WO2023082401A1 - 一种预测抑郁障碍患者对治疗反应的基因诊断试剂盒和系统 - Google Patents

一种预测抑郁障碍患者对治疗反应的基因诊断试剂盒和系统 Download PDF

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WO2023082401A1
WO2023082401A1 PCT/CN2021/137919 CN2021137919W WO2023082401A1 WO 2023082401 A1 WO2023082401 A1 WO 2023082401A1 CN 2021137919 W CN2021137919 W CN 2021137919W WO 2023082401 A1 WO2023082401 A1 WO 2023082401A1
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张志珺
栾迪
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中国科学院深圳理工大学(筹)
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  • the invention belongs to the field of biological diagnosis, and specifically provides a gene diagnosis kit and system for predicting treatment response of depression patients.
  • Depressive disorder refers to a type of mood disorder caused by a variety of reasons, with significant and persistent depressive symptoms as the main clinical feature. Its core symptoms are low mood and loss of interest that are not commensurate with the situation. Only 0.5% of depressive disorder patients received adequate treatment.
  • Depressive disorders are influenced by multiple factors, including genes, environment, and their interactions.
  • TRD Treatment resistant depression. depression
  • researchers have carried out pharmacogenetics and made a series of discoveries. For example, polymorphisms in the pharmacokinetic-related gene ABCB1 affect the efficacy of antidepressants.
  • the present invention predicts the antidepressant treatment effect of the patient by combining the genetic diagnosis kit with the social and psychological factor scale. If it is predicted that the patient will not respond to treatment, other treatments besides antidepressant drugs, such as physical therapy and psychotherapy, can be added to the initial treatment plan to improve the first-episode cure rate and reduce treatment-resistant depression and psychosis. occurrence of disability.
  • One aspect of the present invention provides a system for predicting the antidepressant treatment response of patients with depressive disorder, the system includes a test kit for detecting the genotype of patients with depressive disorder and a social and psychological factor scale; the test kit and the social and psychological factor scale are selected since:
  • the kit contains reagents for detecting the genotype of the single nucleotide polymorphism site rs200494044, and the social and psychological factor scale is selected from the childhood trauma questionnaire;
  • the kit contains reagents for detecting the genotype of the single nucleotide polymorphism site rs117583613, and the social and psychological factor scale is selected from the family environment scale; or
  • the kit includes a reagent for detecting the genotype of the single nucleotide polymorphism site rs45437897, and the social and psychological factor scale is selected from the life event scale.
  • the Childhood Trauma Questionnaire was selected from the physical neglect items in the Childhood Trauma Questionnaire.
  • Another aspect of the present invention provides the use of the above system in preparing a tool for predicting the response to antidepressant treatment of patients with depressive disorders.
  • kits for predicting the response to antidepressant treatment of patients with depressive disorder includes reagents capable of detecting the genotypes of single nucleotide polymorphism sites rs200494044, rs117583613 and rs45437897.
  • Another aspect of the present invention provides the use of the above kit in preparing a tool for evaluating the treatment response of subjects with abnormally elevated scores on the scale of social and psychological factors after receiving antidepressant drugs.
  • Another aspect of the present invention provides a method for predicting the response to antidepressant treatment in patients with depressive disorders, the method comprising:
  • S1 Collect the subject's sample, and detect the genotype of the single nucleotide polymorphism site through a kit for detecting the genotype of the single nucleotide polymorphism site;
  • step S3 Predict the antidepressant treatment response of patients with depressive disorders according to the genotype of the single nucleotide polymorphism site and the scale data of social psychological factors obtained in step S1);
  • the rs200494044 SNP genotype is AG or AA, it can be expected that after taking a single antidepressant drug or taking a single antidepressant drug plus rTMS treatment, the reduction rate of the Hamilton Depression Scale (HAMD-17) will increase with the The subject's score on the Physical Neglect Item of the Childhood Trauma Questionnaire increased with a decrease;
  • the genotype of the rs117583613 SNP locus is AG or AA. It can be expected that after taking a single antidepressant drug or taking a single antidepressant drug plus rTMS treatment, the score reduction rate of the Hamilton Depression Scale will increase with the family environment of the subject Decrease in the total score of the knowledge scale in the scale;
  • the rs45437897 SNP genotype is TC or TT, it can be expected that after taking a single antidepressant drug or taking a single antidepressant drug plus rTMS treatment, the score reduction rate of the Hamilton Depression Scale will increase with the life events of the subject Decreases in total scores on social and other aspects of the scale;
  • the score reduction rate of the Hamilton Depression Scale (the baseline Hamilton Depression Scale score-the Hamilton Depression Scale score after treatment)/the baseline Hamilton Depression Scale score.
