Inhibitors of serine racemase as novel therapeutics for treatment-resistant depression

重度抑郁症（MDD）是一种导致持续悲伤、低自尊和冷漠的情绪紊乱，在2-8%的成年人中会导致自杀。根据世界卫生组织的数据，重度抑郁症是全球致残的第二大原因，仅在美国就造成了约2100亿美元的经济负担。重度抑郁症的标准治疗是抗抑郁药物，如血清素再摄取抑制剂。然而，大约三分之一的患者对这些常见的抗抑郁药没有反应。在这些难治性抑郁症患者中，实验性地使用静脉注射麻醉剂氯胺酮和通过鼻子给药的相关药物艾氯胺酮显示出良好的效果。然而，氯胺酮有一些严重的副作用，包括精神病、认知和身体损伤，它也是一种有成瘾可能的娱乐性药物。因此，一种与氯胺酮作用于相同蛋白质但作用机制截然不同的药物可能会更安全，而且更容易产生b政府将，这使得患者群体对它的耐受性比氯胺酮好得多。常见的抗抑郁药可以调节所谓的“情绪化学物质”血清素的水平，而氯胺酮通过改变大脑中另一种化学物质谷氨酸的功能起作用。因此，氯胺酮通过阻断谷氨酸对n -甲基- d -天冬氨酸受体（NMDARs）的作用而起作用。然而，除了谷氨酸，NMDARs还需要另一种化学物质d -丝氨酸来发挥其功能。因此，我们假设，通过抑制制造d -丝氨酸的蛋白质（丝氨酸消旋酶）来减少大脑中d -丝氨酸的数量，我们应该能够改变NMDARs的功能，其方式类似于氯胺酮在难治病的抑郁症中产生治疗效果的方式。然而，重要的是，丝氨酸消旋酶抑制剂药物的不同作用机制意味着它将是一种比氯胺酮更安全的治疗选择，因为它在大脑中的有限分布意味着它不会产生与氯胺酮相关的令人不快的副作用。

Major depressive disorder (MDD) is a disorder that causes persistent feelings of sadness, low self-esteem and apathy and in 2-8% of adults it leads to suicide. According to the World Health Organisation, MDD is the second leading cause of global disability, with an estimated economic burden of ~$210 billion in the US alone. The standard treatment for MDD is anti-depressant drugs, such as serotonin-reuptake inhibitors. However, around one-third of patients do not respond to these common antidepressants. In these treatment-resistant depression patients, the experimental use of the intravenous anaesthetic ketamine has shown promising results as has a related drug called esketamine which is administered via the nose. Nevertheless, ketamine has several serious side effects including psychosis, cognitive and physical impairment and it is also a recreational drug with potential for addiction. Therefore, a drug that works on the same protein as ketamine but has a very different mechanism of action will likely have a safer profile which along with an easier route of administration would make it much better tolerated than ketamine by this patient population. Common antidepressants, which modulate levels of the so-called "mood chemical" serotonin whereas ketamine acts by altering the function of a different chemical in the brain, glutamate. Hence, ketamine works by blocking the effects of glutamate at proteins called N-methyl-D-aspartate receptors (NMDARs). However, in addition to glutamate, NMDARs also require a second chemical, D-serine to perform their function. Consequently, we hypothesise that by reducing the amount of D-serine in the brain by inhibiting the protein that makes it (serine racemase) we should be able to alter the function of NMDARs in a manner analogous to how ketamine produces its therapeutic benefits in treatment-resistant depression. Importantly, however, the different mechanism of action of a serine racemase inhibitor drug means that it will be a safer therapeutic option than ketamine since its restricted distribution in the brain means that is will not produce the unpleasant side-effects associated with ketamine.