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; 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.

概括 几条证据表明，四环素抗生素，例如米诺环素和强力霉素，是一种 有望探索预防和治疗精神分裂症的新途径。四环素大概是目标 基础精神分裂症基础小胶质细胞消除突触的增加。这是基于疾病的第一个策略 临床前研究发现的机制，包括最大的遗传和转录组研究 以及最先进的基于Stemcell的技术。因此，它可以看作是 全球基因组学联盟为产生新颖的潜在客户所做的巨大努力以理解和治疗 精神分裂症。在过去的几十年中，已经进行了多项小型临床试验以测试潜在的功效 用于预防和治疗精神分裂症的新药。这些试验中的大多数失败或无法复制， 也许是因为科学前提有限。在这里，我们建议建立更好的潜力证据 进行大型临床试验之前，四环素抗生素的功效。我们将使用最大的数据集之一 在世界上，丹麦的所有个人都可以使用两种详细的四环素暴露信息 以及有关在所有精神病治疗环境中诊断出的精神分裂症谱系障碍的信息。这 数据源的纵向性质以及受试者随访的长度和程度是独特的，并且 前所未有的：25年的随访期提供了调查是否暴露的机会 四环素抗生素可防止或延迟精神分裂症谱系障碍。 首先，我们将分析暴露于脑渗透剂后的精神分裂症谱系障碍的风险 强力霉素。接下来，我们将研究时间和暴露于这些抗生素的持续时间的作用。最后，我们会的 比较暴露于痤疮的强力霉素对精神分裂症风险的影响与暴露 针对痤疮和未暴露的个体规定的其他类型的治疗方法。我们将执行匹配的队列 研究将暴露组与未暴露的组进行比较，或与其他类型的组相比 药物。作为混杂因素，我们考虑性别，社会经济地位，精神疾病家族史以及 精神病和躯体合并症。这项研究的结果将更好地理解 四环素抗生素用于预防和治疗精神分裂症谱系障碍，并将告知 安慰剂对照的精神分裂症预防四环素的随机临床试验的设计， 在此发现的结果所告知的发育期和潜在剂量。