  • Another aspect of the present invention provides a method for analyzing the effect of the interaction between the gene of a depressive disorder patient and the social environment in which it is located on the treatment effect of a depressive disorder patient, said method comprising the following steps:
  • the enrollment information is collected, and the collected data includes the patient's blood samples and the social and psychological factor assessment form as the baseline period data;
  • a linear regression model is used to construct a gene-environment interaction model, and the genotyping and social-environmental factor combinations that have an impact on the treatment effect of patients with depression are screened with a P value of less than 1 ⁇ 10 -7 as the screening condition.
  • the criteria for recruiting patients with depressive disorders are: (1) non-psychotic depression in accordance with the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV); (2) Hamilton Depression Scale (17-item Hamilton Depression Rating Scale, HAMD-17) greater than 17; (3) Depressive symptoms lasted for at least 2 weeks; (4) Did not receive drugs or other treatments for at least 2 weeks before enrollment; (5) Signed an informed consent form.
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders
  • the exclusion criteria are: (1) other DSM-IV 1-axis medical history; (2) personality disorders, mental retardation, pregnancy or breastfeeding, organic diseases, and other diseases that affect mental assessment; (3) 6 months after enrollment Receive electroconvulsive therapy (Electroconvulsive therapy, ECT) or repetitive transcranial magnetic stimulation (Repetitive transcranial magnetic stimulation, rTMS); (4) there are rTMS contraindications; (5) there are manic episodes 12 months before enrollment; (6) patients who need to change antidepressant drugs or have poor compliance after enrollment; (7) ) There are serious physical diseases; (8) Those who quit during the research process.
  • the rTMS treatment parameters were: "8" shaped coil, 1 Hz, 80% motor threshold, targeting the right dorsolateral prefrontal cortex, twice a day, 10 minutes each time, with a stimulation interval of 30 seconds, for a total of 14 days.
  • the psychosocial factor assessment form was selected from the childhood trauma questionnaire, family environment scale, social support scale and life event scale.
  • this invention proposes for the first time that gene-environment interaction has a predictive effect on treatment. Specifically, three groups of gene-environment interaction factors were screened out from the combination of more than ten environmental factors and more than 10,000 SNP sites, and The prediction of patients' response to antidepressant treatment was realized by using the genetic diagnostic kit combined with the social and psychological factor scale.
  • the exclusion criteria are: (1) other DSM-IV 1-axis medical history; (2) personality disorders, mental retardation, pregnancy or breastfeeding, organic diseases, and other diseases that affect mental assessment; (3) 6 months after enrollment Received Electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (Repetitive transcranial magnetic stimulation, rTMS); (4) Contraindications to rTMS; (5) Manic episodes 12 months before enrollment; (6) Patients who need to change antidepressant drugs or have poor compliance after enrollment; (7) have serious physical diseases, such as: epilepsy, endocrine diseases, blood diseases, and obvious abnormalities in heart, liver, and kidney functions; (8) research Self-exit during the process.
