Serotonin Reuptake Inhibitors and Bone Mineralization in Adolescents

描述(由申请人提供)：成年早期获得的骨量是终生患骨质疏松症风险的主要决定因素。因此，优化峰值骨量对于避免骨折及其相关的发病率和死亡率至关重要。新出现的证据表明，5-羟色胺在骨骼新陈代谢中起着核心作用。例如，临床前实验表明，骨细胞表达5-羟色胺转运体和各种功能上的5-羟色胺受体，它们的活动调节着骨的周转。流行病学研究表明，选择性5-羟色胺再摄取抑制剂(SSRI)与老年人骨密度降低和骨折风险增加有关。SSRI在年轻人中被广泛用于治疗一些精神疾病。然而，尽管它们的短期疗效和安全性已经确定，但它们的长期安全性仍然很少被调查。在这里，我们建议在一项为期两年的前瞻性观察研究中招募15至20岁的参与者，开始SSRI治疗。在获奖期间，腰椎和全身的骨密度将使用双X射线吸收测量仪测量，桡骨的骨密度将使用外围定量计算机断层扫描进行测量。将进行详细的精神病学评估，以控制作为影响骨矿化的潜在混杂因素的精神病理学。在后续治疗期间，精神病治疗的变化也将被记录和说明。通过使用一组年龄和性别分布相似的健康对照组，我们的目标是评估1)基线时的精神病理学是否与低骨量有关，2)SSRI治疗是否抑制骨矿化，3)SSRI停止后骨矿含量是否恢复。4)此外，基因测试将调查5-羟色胺系统基因的变异是否会缓和SSRI治疗对骨密度的影响。总之，这项工作旨在提高精神治疗的长期安全性，以优化精神障碍患者的功能和生活质量。这与国家精神卫生研究所的使命是一致的。 公共卫生相关性：基于动物研究、儿科临床试验、成人流行病学研究的结果，以及我们实验室在儿童和青少年中的初步发现，该项目旨在调查SSRI，一组广泛使用的精神药物，是否与年轻人的骨矿化受损有关。建立这种联系是最终涉及制定预防性干预措施的进程的第一步。确定使某些年轻人面临这种副作用风险较高的遗传因素，最终将使临床医生能够根据每个年轻人的需求和脆弱性进行量身定制的治疗，从而使这一领域更接近个性化药物。

DESCRIPTION (provided by applicant): Bone mass achieved by early adulthood is a major determinant of lifetime risk for osteoporosis. Therefore, optimizing peak bone mass is crucial to avoiding bone fracture with its associated morbidity and mortality. Emerging evidence suggests that serotonin plays a central role in bone metabolism. For example, preclinical experiments have shown that bone cells express the serotonin transporter and a variety of functional serotonin receptors whose activity modulates bone turnover. Epidemiologic studies have linked selective serotonin reuptake inhibitors (SSRIs) to reduced bone mineral density and increased fracture risk in the elderly. SSRIs are widely used in youths to treat a number of psychiatric disorders. However, while their short-term efficacy and safety have been established, their long-term safety remains little investigated. We, here, propose to recruit, in a 2-year prospective observational study, 15 to 20 year-old participants upon the initiation of SSRI treatment. During the period of the Award, bone mineral density of the lumbar spine and whole body will be measured using dual x-ray absorptiometry and of the radius using peripheral quantitative computerized tomography. A detailed psychiatric assessment will be conducted to control for psychopathology, as a potential confounding factor affecting bone mineralization. Changes in psychiatric treatment during the follow up period will also be documented and accounted for. By using a group of healthy controls, of comparable age and sex distribution, we aim to evaluate 1) whether psychopathology, at baseline, is associated with low bone mass, 2) if treatment with SSRIs suppresses bone mineralization, and 3) if the discontinuation of the SSRI is followed by a restoration of bone mineral accrual. 4) Furthermore, genetic testing will investigate whether variants of the serotonin system genes moderate the effect of SSRI treatment on bone mineral density. In sum, this work aims to improve the long-term safety of psychiatric treatments in order to optimize functioning and the quality of life of those who suffer from psychiatric disorders. This is consistent with the mission of the National Institute of Mental Health. PUBLIC HEALTH RELEVANCE: Building on findings from animal studies, pediatric clinical trials, epidemiologic research in adults, and on preliminary findings from our laboratory in children and adolescents, this project aims to investigate whether SSRIs, a group of widely-used psychotropics, are associated with impaired bone mineralization in youths. Establishing such an association is a first step in a process that would eventually involve developing preventative interventions. Identifying genetic factors that place certain youths at higher risks for this side effect would ultimately allow clinicians to tailor treatment to the needs and vulnerabilities of each youth, moving the field closer towards individualized medicine.