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

摘要 一些证据表明，四环素类抗生素，如米诺环素和多西环素，是一种 为精神分裂症的防治探索新的途径。四环素可能是靶标 精神分裂症背后的小胶质细胞增加突触消除。这是第一个基于疾病的策略 临床前研究发现的机制，包括最大的基因和转录研究，如 以及最先进的干细胞技术。因此，它可以被视为 全球基因组学联盟为产生新的线索来理解和治疗做出了巨大努力 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。这些试验中的大多数都失败了，或者无法复制， 也许是因为有限的科学前提。在这里，我们建议为潜在的可能性建立更好的证据 在进行大规模临床试验之前，四环素类抗生素的疗效。我们将使用最大的数据集之一 在丹麦，所有人都可以获得四环素暴露的详细信息的世界里， 以及在所有精神治疗环境中诊断出的精神分裂症谱系障碍的信息。这个 数据来源的纵向性质以及主题后续行动的长度和范围是独一无二的 史无前例：25年的随访期提供了调查接触的机会 四环素抗生素可以预防或推迟精神分裂症谱系障碍的发病。 首先，我们将分析在接触脑渗透剂后患精神分裂症谱系障碍的风险。 多西环素。接下来，我们将看看接触这些抗生素的时间和持续时间的作用。最后，我们会 暴露于治疗痤疮的多西环素对精神分裂症风险的影响与暴露于 为痤疮和未接触过粉刺的人开的其他类型的治疗。我们将执行匹配的队列 研究比较暴露组与非暴露组，或与暴露于其他类型的 药物治疗。作为混杂因素，我们认为性别、社会经济地位、精神疾病家族史以及 精神和躯体共病。这项研究的结果将是更好地理解 四环素类抗生素用于预防和治疗精神分裂症谱系障碍，并将向 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提供信息。

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.