Association of genetic polymorphisms with drug-response and personality in mood disorders

情绪障碍中基因多态性与药物反应和人格的关联

• 批准号: 10670923
• 负责人: OZAKI Norio
• 金额: $ 2.05万
• 依托单位: Fujita Health University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670923/
• 关键词: MOOD DISOREDERS; GENE; DRUG-RESPONSE; PERSONALITY; BREEDING EXPERIENCE; 免疫学

Lifetime prevalence of mood disorders is estimated about 15% and mood disorders cause a serious social loss and a high suicide rate. There are many treatment-resistant cases with mood disorders although the treatment by antidepressants and mood stabilizers has been established. The pathophysiology of this disorders has not yet unknown, thus the elucidation of the pathophysiology is required to establish the prevention and treatment of this condition. According to the clinical genetic studies, such as the family study, the twin study, and the adopted study, genetic factors are hypothesized to participate in the etiology of mood disorders. In addition, abnormal monoamines in patients with mood disorders and monoaminergic mechanisms of psychotropic drugs suggest that abnormality of monoamines participates in the pathophysiology of mood disorders. These two points mentioned above lead to the monoaminergic genetic studies of mood disorders. No reproducible result, however, has acquired. One … More of the reasons for the obstacle is that mood disorders are etiologically heterogeneous disorders. Therefore, we have to grasp the family history, the response to psychotropic drugs, the personality, the breeding experience and the clinical information in order to elucidate the pathophysiology. In addition, by progress of molecular biology, we can search for monoaminergic molecular genetic mechanisms that is used to be impossible. Thus, we started to examine the monoaminergic molecular genetic background in patients with mood disorders after we obtained their drug-response, other biological data, their breeding experience, personality and the clinical features.We examined the personality using the TC1 in depression. As a result, the severity of depression showed the positive correlation with Harm Avoidance, and the negative correlation with Self-Directedness and Cooperativeness. Furthermore, good responders became close to normal values after an antidepressant treatment, but bad responders did not change. On the other hand, on the breeding experience using PBI, patients with depression and OCD showed a low caring of parents and a high protection of a mother. In addition, patients with atopic dermatitis had high Harm Avoidance with TCI and no characteristics with PBI.On the other hand, according to the molecular genetic study of seasonal affective disorder, the 5HTT polymorphism had the association with the disease, but the 5-HT1a, 1b, 1d, 2a, 2c do not.We are going to continue the molecular genetic research to obtain a marker for the drug response and open the road to the development of a new drug. Furthermore, we are carrying out researches to aim at goals as follows. 1) Developing a tool for early discovery of depression. 2) Frequency of mood disorders and an environment factor in laborers and patient with general medical conditions. 3) Effectiveness of cognitive behavior therapy for depression. Less

据估计，情绪障碍的终生患病率约为15%，情绪障碍造成严重的社会损失和高自杀率。尽管已经建立了抗抑郁药和情绪稳定剂的治疗方法，但仍有许多治疗抵抗性情绪障碍的病例。这种疾病的病理生理尚不清楚，因此病理生理的阐明是建立预防和治疗这种情况的必要条件。根据临床遗传学研究，如家庭研究、双胞胎研究和收养研究，假设遗传因素参与情绪障碍的病因学。此外，情绪障碍患者单胺异常及精神药物单胺能机制提示单胺异常参与了情绪障碍的病理生理。上述两点导致了情绪障碍的单胺能基因研究。然而，没有可重复的结果。造成障碍的另一个原因是情绪障碍在病因上是异质的。因此，我们必须掌握其家族史、对精神药物的反应、个性、饲养经验和临床资料，以阐明其病理生理。此外，随着分子生物学的进步，我们可以探索单胺能分子遗传机制，这在过去是不可能的。因此，在了解了情绪障碍患者的药物反应、其他生物学数据、繁殖经历、个性和临床特征后，我们开始研究情绪障碍患者的单胺能分子遗传背景。我们用TC1测试抑郁症患者的性格。结果表明，抑郁严重程度与伤害回避呈正相关，与自我指导和合作呈负相关。此外，抗抑郁药治疗后，良好反应者接近正常值，但不良反应者没有改变。另一方面，在使用PBI的养育经验上，抑郁症和强迫症患者对父母的关爱程度较低，对母亲的保护程度较高。此外，特应性皮炎患者在TCI中有较高的伤害避免，而在PBI中没有任何特征。另一方面，根据季节性情感障碍的分子遗传学研究，5HTT多态性与疾病相关，但5-HT1a、1b、1d、2a、2c不相关。我们将继续进行分子遗传学研究，以获得药物反应的标记物，为新药的开发开辟道路。此外，我们正在开展的研究目标如下。1)开发一种早期发现抑郁症的工具。2)劳动者和一般医疗条件患者的心境障碍频率及环境因素。3)认知行为治疗抑郁症的有效性。少

项目成果

Hibiya M, Ichinose H, Ozaki N, Fujita K, Nishimoto T, Yoshikawa T, Asano Y, Nagatsu T: "Normal value and age-dependent changes in GTP cyclohydrase I activity in stimulated mononuclear blood cells measured by high-performance liquid chromatography."Journal

Hibiya M、Ichinose H、Ozaki N、Fujita K、Nishimoto T、Yoshikawa T、Asano Y、Nagatsu T：“通过高效液相色谱法测量受刺激的单核血细胞中 GTP 环化酶 I 活性的正常值和年龄依赖性变化。

Kusunoki K, Ozaki N, Sawada M, Sato T, Hirano S, Narita T: "Serum levels of dihydroneopterin and soluble cytokine receptors in major depression"Pteridines. 10. 24-26 (1999)

Kusunoki K、Ozaki N、Sawada M、Sato T、Hirano S、Narita T：“重度抑郁症中二氢新蝶呤和可溶性细胞因子受体的血清水平”蝶啶。