迟发性运动障碍的关联分析

目的　探讨 5 羟色胺 2C(5 HT2C)受体基因启动区 - 759C/T和 - 697G/C单碱基置换多态性与精神分裂症伴迟发性运动障碍 (TD)的相关性。方法　先用异常不自主运动量表 (AIMS)评定精神分裂症男性患者有无TD及其严重程度 ,再对 42例符合TD(AIMS总分≥ 3分 )者和与TD组严格相匹配的 50例非TD者 ,采用简明精神病评定量表 (BPRS)评定精神症状 ,并应用聚合酶链反应 限制性片段长度多态性方法分析 5 HT2C受体基因的分布频率。结果　 (1 )TD组的 - 697C(突变型 )半合子型频率 (38% )高于非TD组 (1 8% ;χ2 =4 7,P =0 0 3 ,OR =2 8)。TD组 - 759T(突变型 )半合子型频率和 - 759T/ - 697C突变型单倍体频率虽高于非TD组 ,但差异均无显著性 (χ2 值分别为 2 9和 4 9,P =0 0 9)。 (2 )TD组的AIMS和BPRS评分分别为 (6 5± 1 8)分和 (51 2± 7 8)分 ,非TD组分别为 0分和(50 0± 7 3)分 ,差异无显著性 (P >0 0 5)。结论　 5 HT2C受体基因启动控制区的 - 697G/T单碱基置换突变可能是精神分裂症患者发生TD的易感因素之一     

5-羟色胺2A受体基因-1438A/G多态性与抑郁症的关联研究

目的探讨中国汉族人群中抑郁症患者与5-羟色胺2A(5-HT2A)受体基因-1438A/G多态性之间的关系。方法采用高温连接酶检测反应法,检测254例抑郁症患者和231例正常对照者的5-HT2A受体基因-1438A/G多态性的基因型和等位基因分布。结果(1)5-HT2A受体基因-1438A/G多态性的基因型和等位基因频率在患者组和对照组的分布差异无统计学意义(P>0.05)。(2)患者组-1438A/G多态性的三种基因型之间的汉密尔顿抑郁量表总分和各因子分的差异无统计学意义(P>0.05)。(3)-1438A/G多态性基因型及等位基因在性别和有无精神病疾病家族史之间无显著差异(P>0.05)。结论在中国汉族人群中未发现5-HT2A受体基因-1438A/G多态性与抑郁症存在关联。     

母女同患精神分裂症与5-羟色胺2A受体基因的关联分析

目的探讨母女精神分裂症患者和女性散发性精神分裂症患者与5-羟色胺2A受体基因(5-HT2A)T102C多态性的关联。方法先用严格的纳入标准收集共患精神分裂症的母女120例和女性散发性精神分裂症250例,分别与200名女性健康者做对照比较,采用聚合酶链反应(PCR)扩增及Mspl内切酶酶切技术,检测各组的5-HT2A受体基因的基因型和等位基因的频率分布。结果120例共患精神分裂症的母女组5-HT2A受体基因各组基因型频率均显著高于女性散发性精神分裂症组及正常女性对照组,经配对比较,女性散发性精神分裂症与女性正常人对照组各基因型和等位基因的构成差异均无显著性意义。结论母女共患精神分裂症的患者与5-HT2A受体基因的各组基因型均有关联,但A1/A2型杂合子可能更易患精神分裂症,女性散发性精神分裂症可能与5-HT2A受体基因无关联。     

Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients.

OBJECTIVE: Multicenter trials with the novel antipsychotic risperidone have suggested a standard dose of 6 mg/day. However, a dose producing the highest response rate in fixed-dose studies is likely to exceed the minimal effective dose in most patients. The aim of this positron emission tomography (PET) study was to suggest a minimal effective dose of risperidone based on measurements of dopamine D2 and serotonin 5-HT2A receptor occupancy. METHOD: Eight first-episode or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for 4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks, with [11C]raclopride to measure D2 receptor occupancy and [11C]N-methylspiperone to measure 5-HT2A receptor occupancy. RESULTS: Seven patients completed the study and responded to treatment with risperidone. No patient had extrapyramidal side effects at the time of inclusion in the study. At the 6-mg/day dose, mean D2 receptor occupancy was 82% (range = 79%-85%), 5-HT2A receptor occupancy was 95% (range = 86%-109%), and six patients had developed extrapyramidal side effects. After dose reduction to 3 mg/day, D2 receptor occupancy was 72% (range = 53%-78%), and 5-HT2A receptor occupancy was 83% (range = 65%-112%). Three patients had extrapyramidal side effects at this time. CONCLUSIONS: Treatment with risperidone, 6 mg/day, is likely to induce unnecessarily high D2 receptor occupancy, with a consequent risk of extrapyramidal side effects. High 5-HT2A receptor occupancy did not prevent extrapyramidal side effects completely. The authors previously suggested an optimal interval for D2 receptor occupancy of 70%-80%. To achieve this, resperidone, 4 mg/day, should be a suitable initial dose for antipsychotic effect with a minimal risk of extrapyramidal side effects in most patients.     