  • ECT Received Electroconvulsive therapy
  • rTMS repetitive transcranial magnetic stimulation
  • Contraindications to rTMS (5) Manic episodes 12 months before enrollment; (6) Patients who need to change antidepressant drugs or have poor compliance after enrollment; (7) have serious physical diseases, such as: epilepsy, endocrine diseases, blood diseases,
  • Antidepressant treatment According to clinical practice, after the patients are enrolled, the enrollment information will be collected, and the collected data will include the patient's blood samples and the following social and psychological factor evaluation form as the baseline period data. All patients then received a single antidepressant for 8 weeks, or added rTMS for the first 2 weeks. Except for the use of small doses of benzodiazepine anxiolytics for the relief of insomnia, other psychotropic drugs were not allowed, otherwise they were excluded from the group.
  • the rTMS treatment parameters were: "8" shaped coil, 1 Hz, 80% motor threshold, targeting the right dorsolateral prefrontal cortex, twice a day, 10 minutes each time, 30 seconds between stimulations, for a total of 14 days.
  • Psychosocial factors include:
  • Childhood trauma questionnaire (Childhood trauma questionnaire-short form, CTQ-SF), including Emotional abuse, Physical abuse, Sexual abuse, Emotional neglect and Physical abuse Physical neglect (Physical neglect) 5 dimensions
  • the scoring standard is: the total score of sexual abuse ⁇ 8 is considered to be sexual abuse; the total score of emotional abuse ⁇ 13 is considered to be emotional abuse; the total score of physical abuse ⁇ 10 is considered to be physical abuse; A total score of neglect ⁇ 10 was considered to be physical neglect; a total score of emotional neglect ⁇ 15 was considered to be emotional neglect.
  • FES-CV Family environment scale-Chinese version
  • SSRS Social support rating scale
