【作者】 张菁；

【导师】 李舜伟；

【作者基本信息】 中国协和医科大学 ， 神经病学， 2007， 博士

【摘要】 【背景】：抑郁症不但是最常见、最严重的精神健康问题之一，而且也是世界范围内诊治花费最高的精神疾病之一。抑郁症的临床表现差异很大，可以大致分为核心症状和伴随症状两大类。这两类症状在临床上的涵义以及对于抗抑郁药物的治疗反应都不尽相同。抑郁症是在病因学上有遗传异质性的脑功能障碍的一组疾病，遗传学标志是与生俱来的，而且具有很高的检测稳定性。通过单核苷酸多态性(SNP)了解疾病的发病机理、疾病的诊断及易感性为复杂性疾病基因的研究提供了重要基础。5羟色胺能(5HT)神经系统改变是抑郁症的重要的病理生理过程之一，我们在预试验期对涉及抑郁症5HT合成代谢通路上的候选基因进行筛查。初步结果发现5HTT(5HT转运体)内含子13 C／T的转换(SNP编号为rs2054847)在抑郁症基线期与临床表型有某种趋势的联系，加之抑郁的发病机制涉及5HTT，SSRI类药物作用的靶点也是5HTT，因此我们决定对此SNP进行探索性的研究分析。【目的】：探索性地研究抑郁患者5HTT SNP(rs2054847)，从分子生物学水平探讨抑郁症患者的基因型与疾病表型之间的关系以及基因型和疗效之间的关系，为患者提供个体化治疗提供客观证据，更为新型抗抑郁药物的研发提供参考。【方法】：研究的第一部分：入选标准为DSM-Ⅳ确诊为重性抑郁的患者，年龄≥18岁，HAMD 17项总分≥16分，无躁狂或轻躁狂发作史，非单纯的心境恶劣障碍的患者。基线期使用遗传研究用诊断标准化精神检查(DIGS)、HAMD 17项量表和临床总体印象量表(CGI)进行评定。在患者签署知情同意后抽取静脉血，应用Taqman SNP技术测定基因型。研究的第二部分：参加第一部分研究的所有患者给予固定剂量的百优解(氟西汀)20 mg／d，分别在治疗的第8，15，29和43天随访评定HAMD量表，评价疗效。【结果】：基线期761例患者入选，性别分布：女性患者是男性患者的1.23倍(420／341)，平均年龄为34.2岁，HAMD分数平均为22.62，单次发作患者是复发的2倍(498／245)。在基线期761例患者中425例(56％)血样进行了DNA检测基因型。各基因型的频率分别是TT 65.4％(278例)，CT31.8％(135例)CC2.8％(12例)；等位基因频率T81.3％，C18.7％，符合Hardy-We土nberg平衡。基线期TT型患者HAMD分数(23.19)高于CT型(21.98)和CC型(20.83)。采用显性遗传模型将CT型和CC型患者合并为一组C+型和TT型患者进行比较。基线期除TT基因型患者1年内有生活事件比例是C+基因型的1.86倍外，其他人口学资料在基因型之间无差异。基线期TT基因型患者迟滞因子分数(8.0)、核心因子分数(9.76)和Maier因子分数(11.81)显著的高于C+基因型的患者(7.33，8.77，10．90)。百优解20mg／d固定剂量治疗，在第43天研究结束时，TT型患者共217例，CT型104例，CC型8例，未测基因型患者273例。完成研究的患者和脱落的患者在基因型，基线期HAMD总分和人口学方面无显著性差别。研究结束时(43d)TT基因型患者HAMD减分(13.91)呈现高于C+型减分(12.41)的趋势；TT基因型患者有效率(74.7％)呈现高于C+型有效率(69.6％)的趋势；在研究结束时，TT基因型患者缓解率(48.3％)是C+型患者的缓解率(39.3％)的1.68倍(P=0.036)。从治疗的第15d起TT型核心因子减分(2.8)高于C+型(1.9)，持续至研究结束。【结论】：抑郁症患者基线抑郁严重程度受到5HTT基因C／T多态性的修饰。基因的修饰作用主要针对抑郁症的核心症状，而对睡眠和焦虑症状没有影响。本研究的发现支持5HTT受体功能与抑郁症发病之间存在内在联系的学说。SSRI类抗抑郁药对抑郁症的疗效，主要是其对抑郁症核心症状的疗效受到基因型的修饰，符合SSRI类药物的作用机制。更多还原

【Abstract】 【Background】: The phenotypes differ among depression patients. Core symptoms (including depressive symptom and retard symptom) and accompanied symptoms (including sleep disorders, anxiety symptoms and somatic symptoms) may vary clinically, as well as pharmaceutical treatment response. Major depression is a heredity characteristic brain dysfunction disorder. Single nucleotide polymorphism (SNP) provides important gene clue in the study of pathogenesis and diagnosis of the disease. Changes of serotonin system are known as important pathophysiology in depression. As the key role in pathogenesis and the target of selective serotonin reuptake inhibitor, serotonin transporter gene becomes a candidate gene for major depression.【Objective】: To explore the relationship between 5HTT inton 13 SNP C/T (db SNP rs 2054847) and phenotype, and then evaluated association of therapeutic respond and 5HTT genotype. At the molecular organism’s level we investigated whether genetic factor can modify the phenotype and the therapeutic effect. Offer objective evidence for individualized treatment and reference for development new type antidepressive agents.【Methods】Part A: 761 patients according to Diagnosis and statistic manual for mental disorder-Ⅳ(DSM-Ⅳ) criterion diagnosed with major depressive disorder were included. The whole patients’ age≥18 year, HAMD-17 scores≥16, without history of mania or hypomania and dysthymic disorder in the baseline. We used DIGS (Diagnostic interview for genetic studies), HAMD-17 and CGI to evaluate the patients’ condition. Apply with the Taqman SNP technology to identification genotype. Part B: we prescribed PROZAC (fluoxetine) 20mg/d (fixed dosage) for the patients, and then followed up and evaluated with HAMD scales on 8d, 15d, 29d and 43d respectively.【results】: In the baseline, 761 cases were included in the study. Female patients(420 cases) were male patients(341cases) 1.23 times, average age was 34.2years. average HAMD scores were 22.62. The single episode patients were 2 times than recurrent patients.56% of the patients (425 cases) had genotype. Genotype frequency were TT:65.4%, CT:31.8% and CC2.8% respectably. Allele frequency T: 81.3%, C: 18.7%, according with Hardy-Weinberg equilibrium. In the base line, the patients with TT genotype have higher HAMD scores and report more life events in one year than CT and CC genotype. The patients with TT genotype had higher scores in core symptom factor, retard factor and Maier factor but not in sleep and anxious symptoms, than other genotypes. All patients with fluoxetine 20 mg/d (fixed dosages) treatment. At the end of study, TT patients have a higher tendency in reduction of HAMD scores and responsive ratio than other genotypes. TT patients’ remitters (48.3%) were 1.68 fold than CC and CT genotype (39.3%). TT patients’ core symptom improvement come up early.【conclusions】In baseline, the severity of patients with depression was modified by 5HTT genotype, especially on core symptoms, but not on sleep and anxious symptoms. This result supports 5HTT receptor had internal association with pathogenesis of depression. Treatment response of SSRI agent was modified by genotype, focusing on core symptom. That accord with the mechanism of drug action.更多还原