Towards a translational experimental model of anxiety for pharmacological and psychological treatment development.

焦虑症状在一般人群中很常见，焦虑症患者有严重和持续的症状，会导致明显的个人痛苦，损害日常功能并降低生活质量。广泛性焦虑症（GAD）是一种严重而持久的疾病，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。药物治疗并非对所有患者都有效，有些会产生不必要的副作用。研究已经确定了大脑中可能参与焦虑发展的几种化学过程，并且可以通过新的，更有效的药物治疗来靶向。然而，现有的开发新药物治疗的方法是昂贵的，并且依赖于小动物的广泛开发工作（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”我们在人类患者中看到的焦虑症状）。这些焦虑的“动物模型”无法有效地预测哪些药物会成为成功的治疗方法，哪些不会，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，临床和经济上需要开发更好、更有效的方法来评估“人类焦虑模型”中潜在的新药物治疗，这些方法能够更好地识别那些可能有助于临床实践的药物。当健康人吸入富含7.5%二氧化碳（CO2）的空气时，他们会感到焦虑和紧张，心率和血压增加，并对环境中的威胁信息保持高度警惕。这种“CO2模型”模拟了（在健康志愿者中）我们在GAD患者中看到的临床症状，并提供了一种新的测试，我们可以用来评估新药物治疗焦虑的潜在有效性。拟议的研究将检查i）一系列新的有前途的药物治疗对健康个体中二氧化碳诱导的焦虑的潜在有效性，以及ii）现有的药物治疗是否可以限制二氧化碳吸入对焦虑症患者的负面影响。 CO2模型也可用于评估新的焦虑心理治疗方法。认知行为疗法（CBT）是一种有效的焦虑心理治疗方法，可以改变焦虑背后的思维和行为模式。然而，CBT并不是对所有患者都有效，因此研究已经转向开发CBT的改进版本（所谓的“第三波干预”），其中包括各种形式的心理训练，帮助个人更好地控制和减少他们的担忧想法，并在出现时科普令人沮丧的想法。虽然“第三波”干预措施对抑郁症有效，但其对焦虑症的有效性尚不清楚，而且这些培训包中的“活性成分”也没有很好的定义。CO2模型提供了一个很好的实验工具，使我们能够检查“第三波治疗”的不同方面（即注意力控制与应对）在多大程度上减少健康个体吸入CO2时的焦虑感，生理唤醒和过度警惕。 最后，获得现有的心理治疗焦虑是有限的，因此努力已经转向开发新的“计算机化”的治疗包，可以在线提供，旨在纠正注意力控制和过度警惕的问题。所谓的“注意力偏差修正”计算机化训练包在减少焦虑方面有一定的效果，但当遇到压力情况时，它们在多大程度上产生长期的好处还不清楚。我们将研究“注意力偏差修正”治疗对健康个体中CO2诱导的焦虑、自主觉醒和过度警觉的影响。

Anxiety symptoms are common in the general population, and patients with anxiety disorders have severe and persistent symptoms that cause significant personal distress, impair everyday function and reduce quality of life. Generalized Anxiety Disorder (GAD) is a severe and long-lasting condition which includes excessive and persistent anxiety and worry, difficulty concentrating and hyper-vigilance. Current treatments for anxiety have limitations. Drug treatments are not effective in all patients, and some produce unwanted side-effects. Research has identified several chemical processes in the brain that might be involved in the development of anxiety, and could be targeted by new, more effective drug treatments. However, existing methods of developing new drug treatments are expensive and rely on extensive development work in small animals, (for example, examining the effects of drugs on patterns of behaviour in animals that 'look like' the anxiety symptoms that we see in human patients). These 'animal models' of anxiety are not effective in predicting which drugs will become successful treatments and which will not, and for every new treatment successfully developed, many more will fail. Thus there is a clinical and economic need to develop better, more efficient ways of evaluating potential new drug treatments in 'human models of anxiety' that are better able to identify those drugs which may be helpful in clinical practice. 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 and become hypervigilant for threatening information in the environment. This 'CO2 model' mimics (in healthy volunteers) the clinical symptoms that we see in patients with GAD and provides a new test that we can use to evaluate the potential effectiveness of new drug treatments for anxiety. The proposed research will examine i) the potential effectiveness of a range of new promising drug treatments on CO2-induced anxiety in healthy individuals, and ii) whether established drug treatments can limit the negative effects of CO2-inhalation in patients with anxiety disorders. The CO2 model can also be used to evaluate new psychological treatments for anxiety. Cognitive-Behaviour Therapy (CBT) is an effective psychological treatment for anxiety that modifies problematic patterns of thinking and behaviour that underlie anxiety. However CBT is not effective in all patients thus research has moved towards developing improved versions of CBT (so called 'third-wave interventions') that include forms of mental training that help individuals to better control and reduce their worrying thoughts and cope with distressing thoughts when they arise. Though 'third-wave' interventions are effective for depression, their effectiveness for anxiety disorders is unclear, furthermore the 'active ingredient(s)' in these training packages are not well defined. The CO2 model provides an excellent experimental tool that will allow us to examine the extent to which different aspects of 'third-wave treatments' (i.e. attention control vs. coping), reduce elevated feelings of anxiety, physiological arousal and hypervigilance in healthy individuals when they inhale CO2. Finally, access to existing psychological treatments for anxiety is limited, therefore efforts have moved towards developing novel 'computerized' treatment packages that can be delivered on-line and that aim to correct problems with attention control and hypervigilance. So called 'attentional bias modification' computerized training packages have some effectiveness in reducing anxiety, but the extent to which they produce prolonged benefits when stressful situations are encountered is not known. We will examine the effects of an 'attentional bias modification' treatment on CO2-induced anxiety, autonomic arousal and hypervigilance in healthy individuals.