  • LES Life event scale
  • HAMD-17 score reduction rate (baseline period - eighth week) / baseline period.
  • Gene sequencing A total of 1309 candidate genes were included in this study.
  • the sample source is peripheral blood.
  • the sequencing range of each gene includes exon region, 5' non-coding region (Untranslated region, UTR), 3'-UTR and exon-intron boundary region.
  • rs200494044 Location: chr16:2071869 (GRCh38.p13), allele: G>A
  • rs117583613 Location: chr3:48561890 (GRCh38.p13), allele: G>A
  • rs45437897 Location: chr20:46011590 (GRCh38.p13), allele: C>T
  • doctors can be instructed to add other therapies besides antidepressants to the initial treatment plan, such as physical therapy and psychotherapy, so as to improve the first-time cure rate and reduce the incidence of treatment-resistant depression and mental disability. occur.

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Abstract

提供了一种预测抑郁障碍患者对治疗反应的基因诊断试剂盒和系统，具体为预测抑郁障碍患者抗抑郁治疗反应的系统，所述系统包含检测抑郁障碍患者基因型的试剂盒和社会心理因素量表；所述试剂盒和社会心理因素量表选自：a)所述试剂盒中包含检测单核苷酸多态性位点rs200494044、rs117583613或rs45437897基因型的试剂，且社会心理因素量表选自儿童期创伤问卷、家庭环境量表；和或生活事件量表。提供了基因与环境交互对于治疗具有预测作用，并实现通过基因诊断试剂盒结合社会心理因素量表实现患者对抗抑郁治疗反应的预测。

Description

一种预测抑郁障碍患者对治疗反应的基因诊断试剂盒和系统 技术领域
本发明属于生物诊断领域，具体提供了一种预测抑郁障碍患者对治疗反应的基因诊断试剂盒和系统。
 背景技术
抑郁障碍是指由多种原因引起的以显著和持久的抑郁症状群为主要临床特征的一类心境障碍，其核心症状是与处境不相称的心境低落和兴趣丧失，仅0.5%的抑郁障碍患者得到了充分的治疗。
抑郁障碍患者受多种因素影响，包括基因、环境及其相互作用。环境因素，尤其是社会心理因素，影响抑郁障碍患者的患病。例如，儿童和青少年期虐待和/或抑郁发作前的负性生活事件往往导致难治性抑郁（Treatment resistant depression，TRD）。为确定影响抗抑郁药物疗效的遗传因素，学者们开展了药物遗传学，取得了一系列发现。例如，药代动力学相关基因ABCB1多态性影响抗抑郁药的疗效。然而，药效动力学相关基因多态性研究尚未取得一致性的结果，如5-羟色胺能基因SLC6A4，5-羟色胺受体基因5HTTLPR、HTR1A和HTR2A，代谢酶基因MAOA、COMT和TPH，谷氨酸能基因GRIK4，神经营养因子基因BDNF以及应激反应调节基因FKBP5。随着测序技术的进步，全基因组关联研究（Genome-wide association study，GWAS）为药物基因组学提供了一种无假设的方法，但只有少数研究达到了全基因组水平显著差异，并且没有得到很好的验证，如ITGA9、NRXN3和AUTS2。
抑郁障碍目前无预测疗效的客观生物标记物，约1/3的抑郁障碍患者对抗抑郁药物无反应，这就导致了部分患者可能中断治疗，迁延不愈，最终导致精神残疾，丧失工作生活能力。