Abnormal plasma monoamine metabolism in schizophrenia and its correlation with clinical responses to risperidone treatment

Abnormalities in plasma monoamine metabolism reflect partly the illness of schizophrenia and sometimes the symptoms. Such studies have been repeatedly reported but have rarely taken both metabolites and parent amines or inter-amine activity ratios into account. In this study, the monoamines, their metabolites, turnovers and between-metabolite ratios in plasma were measured longitudinally in 32 schizophrenic patients treated with risperidone for 6 weeks, to examine possible biochemical alterations in schizophrenia, and to examine the association between treatment responses and psychopathology assessed according to the Positive and Negative Syndrome Scale (PANSS). The results showed lower level of plasma 3,4-dihydroxyphenylacetic acid (DOPAC) in relapsed versus first-episode schizophrenic patients, higher norepinephrine (NE) turnover rate (TR) in undifferentiated in comparison to paranoid schizophrenic patients and relatively higher metabolic activity of dopamine (DA) to serotonin (5-HT) in first-episode versus relapsed schizophrenic patients. Risperidone treatment induced a decrement of plasma DA levels and increments of plasma DOPAC and DA TR in the total group of schizophrenic patients. The turnover rate of 5-HT was was reduced in undifferentiated and relapsed subgroups of schizophrenic patients. The linkages between 5-HT TR, DA/NE relative activity and clinical symptomatology were also identified. These findings are consistent with an involvement of these systems in the pathogenesis of schizophrenia as well as in the responses to treatment, and the usefulness of certain biochemical indices as markers for subgrouping.     

Schizophrenia and the serotonin-2A receptor promoter polymorphism

Serotonin-2A (5-HT2A) receptors have received much investigative attention in schizophrenia because (1) several studies have shown a decrease in the number of 5-HT2A receptors in the prefrontal cortex of postmortem brains of schizophrenic patients; (2) atypical antipsychotic drugs are antagonists for 5-HT2A receptors; and (3) a positive association between a T to C polymorphism at position 102 of the 5-HT2A receptor gene and schizophrenia has been reported. A G to A polymorphism at position -1438 of the 5-HT2A receptor gene was studied in 119 schizophrenic patients and 106 healthy control subjects, all of whom were Japanese. The genotype and allele frequencies did not differ between the patients and control subjects. Furthermore, the genotype frequency did not differ according to diagnostic subtype, family history, age at onset of illness, or daily dosage of antipsychotic medication. Our results suggest that the polymorphism does not contribute to the etiology or clinical characteristics of schizophrenia. However, the gene is greater than 20 kbp in length, and thus it is possible that other areas that affect expression of the gene may vary. We found that the -1438G/A variant was in linkage disequilibrium with the T102C polymorphism.     

T102C polymorphisms at the 5-HT2A receptor gene in Turkish schizophrenia patients: a possible association with prognosis

