Vita Antonio, Minelli Alessandra, Barlati Stefano, Deste Giacomo, Giacopuzzi Edoardo, Valsecchi Paolo, Turrina Cesare, Gennarelli Massimo
Department of Mental Health and Addiction Services, ASST Spedali Civili, Brescia, Italy.
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Front Pharmacol. 2019 Apr 16;10:402. doi: 10.3389/fphar.2019.00402. eCollection 2019.
Schizophrenia is a severe neuropsychiatric disorder that affects approximately 0.5-1% of the population. Response to antipsychotic therapy is highly variable, and it is not currently possible to predict those patients who will or will not respond to antipsychotic medication. Furthermore, a high percentage of patients, approximately 30%, are classified as treatment-resistant (treatment-resistant schizophrenia; TRS). TRS is defined as a non-response to at least two trials of antipsychotic medication of adequate dose and duration. These patients are usually treated with clozapine, the only evidence-based pharmacotherapy for TRS. However, clozapine is associated with severe adverse events. For these reasons, there is an increasing interest to identify better targets for drug development of new compounds and to establish better biomarkers for existing medications. The ability of antipsychotics to improve psychotic symptoms is dependent on their antagonist and reverse agonist activities at different neuroreceptors, and some genetic association studies of TRS have focused on different pharmacodynamic factors. Some genetic studies have shown an association between antipsychotic response or TRS and neurodevelopment candidate genes, antipsychotic mechanisms of action (such as dopaminergic, serotonergic, GABAergic, and glutamatergic) or pharmacokinetic factors (i.e., differences in the cytochrome families). Moreover, there is a growing body of literature on the structural and functional neuroimaging research into TRS. Neuroimaging studies can help to uncover the underlying neurobiological reasons for such resistance and identify resistant patients earlier. Studies examining the neuropharmacological mechanisms of antipsychotics, including clozapine, can help to improve our knowledge of their action on the central nervous system, with further implications for the discovery of biomarkers and the development of new treatments. The identification of the underlying mechanisms of TRS is a major challenge for developing personalized medicine in the psychiatric field for schizophrenia treatment. The main goal of precision medicine is to use genetic and brain-imaging information to improve the safety, effectiveness, and health outcomes of patients via more efficiently targeted risk stratification, prevention, and tailored medication and treatment management approaches. The aim of this review is to summarize the state of art of pharmacogenetic, pharmacogenomic and neuroimaging studies in TRS.
精神分裂症是一种严重的神经精神疾病，影响着约0.5%-1%的人口。对抗精神病药物治疗的反应差异很大，目前尚无法预测哪些患者会对抗精神病药物有反应或无反应。此外，相当比例（约30%）的患者被归类为治疗抵抗（治疗抵抗性精神分裂症；TRS）。TRS的定义是对至少两次足够剂量和疗程的抗精神病药物试验无反应。这些患者通常使用氯氮平治疗，氯氮平是唯一有循证依据用于TRS的药物治疗方法。然而，氯氮平会引发严重不良事件。出于这些原因，人们越来越有兴趣为新化合物的药物开发确定更好的靶点，并为现有药物建立更好的生物标志物。抗精神病药物改善精神病症状的能力取决于它们在不同神经受体上的拮抗剂和反向激动剂活性，一些TRS的基因关联研究聚焦于不同的药效学因素。一些基因研究表明，抗精神病药物反应或TRS与神经发育候选基因、抗精神病药物作用机制（如多巴胺能、5-羟色胺能、γ-氨基丁酸能和谷氨酸能）或药代动力学因素（即细胞色素家族的差异）之间存在关联。此外，关于TRS的结构和功能神经影像学研究的文献越来越多。神经影像学研究有助于揭示这种抵抗的潜在神经生物学原因，并更早地识别出抵抗患者。研究抗精神病药物（包括氯氮平）的神经药理学机制，有助于增进我们对其在中枢神经系统作用的了解，进而对生物标志物的发现和新治疗方法的开发产生影响。确定TRS的潜在机制是精神分裂症治疗领域开发个性化药物的一项重大挑战。精准医学的主要目标是利用基因和脑成像信息，通过更有效的靶向风险分层、预防以及定制化药物和治疗管理方法，改善患者的安全性、有效性和健康结局。本综述的目的是总结TRS的药物遗传学、药物基因组学和神经影像学研究的现状。