发明内容
为解决上述现有技术中存在的问题，提高对于抑郁障碍患者的服药后药效预测的准确性和可预期性，本发明通过基因诊断试剂盒结合社会心理因素量表来预测患者对抗抑郁治疗的反应，倘若预测患者对治疗无反应，则可在最初的治疗方案中加用除抗抑郁药物外的其他疗法，如物理治疗和心理治疗等，以提高首发治愈率，减少难治性抑郁和精神残疾的发生。
本发明一个方面提供了一种预测抑郁障碍患者抗抑郁治疗反应的系统，所述系统包含检测抑郁障碍患者基因型的试剂盒和社会心理因素量表；所述试剂盒和社会心理因素量表选自：
a）所述试剂盒中包含检测单核苷酸多态性位点rs200494044基因型的试剂，且社会心理因素量表选自儿童期创伤问卷；
b）所述试剂盒中包含检测单核苷酸多态性位点rs117583613基因型的试剂，且社会心理因素量表选自家庭环境量表；或者
c）所述试剂盒中包含检测单核苷酸多态性位点rs45437897基因型的试剂，且社会心理因素量表选自生活事件量表。
进一步地，儿童期创伤问卷选自儿童期创伤问卷中的躯体忽视项目。
本发明另一个方面提供了上述系统在制备预测抑郁障碍患者抗抑郁治疗反应的工具中的用途。
本发明再一个方面提供了一种预测抑郁障碍患者抗抑郁治疗反应的试剂盒，所述试剂盒中包含能够检测单核苷酸多态性位点rs200494044、rs117583613和rs45437897的基因型的试剂。
本发明再一个方面提供了上述试剂盒在制备针对社会心理因素量表评分异常升高的受试者，评估其在接受抗抑郁治疗药物后治疗反应的工具中的用途。
本发明再一个方面提供了一种预测抑郁障碍患者抗抑郁治疗反应的方法，所述方法包括：
S1)采集受试者样品，通过检测单核苷酸多态性位点基因型的试剂盒，检测单核苷酸多态性位点基因型；
S2) 采集受试者社会心理因素量表数据；
S3)根据步骤S1)所得单核苷酸多态性位点基因型和社会心理因素量表数据预测抑郁障碍患者抗抑郁治疗反应；
其中，以下受试者对于抗抑郁治疗反应低于平均水平：
a）rs200494044 SNP位点基因型为AG或AA，可以预期在服用单一抗抑郁药物或服用单一抗抑郁药物且加用rTMS治疗后，汉密尔顿抑郁量表（HAMD-17）的减分率会随着该受试者儿童期创伤问卷中躯体忽视项目的分数的降低而升高；
b）rs117583613SNP位点基因型为AG或AA，可以预期在服用单一抗抑郁药物或服用单一抗抑郁药物且加用rTMS治疗后，汉密尔顿抑郁量表的减分率会随着该受试者家庭环境量表中知识性评分的总分数的降低而升高；
c）rs45437897SNP位点基因型为TC或TT，可以预期在服用单一抗抑郁药物或服用单一抗抑郁药物且加用rTMS治疗后，汉密尔顿抑郁量表的减分率会随着该受试者生活事件量表中社交和其他方面评分的总分数的降低而升高；
所述汉密尔顿抑郁量表的减分率=(基线期汉密尔顿抑郁量表评分-治疗后汉密尔顿抑郁量表评分)/基线期汉密尔顿抑郁量表评分。
本发明再一个方面提供了一种分析抑郁障碍患者的基因和所处社会环境之间相互作用对抑郁障碍患者治疗效果影响的方法，所述方法包括以下步骤：
S01)招募抑郁障碍患者；
S02)患者入组后进行入组信息采集，采集数据包含患者血液样品和社会心理因素评估表作为基线期数据；
S03) 给予患者抗抑郁治疗方案，所述治疗治疗方案包括接受单一抗抑郁药物治疗8周，或接受单一抗抑郁药物治疗8周且在前2周加用rTMS治疗；
S04)统计基线期、第2周、第4周及第8周汉密尔顿抑郁量表评分；
S05) 对患者血液样品进行基因测序，获得候选基因的序列。
S06)采用线性回归模型构建基因-环境交互作用模型，以 P值小于1×10 -7作为筛选条件筛选对抑郁障碍患者治疗效果有影响的基因分型以及社会环境因素组合。
进一步地，招募抑郁障碍患者标准为：（1）符合《诊断与统计手册：精神障碍》第四版（Diagnostic and Statistical Manual of Mental Disorders-Ⅳ，DSM-Ⅳ）非精神病性抑郁症；（2）汉密尔顿抑郁量表（17-item Hamilton Depression Rating Scale，HAMD-17）大于17；（3）抑郁症状至少持续2周；（4）入组前至少2周没有接受药物或其他治疗；（5）签署知情同意书。