BACKGROUND: Serotonergic system abnormalities have been implicated in the pathogenesis of schizophrenia. The 5-HT2A receptor gene polymorphism has long been implicated to play a role in the pathogenesis of schizophrenia. AIM: In this study, we assessed the relationship of schizophrenia and its subgroups with 5-HT2A receptor gene polymorphism, and attempted to evaluate a possible correlation between the severity and prognosis of the illness and 5-HT2A receptor gene polymorphism. METHOD: Our study comprised 141 unrelated subjects who strictly met DSM-IV criteria for schizophrenia, and 79 healthy unrelated controls, all of Turkish origin. A clinical evaluation of all patients was accomplished applying the Brief Psychiatric Rating Scale (BPRS) test. The analysis of 5-HT2A receptor gene polymorphism was performed using the polymerase chain reaction technique. RESULTS: Regarding 5-HT2A receptor gene polymorphisms, no statistically significant difference was found between schizophrenic patients and control subjects (p > 0.05). There was no significant difference between the average of BPRS points of the patients and 5-HT2A receptor gene polymorphisms (p > 0.05). Although there was no correlation between the duration of illness and polymorphism (p > 0.05), the frequency of hospitalization was found to be higher in the patients with T/C and T/T genotypes compared with the patients with C/C genotype (p < 0.05). CONCLUSION: Our findings indicate that the T102C polymorphisms of the 5-HT2A receptor gene does not play a substantial role in schizophrenia nor help evaluate susceptibility to schizophrenia. Since the 5-HT2A receptor gene polymorphism is associated with the frequency of hospitalization of the patients, it may be an indicator of prognosis in schizophrenia or help differentiate the patients who are somewhat refractory to antipsychotic treatment.     

Desensitization of 5-HT2A receptor function by chronic administration of selective serotonin reuptake inhibitors

We have previously shown that chronic treatment with selective serotonin reuptake inhibitors (SSRIs), fluvoxamine and paroxetine, attenuated m-chlorophenylpiperazine (mCPP)-induced hypolocomotion in rats. The effect of these SSRIs on the response to mCPP is thought to be caused by the desensitization of 5-HT2C receptor function. In the present study, we investigated whether chronic administration of SSRI could reduce another pharmacological response to mCPP in rats, i.e., the induction of the secretion of corticosterone. The mCPP-induced increase in the serum concentration of corticosterone was not blocked by the 5-HT2C antagonist SB242084, but was blocked by the 5-HT2A antagonist ketanserin. Chronic treatment with fluvoxamine and paroxetine attenuated the response to mCPP, while these SSRIs had no effects in control rats. These results suggest that the desensitization of 5-HT2A receptor function occurs in the same way as that of 5-HT2C receptor function through chronic treatment with either fluvoxamine or paroxetine as a consequence of prolonged exposure to elevated levels of serotonin. The hypersensitivity of 5-HT2A receptors is observed in depressed patients, and chronic treatment with many antidepressants such as tricyclic antidepressants have been reported to reduce 5-HT2A receptor density and/or efficacy. The desensitization of 5-HT2A receptor function might contribute to the therapeutic mechanism of action of these SSRIs, as seen with other classes of antidepressants.     

Effect of the serotonin agonist, MK-212, on body temperature in schizophrenia.

The effects of 6-chloro-2-(1-piperaziny)pyrazine (MK-212), a centrally acting 5-HT1C/5-HT2 agonist, on body temperature and behavior were assessed using a single-blind cross-over design in 23 schizophrenic patients and 22 normal controls. Body temperature was assessed before drug administration and at 30-min intervals for 3 hr. Each subject was administered placebo or MK-212. MK-212 significantly elevated temperature in normal controls. There was no overall MK-212-induced increase in temperature compared to placebo in the schizophrenic patients; however, 13 of 23 (56.5%) patients had a larger increase in temperature after MK-212 than placebo, 3 of 23 (13.1%) had no change, whereas the temperature change after placebo was greater than after MK-212 in 7 of 23 (30.4%) patients. MK-212 produced significant increases in nausea, feeling strange, and arousal but these effects did not differ between groups. These results are consistent with decreased 5-HT2 receptor responsivity in some patients with schizophrenia.     

精神分裂症与5—HT2A受体基因相关联

目的：探讨中国汉族人群精神分裂症与5－HT2A受体基因T102C多态性之间的关系。方法：选择精神分裂症患者286例,按病期分一般组和慢性组;以291例正常人对照,也按现年龄相应地分为一般对照组和慢性对照组,分生物学技术采用PCR扩增及MSPI内切酶酶切技术,检测各组研究对象的5－HT2A受体基因的基因型和等位基因的频率分布,结果：一般组精神分裂症患者5－HT2A受体基因A2／A2型频率及A2等位基因频率均显著高于对照组（ZA2／A2＝2．97,P＜0．05;ZA2＝2．19,P＜0．05）。经关联分析,其OR值分别为2．35（P＜0．05）和1．45（P＜0．05）。结论：提示中国汉族人群中5－HT2A受体基因多态性可能与精神分裂症呈正关联,而与慢性精神分裂症无关联。