The role of glutamatergic function in the pathophysiology of treatment-resistant schizophrenia and the potential of novel treatment targeting it

精神分裂症影响1在100人，是一种慢性和致残性精神疾病。抗精神病药物是精神分裂症的一线治疗药物。但对许多患者无效。对两种或两种以上足够剂量和持续时间的抗精神病药物治疗无效的患者被称为难治性精神分裂症（TRS）。TRS很常见，影响约三分之一的患者，并且与一般精神分裂症患者相比，与更差的生活质量，更长的住院时间和更差的功能有关。在英国，精神分裂症的费用估计为每年118亿英镑，在TRS中也高出3至11倍。氯氮平是唯一被许可用于治疗TRS的抗精神病药物。然而，它的使用受到耐受性差、危及生命的副作用和频繁血液监测要求的限制。事实上，不到三分之一的TRS患者接受氯氮平治疗。此外，即使使用氯氮平，许多患者对氯氮平的反应也不充分。鉴于这些局限性，显然需要替代药物治疗TRS。然而，缺乏对TRS的神经生物学的了解一直是寻找新的TRS治疗方法的主要障碍。近年来，一些影像学研究表明，TRS有不同的潜在神经生物学的患者谁对非氯氮平抗精神病药物反应。虽然在精神分裂症中常见的多巴胺传递的变化在TRS中不存在，但另一种称为谷氨酸的神经递质的水平增加了，特别是在称为前扣带皮层（ACC）的大脑区域。这表明TRS可能存在不同的潜在机制。总之，这一证据暗示谷氨酸系统在TRS的神经生物学中，并表明靶向谷氨酸可能是一种新的治疗方法。然而，目前还不清楚谷氨酸是否是TRS的基础，或者靶向谷氨酸水平是否是一种有效的治疗方法。关键的测试是降低谷氨酸水平，并确定对症状的影响。为了实现这一目的，我们的目标是使用一种名为利鲁唑的药物，降低大脑谷氨酸水平。一项小型临床研究的初步证据表明，利鲁唑可能改善TRS的症状。此外，在我们的研究小组进行的一项初步研究中，我们发现利鲁唑降低了TRS患者的谷氨酸水平。然而，这项研究没有测试是否降低谷氨酸水平导致症状减轻，临床研究需要在确诊的TRS患者中进行复制。第一个问题是，脑神经元功能是否是TRS病理生理学的核心。另一个问题是是否有可能降低TRS中的谷氨酸水平，以及这是否会改善症状。为了回答这些问题，我们将使用一种称为磁共振波谱（MRS）的成像技术来测量TRS患者ACC中的谷氨酸水平。我们将采用随机、双盲安慰剂对照设计。患有TRS的患者将接受基线扫描，然后接受利鲁唑或安慰剂，持续56天的时间，并在此时进行随访扫描，以便：i）确定当与安慰剂相比时，利鲁唑治疗是否导致谷氨酸水平的降低，如通过MRS成像评估的; ii）确定利鲁唑相对于安慰剂是否改善症状，以及iii）谷氨酸水平的变化是否与症状严重程度的减轻直接相关。本研究将提供靶向谷氨酸系统用于治疗TRS的潜力的关键证据，提高我们对TRS神经生物学的理解，最终将有助于指导开发针对谷氨酸系统的治疗TRS的新药。

Schizophrenia affects 1 in 100 people and is a chronic and disabling psychiatric illness. Antipsychotic drugs are the first-line treatment for schizophrenia. However, they are ineffective for many patients. Patients who do not respond to two or more antipsychotic treatments of adequate dose and duration are said to have treatment-resistant schizophrenia (TRS). TRS is common, affecting about one third of patients, and is associated with worse quality of life, longer hospital admissions, and worse functioning than in schizophrenia in general. Schizophrenia costs, which in the UK are estimated to be £11.8 billion per year, are also 3 to 11-fold higher in TRS.Clozapine is the only antipsychotic that has been licensed for the treatment of TRS. However, its use is limited by poor tolerability, life-threatening side-effects and requirements for frequent blood monitoring. In fact, less than one third of TRS patients receive clozapine. Moreover, even when it is used, many patients show inadequate response to clozapine.Given these limitations, there is a clear need for alternative medications for TRS. However, the lack of understanding of the neurobiology of TRS has been a major impediment to finding novel treatments for TRS.In recent years several imaging studies have suggested that TRS has a different underlying neurobiology to that seen in patients who respond to non-clozapine antipsychotics. While changes in dopamine transmission usually seen in schizophrenia are absent in TRS, levels of another neurotransmitter called glutamate have are increased, particularly in a brain region called the anterior cingulate cortex (ACC). This suggests that a different underlying mechanism may underlie TRS.Taken together, this evidence implicates the glutamate system in the neurobiology of TRS, and indicates that targeting glutamate could be a new approach to treatment. However, it is still unknown if glutamate underlies TRS or if targeting glutamate levels could be an effective treatment. The key test is to reduce glutamate levels and determine the effect on symptoms.To achieve this purpose we aim to use a drug called riluzole that reduces brain glutamate levels. There is preliminary evidence from a small clinical study that riluzole may improve symptoms in TRS. Moreover, in a pilot study conducted by our research group we showed that riluzole reduces glutamate levels in patients with TRS. However, this study did not test if reducing glutamate levels led to a reduction in symptoms, and the clinical study needs replication in patients with confirmed TRS.In this proposal we plan to test two critical gaps in knowledge. The first is whether brain glutamatergic function is central to the pathophysiology of TRS. The other is whether it is possible to reduce glutamate levels in TRS and if this will improve symptoms.To answer these questions we will use an imaging technique called magnetic resonance spectroscopy (MRS) to measure glutamate levels in the ACC of TRS patients. We will use a randomised, double-blind placebo controlled design. Patients with TRS will receive a baseline scan and then riluzole or placebo for a period of 56 days and follow-up scans at this point in order to: i) determine if treatment with riluzole leads to a reduction in glutamate levels, as assessed via MRS imaging, when compared to placebo; ii) determine if riluzole improves symptoms relative to placebo, and iii) if change in glutamate levels is directly associated with a reduction in symptom severity.This study will provide critical evidence of the potential to target the glutamate system for the treatment of TRS, improve our understanding on the neurobiology of TRS, and finally will help guide the development of new drugs targeting the glutamate system for the treatment of TRS.