Theme: Mechanisms

Project Description

Psychosis describes a clinically and biologically heterogeneous group of disorders. For most patients, diagnosis remains based on symptoms rather than underlying biology, limiting our ability to identify causal mechanisms or develop precision treatments. One important exception is the discovery that neuronal surface autoantibodies can cause severe neuropsychiatric syndromes, including presentations dominated by psychosis. This raises an ongoing questions for clinical translation: does neuronal autoimmunity account for a biologically distinct subgroup of people currently diagnosed with primary psychotic disorders? This PhD will investigate neuronal autoimmunity across psychosis, focusing particularly on clinically atypical phenotypes in which an autoimmune mechanism may be enriched. These include abrupt or polymorphic presentations, catatonia and unusual treatment trajectories, with postpartum psychosis providing a particularly informative model phenotype. Postpartum psychosis has a rapid, distinctive clinical presentation and previous studies have identified NMDA receptor and unidentified neuronal autoantibodies in a minority of patients, but this observation has received remarkably little subsequent investigation. Our existing work similarly suggests that combining detailed clinical phenotyping with more sensitive approaches to antibody discovery could uncover previously unrecognised forms of autoimmune psychosis. The project will span clinical characterisation, patient recruitment and experimental neuroimmunology. The fellow will have access to established psychosis cohorts, stored bio-samples and prospective recruitment infrastructure, providing a platform from which to define and compare clinically relevant patient groups. Clinical information may include psychopathology, illness onset and course, treatment response and longitudinal health-record data. Recruitment can be extended towards phenotypes of particular interest, including postpartum psychosis through UK perinatal services and established patient and professional networks. The existing PPiP (Prevalence of Pathogenic antibodies in Psychosis) infrastructure provides both deeply characterised samples and an established framework for psychosis recruitment and follow-up. Laboratory work will ask whether patient antibodies recognise neuronal targets and, where appropriate, investigate their identity and biological effects. Depending on the fellow’s interests, mechanistic work could investigate antibody effects on neuronal function or explore the B-cell origins of selected autoantibodies through monoclonal antibody generation and immunological characterisation. These methods are already established within the supervisory team’s wider research programme and collaborative networks within Oxford and internationally. The precise emphasis will be co-developed with the successful fellow. A clinically oriented fellow might focus on defining phenotypes that predict neuronal autoimmunity and developing recruitment cohorts; another could concentrate on novel autoantibody discovery; while a laboratory-focused fellow could pursue molecular targets, B-cell origins or neuronal pathogenic mechanisms. Moreover, there is precedent for combining these approaches ‘from bedside to bench’. This is an exciting project with clear translational implications which we envisage will be complementary to specialty trainees in psychiatry with interested neurologists also welcome, as well as those from non-medical allied healthcare background.