排除标准为：（1）其他DSM-Ⅳ 1轴病史；（2）存在人格障碍、智力迟钝、怀孕或哺乳、器质性疾病以及影响精神评估的其他疾病；（3）入组后6个月内接受电抽搐治疗（Electroconvulsive therapy，ECT）或重复经颅磁刺激治疗（Repetitive transcranial magnetic stimulation，rTMS）；（4）存在rTMS禁忌症；（5）入组前12个月存在躁狂发作情况；（6）需要改变抗抑郁治疗药物或入组后依从性差的患者；（7）存在严重躯体疾病；（8）研究过程中自行退出者。
进一步地，rTMS治疗参数为：“8”字形线圈，1 Hz，80%运动阈值，靶向右背外侧前额叶皮层，每天两次，每次10分钟，刺激间隔30秒，共计14天。
进一步地，社会心理因素评估表选自儿童期创伤问卷、家庭环境量表、社会支持量表和生活事件量表。
 有益效果
针对抑郁障碍患者的治疗本发明首次提出基因与环境交互对于治疗具有预测作用，具体地，在十余种环境因素和超过一万个SNP位点的组合中筛选出3组基因环境交互因素，并通过基因诊断试剂盒结合社会心理因素量表实现患者对抗抑郁治疗反应的预测。
具体实施方式
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方式做详细的说明，但不能理解为对本发明的可实施范围的限定。
实施例
研究对象：本研究共计招募1331例抑郁障碍患者，最终纳入984例进行统计分析。抑郁障碍患者纳入标准为：（1）符合《诊断与统计手册：精神障碍》第四版（Diagnostic and Statistical Manual of Mental Disorders-Ⅳ，DSM-Ⅳ）非精神病性抑郁症；（2）汉密尔顿抑郁量表（17-item Hamilton Depression Rating Scale，HAMD-17）大于17；（3）抑郁症状至少持续2周；（4）入组前至少2周没有接受药物或其他治疗；（5）签署知情同意书。排除标准为：（1）其他DSM-Ⅳ 1轴病史；（2）存在人格障碍、智力迟钝、怀孕或哺乳、器质性疾病以及影响精神评估的其他疾病；（3）入组后6个月内接受电抽搐治疗（Electroconvulsive therapy，ECT）或重复经颅磁刺激治疗（Repetitive transcranial magnetic stimulation，rTMS）；（4）存在rTMS禁忌症；（5）入组前12个月存在躁狂发作情况；（6）需要改变抗抑郁治疗药物或入组后依从性差的患者；（7）存在严重躯体疾病，如：癫痫、内分泌疾病、血液疾病及心、肝、肾功能明显异常等；（8）研究过程中自行退出者。
抗抑郁治疗：依据临床实践，患者入组后进行入组信息采集，采集数据包含患者血液样品和下述社会心理因素评估表作为基线期数据。然后所有患者接受单一抗抑郁药物8周，或在前2周加用rTMS治疗。除为缓解失眠而使用小剂量的苯二氮卓类抗焦虑药外，不允许使用其他精神类药物，否则排除出组。rTMS治疗参数为：“8”字形线圈，1 hz，80%运动阈值，靶向右背外侧前额叶皮层，每天两次，每次10分钟，刺激间隔30秒，共计14天。
社会心理因素及终点事件评估：社会心理因素包括：
（1）儿童期创伤问卷（Childhood trauma questionnaire-short form，CTQ-SF），包括情感虐待（Emotional abuse）、躯体虐待（Physical abuse）、性虐待（Sexual abuse）、情感忽视（Emotional neglect）和躯体忽视（Physical neglect）5个维度，评分标准为：性虐待总分≥8视为存在性虐待；情感虐待总分≥13视为存在情感虐待；躯体虐待总分≥10视为存在躯体虐待；躯体忽视总分≥10视为存在躯体忽视；情感忽视总分≥15视为存在情感忽视。
（2）家庭环境量表中文版（Family environment scale-Chinese version，FES-CV），包括10个维度，即亲密度（Cohesion）、情感表达（Expressiveness）、矛盾性（Conflict）、独立性（Independence）、成功性（Achievement）、知识性（Intellectual_cultural）、娱乐性（Recreational）、道德宗教观（Moral_religious）、组织性（organization）及控制性（Control）。
（3）社会支持量表（Social support rating scale，SSRS），包括客观支持（Objective support）、主观支持（Subjective support）及支持利用度（Support-seeking behavior）3个维度。
