Treatment-resistant schizophrenia (TRS), the persistence of positive symptoms despite ≥2 trials of adequate dose and duration of antipsychotic medication with documented adherence, is a serious clinical problem with heterogeneous presentations. TRS can vary in its onset (at the first episode of psychosis or upon relapse), in its severity, and in the response to subsequent therapeutic interventions (i.e., clozapine, electroconvulsive therapy). The heterogeneity of TRS indicates that the underlying neurobiology of TRS may differ not only from treatment-responsive schizophrenia but also among patients with TRS. Several hypotheses have been proposed for the neurobiological mechanisms underlying TRS, including dopamine supersensitivity, hyperdopaminergic and normodopaminergic subtypes, glutamate dysregulation, inflammation and oxidative stress, and serotonin dysregulation. Research supporting these hypotheses is limited in part by variations in the criteria used to define TRS, as well as by the biological and clinical heterogeneity of TRS. Clinical trial designs for new treatments should be informed by this heterogeneity, and further clinical research is needed to more clearly understand the underlying neurobiology of TRS and to optimize treatment for patients with TRS.

中文翻译：

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难治性精神分裂症的神经生物学：抗精神病药物耐药的途径和未来研究的路线图。

难治性精神分裂症（TRS）是一种具有异质性表现的严重临床问题，即尽管进行了≥2次足够剂量和持续时间的抗精神病药物试验并记录了依从性，但阳性症状持续存在。TRS 的发作（精神病首次发作或复发时）、严重程度以及对后续治疗干预（即氯氮平、电休克治疗）的反应各不相同。TRS 的异质性表明，TRS 的潜在神经生物学不仅可能与治疗反应性精神分裂症不同，而且在 TRS 患者之间也可能不同。对于 TRS 的神经生物学机制提出了几种假设，包括多巴胺超敏性、高多巴胺能和正常多巴胺能亚型、谷氨酸失调、炎症和氧化应激以及血清素失调。支持这些假设的研究部分受到用于定义 TRS 的标准的变化以及 TRS 的生物学和临床异质性的限制。新疗法的临床试验设计应考虑到这种异质性，并且需要进一步的临床研究来更清楚地了解 TRS 的潜在神经生物学并优化 TRS 患者的治疗。