EXPOSURE TO TETRACYCLINE ANTIBIOTICS AND THE POTENTIAL PROTECTIVE EFFECT ON SCHIZOPHRENIA RISK.

接触四环素抗生素及其对精神分裂症风险的潜在保护作用。

• 批准号: 10039207
• 负责人: Veerle Bergink
• 金额: $ 41.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10039207
• 关键词: Acne; Adolescence; Adolescent; Adult; Age; Antibiotics; Brain; Cell Culture Techniques; Chronic; Clinical Research; Clinical Trials; Cohort Studies; Complement; Data; Data Set; Data Sources; Denmark; Development; Diagnosis; Disease; Dose; Doxycycline; Electronic Health Record; Exposure to; Family history of; Functional disorder; Genetic; Genetic study; Genomics; In Vitro; Individual; Lead; Length; Medical center; Mental Health; Mental disorders; Microglia; Minocycline; National Institute of Mental Health; Nature; Onset of illness; Outcome; Outcome Study; Parents; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacological Treatment; Pharmacology; Population; Prevention; Process; Psychiatric Diagnosis; Psychiatric epidemiology; Psychiatric therapeutic procedure; Publications; Randomized Clinical Trials; Records; Registries; Reproducibility; Research; Resources; Risk; Role; Schizophrenia; Series; Socioeconomic Status; Synapses; Technology; Testing; Tetracyclines; Time; Work; base; comorbidity; cost; design; electronic data; experimental study; follow-up; hazard; large scale data; longitudinal dataset; monocyte; novel; novel therapeutics; population based; preclinical study; prevent; protective effect; psychotic symptoms; randomized placebo-controlled clinical trial; sex; side effect; synaptic pruning; transcriptome; transcriptomics

SUMMARY Several lines of evidence suggest that tetracycline antibiotics, such as minocycline and doxycycline, are a promising new avenue to explore for prevention and treatment of schizophrenia. Tetracycline presumably targets increased synapse elimination by microglia underlying schizophrenia. This is the first strategy based on disease mechanism that is uncovered by preclinical studies, including the largest genetic and transcriptomic studies, as well as state-of-the-art stemcell-based technologies. It can therefore be viewed as the first pay-off of the tremendous efforts made by the global genomics consortia to generate novel leads to understand and treat schizophrenia. Over the last decades, multiple small clinical trials have been performed to test potential efficacy of new drugs for prevention and treatment of schizophrenia. Most of these trials failed or could not be replicated, perhaps because of a limited scientific premise. Here we suggest building better evidence for the potential efficacy of tetracycline antibiotics before performing large clinical trials. We will use one of the largest datasets in the world for which both detailed information of tetracycline exposure is available for all individuals in Denmark, as well as information on schizophrenia spectrum disorders diagnosed in all psychiatric treatment settings. The longitudinal nature of the data sources, and the length and extent of the follow-up of the subjects, is unique and unprecedented: 25 years follow-up period provides the opportunity to investigate whether the exposure to tetracycline antibiotics prevents or delays onset of a schizophrenia spectrum disorder. First, we will analyze the risk of a schizophrenia spectrum disorder after exposure to the brain-penetrant doxycycline. Next, we will look at the role of timing and duration of exposure to these antibiotics. Finally, we will compare the influence of exposure to doxycycline prescribed for acne on schizophrenia risk with exposure to other types of treatments prescribed for acne and to unexposed individuals. We will perform matched cohort studies to compare the exposed group with an unexposed group, or with a group exposed to other types of medication. As confounders we consider sex, socioeconomic status, family history of mental illness, and psychiatric and somatic comorbidity. The outcome of this study will be a better understanding of the utility of tetracycline antibiotics for prevention and treatment of schizophrenia spectrum disorders and will inform the design of a placebo-controlled randomized clinical trial of tetracycline for schizophrenia prevention, with the developmental period and potential dose informed by the results found here.

总结 一些证据表明，四环素类抗生素，如米诺环素和强力霉素，是一种有效的抗生素。 为精神分裂症的防治探索了一条新的途径。四环素可能靶向 小胶质细胞引起的突触消除增加是精神分裂症的基础。这是第一个基于疾病的策略 临床前研究发现的机制，包括最大的遗传和转录组学研究， 以及最先进的干细胞技术。因此，它可以被看作是第一次支付的 全球基因组学联盟为产生新的线索以了解和治疗 精神分裂症在过去的几十年里，已经进行了多项小型临床试验来测试潜在的疗效 用于预防和治疗精神分裂症的新药。这些试验大多失败或无法复制， 也许是因为有限的科学前提。在这里，我们建议为潜力建立更好的证据 在进行大型临床试验之前，对四环素类抗生素的疗效进行评估。我们将使用最大的数据集之一 在世界范围内，丹麦的所有个体均可获得四环素暴露的详细信息， 以及在所有精神病治疗环境中诊断的精神分裂症谱系障碍的信息。的 数据来源的纵向性质以及受试者随访的长度和范围是独特的， 前所未有的：25年随访期提供了调查暴露是否 四环素类抗生素预防或延迟精神分裂症谱系障碍的发作。 首先，我们将分析暴露于脑渗透剂后精神分裂症谱系障碍的风险 强力霉素接下来，我们将研究接触这些抗生素的时间和持续时间的作用。最后我们将 比较暴露于治疗痤疮的强力霉素对精神分裂症风险的影响， 其他类型的治疗处方痤疮和未暴露的个人。我们将进行配对队列研究 研究比较暴露组与未暴露组，或与暴露于其他类型的 药作为混杂因素，我们考虑性别、社会经济地位、精神疾病家族史， 精神和躯体共病这项研究的结果将是更好地了解的效用， 四环素类抗生素用于预防和治疗精神分裂症谱系障碍，并将告知 四环素预防精神分裂症的安慰剂对照随机临床试验设计， 发育期和潜在剂量由这里发现的结果告知。

项目成果

A Sex-Dependent Association Between Doxycycline Use and Development of Schizophrenia.

强力霉素使用与精神分裂症发展之间的性别依赖性关联。

• DOI: 10.1093/schbul/sbad008
• 发表时间: 2023
• 期刊: Schizophrenia bulletin
• 影响因子: 6.6
• 作者: deWitte,LotD;MunkLaursen,Thomas;Corcoran,CherylM;Kahn,RenéS;Birnbaum,Rebecca;Munk-Olsen,Trine;Bergink,Veerle
• 通讯作者: Bergink,Veerle