Overview

Theme leads

Research Focus

This Theme is focused on advancing the development of novel and improved treatments for depression, through the use of human neurocognitive models of antidepressant action. These models offer a powerful translational tool to evaluate interventions (in both healthy individuals and patients with depression) efficiently and ethically, leveraging innovative neuroscience-based approaches. This bridges the translational gap between laboratory research and clinical application, enabling more effective and targeted interventions for individuals with depression and extending the approach to improve treatment for young people.

Regional Context

The work is led from Oxford, with key contributions from the Universities of Birmingham and Reading. This tri-institutional collaboration brings together complementary expertise in clinical psychiatry, neuroscience, and translational research. In addition, the Theme is furthering the establishment of mood disorder clinics across Oxford and Birmingham, which – alongside the NIHR MH-TRC Mission -will enhance clinical excellence and broaden access to research participation across diverse populations. The partnership also supports the integration of academic, clinical, and industry stakeholders (through our Experimental Medicine in Industry Partnership), strengthening the translational pipeline from discovery to implementation.

Research Aims

The Theme is structured around five interrelated sub-themes, each addressing a critical aspect of depression treatment innovation:

• Sub-Theme 1: Fast-Acting Antidepressants
  This sub-theme investigates the neurocognitive effects of fast-acting antidepressants with a focus on symptoms such as anhedonia (the inability to experience pleasure from activities that were previously found enjoyable) and persistent negative memories. Ketamine is being used to develop and validate neurocognitive models that will enable further rapid testing of additional next-generation treatments
• Sub-Theme 2: Repurposing
  This sub-theme capitalises on the potential to accelerate drug discovery for mood disorders by repurposing existing medications developed for general medical conditions. Using neurocognitive models, we are characterising the effects of repurposed agents to further understand the therapeutic potential of novel targets(such as 5-HT4 agonists and histamine 3 antagonists)
• Sub-Theme 3: Computational Modelling
  This sub-theme applies computational approaches to refine the prediction of treatment outcomes, particularly for clinical anhedonia, which is a critical problem for many people with treatment-resistant depression (depression that has not responded to conventional treatment). These models aim to enhance the precision of personalised treatment strategies.
• Sub-Theme 4: Adolescent Depression
  This sub-theme develops neurocognitive models to investigate the mechanisms of antidepressant treatments specifically in adolescent populations, addressing a critical gap in current mental health research
• Sub-Theme 5: Combination Therapies
  Building on insights from the other sub-themes, this sub-theme will design and test novel combination treatments that integrate pharmacological and non-pharmacological approaches to improve outcomes in depression.

Impact

Depression remains a leading global cause of disability, and current treatments often result in incomplete recovery. This Theme is positioned to make a significant contribution to the future of depression treatment by accelerating the development of next-generation fast-acting therapies and personalised treatment strategies. This is supported by collaborations with young people and adults who have lived experience of depression, to help ensure a meaningful impact for patients. The harmonised clinical research infrastructure across sites will enhance recruitment, data quality, and generalisability. In parallel, the Theme is committed to building research capacity through joint clinical posts and mentorship of early-career researchers, ensuring a sustainable pipeline of expertise in translational psychiatry.