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

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.

There is a need to improve outcomes in patients with anxiety disorders by using innovative approaches to rigorously evaluate new drugs and re-purpose existing medicines as novel treatments. As part of MRC award/J011754 we extended and validated an experimental carbon-dioxide (CO2) inhalation human model of anxiety for treatment development. This model induces subjective, autonomic and neuropsychological features of anxiety and has been validated with the established drug duloxetine, which is known to be effective in generalized anxiety disorder. We will use this model to evaluate the therapeutic potential of a novel mechanism of anxiolytic drug action - acid sensing ion channels (ASICs).
Recent animal studies using lesion, knock-out/in, agonism and antagonism methods implicate ASIC1 activation in anxious behavior and inhibition in anxiolysis in mice. Consequently the existing evidence provides strong support for the hypothesis that ASIC inhibitors should have therapeutic potential in human anxiety - our study will provide a timely, cost-effective and efficient first test of this hypothesis in humans. In a double-blind placebo controlled study we will compare the effects of the ASIC inhibitor amiloride on subjective, autonomic and neuropsychological outcomes in our extended carbon dioxide inhalation model of anxiety in healthy humans.

We are confident that the proposed research will have implications both in the short and longer term, and will go beyond academic beneficiaries to influence patients, industry, and the wider economy.

People: Anxiety symptoms are common in the community, and anxiety disorders are common in primary and secondary medical care with estimated 12-month prevalence of 12% and life-time prevalence of 17-21% (Wittchen et al., 2011). Generalized anxiety disorder (GAD) is characterized by excessive worry that is difficult to control, irritability, poor concentration, sleep disturbance, and increased risk of co-morbid psychiatric and physical illness. The reduction in quality of life in GAD is at least comparable with that observed in major depressive disorder and greater than substance use disorders, with significant burden experienced by the individual and their families (Hoffman et al. 2008). The estimated total cost of anxiety disorders in Europe is around EUR 41 billion with the average annual additional cost per person with GAD estimated at EUR 1,628 (76% = provision of healthcare services; 24% = productivity loss due to sick leave; Andlin-Sobocki & Wittchen, 2005).

The 'ideal treatment' for GAD does not yet exist - 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. Consequently there is a need to improve outcomes in patients through using validated experimental human models of anxiety that improve on the poor predictability of preclinical animal models and allow us to effectively evaluate novel pharmacological compounds and re-purpose existing medicines as novel treatments for anxiety, prior to evaluation in clinical trials with patients (Nutt & Goodwin, 2011). The MRC: review of mental health research calls for the development of improved treatments for mental illness (see also Sahakian et al. 2010, Lancet). Our proposed research uses a validated experimental model of anxiety to evaluate the therapeutic potential of an existing medicine that targets a novel mechanism of anxiolytic drug action. Our study will be the first evaluation of this drug mechanism in human anxiety. Positive results would in the medium term help translate this and related drugs into phase III trials in patients, and in the longer term could provide alternative cost-effective evidence-based treatments for anxiety disorders. Clinicians caring for patients with anxiety disorders are familiar with the limitations and drawbacks of existing treatments, and with uncertainties regarding their mechanism of action. The proposed study could validate a new mechanism in human anxiety, and could lead to changes in treatment approaches for patients with GAD.

Industry: Consolidating links between academic and industrial partners/consortia is likely to become increasingly important in a future where industry is no longer motivated to alone meet the costly demands associated with successfully developing effective treatments for mental health. Indeed a major cause of late failures in CNS drug development is the lack of efficacy in patients due in part to the poor predictive validity of pre-clinical animal models. We will seek to embed the model with our existing industrial collaborators and with pharma consortia to evaluate developmental compounds that target novel mechanisms of anxiolytic action, and which in time might include ASIC mechanisms outlined in the current proposal.

Impact through broad dissemination to the public, user groups (in collaboration with AnxietyUK), clinicians and others is summarized in the Communication Plan.