Leung Cheryl Cheuk-Yan, Gadelrab Romayne, Ntephe Chukwuma Uchenna, McGuire Philip K, Demjaha Arsime
Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King's College London, London, United Kingdom.
South London and Maudsley NHS Foundation Trust, London, United Kingdom.
Front Psychiatry. 2019 Sep 3;10:601. doi: 10.3389/fpsyt.2019.00601. eCollection 2019.
Despite considerable psychotherapeutic advancement since the discovery of chlorpromazine, almost one third of patients with schizophrenia remain resistant to dopamine-blocking antipsychotics, and continue to be exposed to unwanted and often disabling side effects, but little if any clinical benefit. Even clozapine, the superior antipsychotic treatment, is ineffective in approximately half of these patients. Thus treatment resistant schizophrenia (TRS), continues to present a major therapeutic challenge to psychiatry. The main impediment to finding novel treatments is the lack of understanding of precise molecular mechanisms leading to TRS. Not only has the neurobiology been enigmatic for decades, but accurate and early detection of patients who are at risk of not responding to dopaminergic blockade remains elusive. Fortunately, recent work has started to unravel some of the neurobiological mechanisms underlying treatment resistance, providing long awaited answers, at least to some extent. Here we focus on the scientific advances in the field, from the clinical course of TRS to neurobiology and available treatment options. We specifically emphasize emerging evidence from TRS imaging and genetic literature that implicates dysregulation in several neurotransmitters, particularly dopamine and glutamate, and in addition genetic and neural alterations that concertedly may lead to the formation of TRS. Finally, we integrate available findings into a putative model of TRS, which may provide a platform for future studies in a bid to open the avenues for subsequent development of effective therapeutics.
尽管自氯丙嗪被发现以来心理治疗取得了长足进步，但几乎三分之一的精神分裂症患者对多巴胺阻断型抗精神病药物仍有抗性，持续遭受不良且往往致残的副作用，却几乎没有临床益处。即便氯氮平这种更优的抗精神病药物，在大约一半的此类患者中也无效。因此，难治性精神分裂症（TRS）仍然是精神病学面临的重大治疗挑战。寻找新疗法的主要障碍在于缺乏对导致TRS的精确分子机制的理解。几十年来，神经生物学一直谜团重重，而且准确、早期检测出对多巴胺能阻断无反应风险的患者仍然难以实现。幸运的是，最近的研究已开始揭示一些治疗抗性背后的神经生物学机制，至少在一定程度上提供了期待已久的答案。在此，我们聚焦于该领域的科学进展，从TRS的临床病程到神经生物学以及可用的治疗选择。我们特别强调来自TRS影像学和遗传学文献的新证据，这些证据表明几种神经递质，尤其是多巴胺和谷氨酸存在失调，此外还有可能共同导致TRS形成的基因和神经改变。最后，我们将现有发现整合到一个TRS的假定模型中，这可能为未来研究提供一个平台，以开辟后续有效治疗方法开发的途径。
