Angiotensin II type 1 receptor blockade as a novel mechanism of antidepressant action - a proof-of-mechanism study

Depression is a common and disabling condition, affecting ~280 million adults worldwide. Annual treatment costs in the UK alone exceed ~£3bn, yet interventions are only effective in 1 in 2 patients. Treatment is particularly unsuccessful in depressed patients with symptoms of anhedonia - a lack of positive emotions such as enthusiasm for once rewarding activities. When anhedonia is present – as is the case in 50-70% of depressed patients – this increases the risk of poorer course of illness and suicidality. There is an urgent need to drive forward the development of more targeted interventions. Current standard antidepressants have been introduced decades ago, and we have made little progress since in identifying more effective treatments. Traditionally, research directly translated promising animal findings to lengthy, costly trials in patients, which then often failed. Human experimental medicine models help bridge the gap in animal-to-human translation, by initially establishing in cost- and time-efficient studies whether brief treatment with a candidate drug has any effects on objective markers of clinical response. In depression, one such objective marker is thought to be reward processing, measured with psychological computer tasks and brain imaging. For instance, a task may involve “gambling” for points, where one repeatedly chooses from two abstract shapes presented on a screen. Healthy reward function is reflected in quickly learning which shape wins more often, and choosing this shape more frequently. Such effects are driven by appropriate brain activation in response to reward, particularly in an area called the striatum. Translated to every-day life, these processes might be reflected in making positive choices such as deciding to go on holiday with a friend whose company has been beneficial to our well-being recently. Healthy reward function also includes experiencing rewards – such as a holiday - as pleasant and looking forward to them. There is strong evidence that anhedonia is linked to deficits in all these reward domains, and that getting better very much depends on restoring reward function. Such findings suggest that clinical outcome in anhedonic depression may be improved by finding new strategies that target improvements in reward function more directly. Recent evidence suggests a crucial but so far underexplored role of the renin-angiotensin system (RAS) in reward function. The RAS is a neuroendocrine circuit involved in blood pressure regulation, but its major receptors, such as the AT1 receptor, are also expressed in brain regions relevant to anhedonia. We and others have shown in healthy participants that AT1 receptor blockade can rapidly reverse reward deficits typically seen in anhedonia, after only one treatment dose. These effects highlight the RAS as a promising new target for restoring reward processing in anhedonic depression, which may lead to improved positive mood. In support of this notion, medication that modulates AT1 receptor function, such as losartan, has been linked to reduced rates of psychiatric hospitalisation and mortality. However, the effect of AT1 receptor blockade on reward function has never been investigated in patient groups. This study is the first to test in depressed patients the hypothesis that 14-day treatment with the licensed medication losartan (versus placebo) will improve cognitive-psychological and brain markers of reward processing typically seen in anhedonic depression. Such an experimental medicine approach will establish the role of the RAS in reward function in depression and may stimulate the discovery of more effective pharmacological treatments.