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

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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.