（4）生活事件量表（Life event scale，LES），包括正性生活事件（Positive events）、负性生活事件（Negative events）、家庭生活方面（Family life events）、工作学习方面（Work events）及社交和其他方面（Social and other aspects）。
终点事件：基线期、第2周、第4周及第8周汉密尔顿抑郁量表（17-item Hamilton Depression Rating Scale，HAMD-17）评分。HAMD-17减分率=(基线期-第八周)/基线期。
基因测序：本研究共计纳入1309个候选基因。样本来源为外周血。每个基因的测序范围包括外显子区、5’非编码区（Untranslated region，UTR）、3’-UTR以及外显子-内含子边界区。
统计分析：采用线性回归模型构建基因-环境交互作用模型。以 P值小于1× 10 -07作为筛选条件。
结果：如下表所示:
（1）rs200494044与儿童期虐待量表中的躯体忽视维度存在交互作用，影响抑郁障碍患者治疗8周后HAMD-17的减分率；
（2）rs117583613 与家庭环境量表中的知识性维度存在交互作用，影响抑郁障碍患者治疗8周后HAMD-17的减分率；
（3）rs45437897 与生活事件量表中的社交和其他方面存在交互作用，影响抑郁障碍患者治疗8周后HAMD-17的减分率。
Figure dest_path_image001
rs200494044：所在位置：chr16:2071869 (GRCh38.p13)，等位基因：G>A
rs117583613：所在位置：chr3:48561890 (GRCh38.p13)，等位基因：G>A
rs45437897：所在位置：chr20:46011590 (GRCh38.p13)，等位基因：C>T
通过 P值结果可知结合基因和环境之间交互作用后这3组相互作用数据可以用于对于抑郁障碍患者治疗后治疗效果的预测。rs200494044 SNP位点基因型为AG或AA的患者，其儿童期创伤问卷中躯体忽视项目的分数每升高一单位，其服用单一抗抑郁药物或服用单一抗抑郁药物且在前2周加用rTMS治疗后， HAMD-17的减分率降低0.06单位，由此预测该患者服用单一品种抗抑郁药物治疗效果差。
同理，rs117583613 SNP位点基因型为AG或AA的患者，其家庭环境量表中知识性评分的总分数每升高一单位，其服用单一抗抑郁药物或服用单一抗抑郁药物且在前2周加用rTMS治疗后，HAMD-17的减分率降低0.12单位，由此可预测该患者服用单一品种抗抑郁药物治疗效果差。
rs45437897 SNP位点基因型为TC或TT的患者，其生活事件量表中社交和其他方面评分的总分数每升高一单位，其服用单一抗抑郁药物或服用单一抗抑郁药物且在前2周加用rTMS治疗后， HAMD-17的减分率降低0.12单位，由此可预测该患者服用单一品种抗抑郁药物治疗效果差。
对于预测疗效差的患者，可以指导医生在最初的治疗方案中加用除抗抑郁药物外的其他疗法，如物理治疗和心理治疗等，以提高首发治愈率，减少难治性抑郁和精神残疾的发生。
由于抑郁障碍患者病情的特殊性，导致这种疾病的用药治疗效率远低于其他疾病，而这类疾病的用药对于患者心肺肝肾毒性已多有报道，本发明首次提出了对于用药的药效预测上，除了个体基因型的影响外，还存在环境因素，而基因型和环境因素二者相辅相成，综合作用导致了对用药效果的影响。由于患者的血液和各项评分表是在诊疗初期就可以获得的样品或数据，而通过这些容易获得的数据，能够大大提高抑郁障碍患者的治疗效率。

Claims (10)

  1. 一种预测抑郁障碍患者抗抑郁治疗反应的系统，其特征在于，所述系统包含检测抑郁障碍患者基因型的试剂盒和社会心理因素量表；所述试剂盒和社会心理因素量表选自：
    a）所述试剂盒中包含检测单核苷酸多态性位点rs200494044基因型的试剂，且社会心理因素量表选自儿童期创伤问卷；
    b）所述试剂盒中包含检测单核苷酸多态性位点rs117583613基因型的试剂，且社会心理因素量表选自家庭环境量表；和或
    c）所述试剂盒中包含检测单核苷酸多态性位点rs45437897基因型的试剂，且社会心理因素量表选自生活事件量表。
  2. 根据权利要求1所述的预测抑郁障碍患者抗抑郁治疗反应的系统，其特征在于，儿童期创伤问卷选自儿童期创伤问卷中的躯体忽视项目。
