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

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.

There is considerable need to improve outcomes in patients with anxiety through developing valid experimental human models of anxiety that improve on the poor predictability of preclinical animal models and allow us to more effectively evaluate novel pharmacological and psychological treatments (and mechanisms of action) in healthy volunteers, prior to phase II/III clinical trials in patients.
Inhalation of 7.5% carbon dioxide increases anxiety, autonomic arousal and induces neuropsychological deficits and biases in emotion processing in healthy individuals, and provides a putative translational experimental model of generalized anxiety disorder.
Using a new extended version of the CO2-model we will evaluate the effects of promising drug treatments with varied mechanisms of action (e.g. serotonin, noradrenaline, glutamate & melatonin) across CO2-induced subjective, autonomic and neuropsychological outcomes.
Third-wave cognitive behavioural psychological treatments may alleviate anxiety symptoms but future development will require clarification and experimental comparison of core component processes that may differentially mediate clinical improvement. Using the CO2 model we will evaluate 'attention control' and 'acceptance' modules emphasized in third-wave CBT interventions. We will also examine the effect of a computerized 'attentional bias modification' training protocol on subjective, autonomic and neuropsychological response to CO2 challenge, consistent with a need to evaluate its generality over time, stressful situation and across multiple outcome measures.
We will translate the CO2 model into the clinic to examine whether subjective, autonomic and neuropsychological response profiles to CO2 in GAD pretreatment i) covary with illness severity, and comorbidity, ii) distinguish/differ across GAD, unipolar depression and comorbid GAD/depression, iii) predict subsequent response to treatment, and iv) resolve (at follow-up) with pharmacological treatment.

We are confident that the proposed research will have implications both in the short and longer term, and will go beyond academic beneficiaries to 'impact' patients, industry, society and the 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 is characterized by excessive worry that is difficult to control, irritability, poor concentration, sleep disturbance, and increased risk of co-morbid psychiatric illness. Poor 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 41 billionEuro with the average annual additional cost per person with GAD estimated at 1,628Euro (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 - current treatments have insufficient efficacy both in the short- and long-term. Thus there is considerable need to improve outcomes in patients with anxiety through developing valid experimental human models of anxiety that improve on the poor predictability of preclinical animal models and allow us to more effectively evaluate novel pharmacological and psychological treatments (and mechanisms of action) in healthy volunteers, prior to evaluation in clinical trials with patient populations (Nutt & Goodwin, 2011). The MRC: review of mental health research (May 2010) calls for the development of more effective pharmacological and psychological treatments for mental illness and their earlier and more effective delivery (see also Sahakian et al. 2010, Lancet). Our research will validate an extended neuropsychological experimental model of anxiety (carbon dioxide challenge) that will enable straightforward and efficient evaluation of future pharmacological, psychological and combination treatments for anxiety that in the medium term will speed the translation of therapeutic interventions into phase III trials in patients, and in the longer term will deliver improved cost-effective evidence-based treatments for patients with anxiety disorders.

Industry: Knowledge transfer 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 failure in CNS clinical drug development is the lack of efficacy in patients due in part to the poor predictive validity of pre-clinical models. We will embed the model with individual industrial partners and pharma consortia to evaluate novel treatments and also 'repurpose' old/shelved compounds with novel therapeutic uses.

Beyond drug development, the proposed research provides a practical experimental method with which to evaluate i) psychological component processes/mechanisms that can be emphasised in refined (e.g. third-wave) cognitive-behavioural interventions and ii) non-traditional (computerized) delivery systems that expand accessibility and cost-effectiveness (e.g. cognitive bias modification). This work will support broader initiatives that seek to achieve impact through improving cost-effective evidence-based psychological therapies (e.g. Improving Access to Psychological Therapies, Department of Health; and collaborations between professional bodies, charities and service providers, e.g. New Savoy Partnership). Impact through broad dissemination to the public, users (in collaboration with AnxietyUK) and others is summarized in the Communication Plan.