Targeting acid sensing ion channels in anxiety - a first experimental study in humans.

焦虑症状在一般人群中很常见，焦虑症患者通常会出现严重且持续的症状，导致严重的个人痛苦，损害日常功能并降低生活质量。广泛性焦虑症（GAD）是一种负担沉重且持久的疾病，包括过度和持续的焦虑和担忧，难以集中注意力和过度警惕。 目前治疗焦虑症的方法有局限性。许多患者对心理或药理学方法没有反应;心理治疗的可用性仍然有限，药物治疗往往与不必要的副作用有关。焦虑症的治疗指南建议使用针对神经递质血清素和去甲肾上腺素的药物。然而，最近的研究已经确定了其他药理学机制，可以有针对性地改善焦虑症的治疗。 酸敏感离子通道（ASIC）涉及许多健康状况，包括疼痛，神经系统疾病和焦虑。动物的初步研究表明，增加或减少ASIC活性的药物会导致焦虑行为的相应增加和减少。然而，ASIC抑制对人类焦虑的影响尚不清楚。这项拟议中的研究是第一个测试靶向ASIC的药物是否可以减少人类焦虑的研究。 目前，我们几乎没有药物可以靶向人类的ASIC。ASIC抑制剂阿米洛利可以减轻动物的焦虑，并且在人类中耐受良好。因此，我们将测试阿米洛利是否可以减少人类的焦虑。 我们将如何测试这种新型治疗方法的治疗潜力？现有的药物开发方法昂贵，并且依赖于在小动物身上进行的大量工作（例如，检查药物对动物行为模式的影响，这些行为模式“看起来像”我们在人类身上看到的焦虑症状）。这些焦虑的“动物模型”在预测哪些药物会成为成功的治疗方法，哪些不会方面并不足够有效，而且对于每一个成功开发的新治疗方法，都会有更多的失败。因此，有一个临床和经济的需要，采用“人类模型的焦虑”，以确定这些药物，可能有助于临床实践。最佳模型不仅应该测试尚未获得许可的新药，还应该评估用于治疗其他健康状况的现有药物是否也有助于治疗焦虑。这种对现有药物的“再利用”最近被专业机构和临床学术审查委员会强调为一种重要的，但明显未被充分利用的方法，以确定改善精神健康状况的治疗方法，包括焦虑。 我们最近由MRC资助的研究开发并验证了一种用于评估新治疗方法的人类焦虑模型。当健康人吸入含有7.5%二氧化碳的空气时，他们会感到焦虑和紧张，心率和血压增加，难以控制注意力，并对环境中的威胁信息变得“高度警惕”。这种焦虑的实验模型模拟了（在健康志愿者中）广泛性焦虑症患者的一系列症状。我们已经验证了这个模型，证明了已建立的药物度洛沙汀可以限制二氧化碳对焦虑，分心和侵入性担忧想法的影响。因此，这个实验模型提供了一个敏感和全面的测试，阿米洛利是否是一个有前途的新药治疗焦虑，以及未来的研究是否应该开发和评估其他焦虑药物的目标ASIC在人类。

Anxiety symptoms are common in the general population, and people with anxiety disorders typically have severe and persistent symptoms that cause significant personal distress, impair everyday function and reduce quality of life. Generalized Anxiety Disorder (GAD) is a burdensome and long-lasting condition that includes excessive and persistent anxiety and worry, difficulty concentrating and hyper-vigilance. Current treatments for anxiety have limitations. Many patients do not respond to psychological or pharmacological approaches; psychological treatments remain limited in availability, and drug treatments are often linked to unwanted side-effects. Treatment guidelines for anxiety disorders recommend the use of drugs that target the neurotransmitters serotonin and noradrenaline. However recent research has identified other pharmacological mechanisms that could be targeted to improve treatments for anxiety. Acid-sensing ion channels (ASIC) are implicated in a number of health conditions including pain, neurological disease and anxiety. Initial studies in animals suggest that drugs that increase or decrease ASIC activity lead to corresponding increases and decreases in anxious behaviour. However, the effects of ASIC inhibition on human anxiety are unknown. The proposed research is the first to test whether drugs that target ASIC can reduce anxiety in humans. At present we have few drugs that can target ASIC in humans. The ASIC inhibitor amiloride can reduce anxiety in animals, and is well tolerated in humans. We will therefore test whether amiloride can reduce anxiety in humans. How will we test the therapeutic potential of this novel treatment approach? Existing methods of drug development are expensive and rely on extensive work in small animals (e.g. examining the effects of drugs on patterns of behaviour in animals that 'look like' the anxiety symptoms that we see in humans). These 'animal models' of anxiety are not sufficiently effective in predicting which drugs will become successful treatments and which will not, and for every new treatment successfully developed, many more will fail. Consequently there is a clinical and economic need to employ 'human models of anxiety' to identify those drugs which could be helpful in clinical practice. Optimal models should not only test new yet-to-be licenced drugs, but also evaluate whether existing medicines, used to treat other health conditions, can also help treat anxiety. This 're-purposing' of existing drugs has recently been highlighted by professional bodies and clinical-academic review committees as a crucial, but significantly underused way to identify improved treatments for mental health conditions, including anxiety. Our recent research funded by the MRC has developed and validated a human model of anxiety for evaluating new treatments. When healthy humans inhale air 'enriched' with 7.5% carbon dioxide (CO2) they report feeling anxious and nervous, experience increased heart rate and blood pressure, have difficulty controlling their attention and become 'hypervigilant' for threatening information in their environment. This experimental model of anxiety mimics (in healthy volunteers) the range of symptoms seen in patients with GAD. We have validated this model by showing that the established drug duloxetine can limit the effects of CO2 on anxiety, distractibility and intrusive worrying thoughts. This experimental model therefore provides a sensitive and comprehensive test of whether amiloride is a promising new drug treatment for anxiety, and whether future research should develop and evaluate other anxiety drugs that target ASIC in humans.