  3. 权利要求1或2所述的预测抑郁障碍患者抗抑郁治疗反应的系统在制备预测抑郁障碍患者抗抑郁治疗反应的工具中的用途。
  4. 一种预测抑郁障碍患者抗抑郁治疗反应的试剂盒，其特征在于，所述试剂盒中包含能够检测单核苷酸多态性位点rs200494044、rs117583613和rs45437897的基因型的试剂。
  5. 权利要求4所述的试剂盒在制备针对社会心理因素量表评分异常升高的受试者，评估其在接受抗抑郁治疗药物后治疗反应的工具中的用途。
  6. 一种预测抑郁障碍患者抗抑郁治疗反应的方法，其特征在于，所述方法包括：
    S1)采集受试者样品，通过检测单核苷酸多态性位点基因型的试剂盒，检测单核苷酸多态性位点基因型；
    S2) 采集受试者社会心理因素量表数据；
    S3)根据步骤S1)所得单核苷酸多态性位点基因型和社会心理因素量表数据预测抑郁障碍患者抗抑郁治疗反应；
    其中，
    a）rs200494044 SNP位点基因型为AG或AA，可以预期在服用单一抗抑郁药物或服用单一抗抑郁药物且加用rTMS治疗后，汉密尔顿抑郁量表（HAMD-17）的减分率会随着该受试者儿童期创伤问卷中躯体忽视项目的分数的降低而升高；
    b）rs117583613SNP位点基因型为AG或AA，可以预期在服用单一抗抑郁药物或服用单一抗抑郁药物且加用rTMS治疗后，汉密尔顿抑郁量表的减分率会随着该受试者家庭环境量表中知识性评分的总分数的降低而升高；
    c）rs45437897SNP位点基因型为TC或TT，可以预期在服用单一抗抑郁药物或服用单一抗抑郁药物且加用rTMS治疗后，汉密尔顿抑郁量表的减分率会随着该受试者生活事件量表中社交和其他方面评分的总分数的降低而升高；
    所述汉密尔顿抑郁量表的减分率=(基线期汉密尔顿抑郁量表评分-治疗后汉密尔顿抑郁量表评分)/基线期汉密尔顿抑郁量表评分。
  7. 一种分析抑郁障碍患者的基因和所处社会环境之间相互作用对抑郁障碍患者治疗效果影响的方法，其特征在于，所述方法包括以下步骤：
    S01)招募抑郁障碍患者；
    S02)患者入组后进行入组信息采集，采集数据包含患者血液样品和社会心理因素评估表作为基线期数据；
    S03) 给予患者抗抑郁治疗方案，所述治疗治疗方案包括接受单一抗抑郁药物治疗8周，或接受单一抗抑郁药物治疗8周且在前2周加用rTMS治疗；
    S04)统计基线期、第2周、第4周及第8周汉密尔顿抑郁量表评分；
    S05) 对患者血液样品进行基因测序，获得候选基因的序列；
    S06)采用线性回归模型构建基因-环境交互作用模型，以 P值小于1×10 -7作为筛选条件筛选对抑郁障碍患者治疗效果有影响的基因分型以及社会环境因素组合。
  8. 根据权利要求7所述的方法，其特征在于，步骤S1）中招募抑郁障碍患者标准为：（1）符合《诊断与统计手册：精神障碍》第四版（Diagnostic and Statistical Manual of Mental Disorders-Ⅳ，DSM-Ⅳ）非精神病性抑郁症；（2）汉密尔顿抑郁量表（17-item Hamilton Depression Rating Scale，HAMD-17）大于17；（3）抑郁症状至少持续2周；（4）入组前至少2周没有接受药物或其他治疗；（5）签署知情同意书；
    排除标准为：（1）其他DSM-Ⅳ 1轴病史；（2）存在人格障碍、智力迟钝、怀孕或哺乳、器质性疾病以及影响精神评估的其他疾病；（3）入组后6个月内接受电抽搐治疗（Electroconvulsive therapy，ECT）或重复经颅磁刺激治疗（Repetitive transcranial magnetic stimulation，rTMS）；（4）存在rTMS禁忌症；（5）入组前12个月存在躁狂发作情况；（6）需要改变抗抑郁治疗药物或入组后依从性差的患者；（7）存在严重躯体疾病；（8）研究过程中自行退出者。
  9. 根据权利要求7所述的方法，其特征在于，步骤S02)中社会心理因素评估表选自儿童期创伤问卷、家庭环境量表、社会支持量表和生活事件量表。
  10. 根据权利要求7所述的方法，其特征在于，步骤S03)中 rTMS治疗参数为：“8”字形线圈，1 Hz，80%运动阈值，靶向右背外侧前额叶皮层，每天两次，每次10分钟，刺激间隔30秒，共计14天。
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