GENOMIC STUDIES OF TREATMENT RESISTANCE IN BIPOLAR, DEPRESSION AND SCHIZOPHRENIA

Overall Abstract Across major mental illnesses, around one third of people have symptoms that do not respond to standard therapies. People with such 'treatment-resistant' symptoms experience poorer outcomes across domains of health and functioning, have higher use of services and greater premature mortality compared to those whose symptoms respond to treatment. Thus 'treatment-resistance' in conditions such as bipolar, depression and schizophrenia is considered a priority for stratified or personalised psychiatry. We currently have a rudimentary knowledge of the biopsychosocial aetiology of treatment-resistance across these conditions and cannot predict who will develop treatment-resistance in a clinically-meaningful way. Genetics can help address these shortcomings and large-scale genetic studies are beginning to delineate a genetic contribution to treatment-resistance that has the potential to provide biological insights and inform prediction modelling. This symposium will present the state-of-the-art in treatment-resistant genetic research across depression, bipolar and schizophrenia. We will summarise the key challenges of conducting treatment-resistant genomic research in these conditions and will present new findings of genome-wide association studies in depression, bipolar and schizophrenia in the largest datasets compiled to date. We will outline the importance of accurate and consistent definitions of treatment-resistance, consider how conceptions and measurement of treatment resistance differ and align across conditions, and indicate how routine and research-derived data can be leveraged to address these challenges. We will then present the results of genome-wide association studies in each of the three conditions, report the first genome-wide significant results in this field and present post-GWAS analyses and biological interpretations. We will determine the heritabilities of treatment-resistance in depression, bipolar and schizophrenia, their genetic correlations and report on polygenic prediction of treatment-resistance in independent samples. This work is being developed as part of EU (PsychSTRATA, REALMENT), UK (GENios) and USA (PGC) funded projects, and we will also consider how ongoing and future international co-ordination and collaboration can help advance genomics research of treatment-resistance in major mental illnesses.