Evaluation of the central effects of a delta opioid agonist on biomarkers of efficacy in anxiety and depression

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Most drugs for mental illness which look promising and novel in the laboratory, fail to reach the bedside. This is generally because they do not work when they are tested in large and very expensive clinical studies in patients for which the drug is intended. Increasingly, the financial risk of failure is seen as generally too great to maintain the major infrastructure necessary for development. Several companies have closed down their development programs even though they have novel drugs which show promise. These drugs are often very well characterised with highly selective actions on specific neurotransmitter systems. They are therefore of great interest to the scientific community as tools to understand the role of neurotransmitters in mental illnesses. Furthermore, the community has the expertise and capacity to take on some of the clinical development, especially when targeted at identifiable subgroups within a disorder.One approach to de-risking development is to attempt to detect efficacy early in clinical development, even in healthy volunteers, using tests of brain functioning (biomarkers) that probe relevant actions of drugs. The applicants are known to Industry and Academia for their development of biomarkers for CNS processes that underpin anxiety and depression. The biomarkers are based on measuring people's automatic and usually unconscious responses to mildly emotional images of faces or scenes that evoke little or no emotion in the viewer. The measures typically involve reaction times, accuracy or automatic memorising. Importantly, the responses of brain systems can also be visualised and quantified using functional magnetic resonance imaging (fMRI). Studies using these measures suggest that the risk of depression is associated with an unconscious tendency to automatically attend to, and process negative information in the world and about themselves. Remarkably, antidepressant drugs can shift biases in a positive direction even in people with no risk of depression and without affecting mood. Some of the most efficient measures at detecting drug effects have been collated into the Emotional Test Battery (ETB). This proposal is to rescue a drug (AZD7268), which has well-defined actions at the delta opioid receptor (DOR), from the closed AstraZeneca psychiatry program. The DOR detects and transmits the effects of endorphins in the brain called enkephalins. AZD7268 mimics the effects of enkephalins in stimulating the DOR. Preclinical and clinical data suggested that AZD7268 would be effective in depressive illnesses associated with high levels of anxiety. The DOR is located specifically in regions of the brain such as the amygdala and hippocampus that mediate behavioural effects of stress in animals and its subjective effects in humans. Genetically modified mice made to lack the DOR or to lack enkephalin show behavioural characteristics of fearfulness and depression (learned helplessness) and DOR drugs such as AZD7268 have the opposite effect. In a clinical trial in 247 patients, AZD7268 was effective in reducing depression compared to placebo only in the predicted anxious-depressed group and not in depression without marked anxiety. We aim to build confidence in this finding by using the ETB to profile the effects of AZD72688 on performance and brain imaging measures of psychological tasks that assess reward, punishment and emotion processing in a non-clinical sample of volunteers. Half the volunteers will be selected for high levels of anxiety and depression using standard self-rating questionnaires. Robust effects of AZD7268 on the ETB would suggest that DORs have at least a modulatory role in the causation of anxiety and depression that is worth pursuing therapeutically in a joint development programme between the MRC and AstraZeneca.