This series of studies examined the extent to which the genetic and environmental causes, and mechanisms, underlying bipolar disorder, depressive psychosis and schizophrenia overlap, and where they differ from each other. 

Genetic Predisposition: The first study used molecular genetics to examine the extent to which genetic loading for bipolar disorder, depressive psychosis and schizophrenia overlap by examining polygenic risk scores in a large Trans-European sample (approximately 2,500 subjects from the EU-GEI study).  We found that, not surprisingly, genetic predisposition for schizophrenia strongly predicted schizophrenia but more unexpectedly also predicted bipolar disorder and to a lesser extent depressive psychosis (See Figure). Predisposition for bipolar disorder predicted both bipolar disorder and schizophrenia but to a more modest extent while predisposition to depressive psychosis also showed some overlap with that to bipolar disorder. 

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A further molecular genetics study used the huge GLAD study of some 40,000 people to explore the genetic relationship between anxiety disorder and major depressive disorder. This demonstrated a considerable genetic overlap between mood disorder, anxiety disorder and post-traumatic stress disorder, thus showing that some people with each condition inherit a genetic susceptibility to be particularly sensitive to trauma.

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Environmental Risk Factors: Expanding our investigations into environmental factors, we carried out the largest ever review of the world literature examining the environmental factors which increase risk for bipolar disorder, depressive psychosis and schizophrenia. Here there were both similarities and differences. For example childhood adversity and drug abuse increased risk of all three conditions while urban upbringing and obstetric complications were more confined to schizophrenia. Adverse life events has most influence on depression, followed by bipolar disorder and had a more modest role in schizophrenia.  

We used the EU-GEI sample to address the important question of whether young people with serious mental illness become vulnerable to starting abusing drugs because of their illness, or alternatively whether they start abusing drugs before the illness and this precipitates the onset of illness. We found that it is usually the latter, although it is the former in about 15% of people.  

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Our work was carried out during the COVID pandemic which necessitated a lot of alternations in our planning.  We also examined the extent to which the Pandemic affected the occurrence of serious mental illnesses like bipolar disorder, depressive psychosis and schizophrenia. These conditions increased in incidence during the pandemic by about 25%, partly an effect of the stress of the pandemic and lockdown and partly through an increase in drug use during the lockdown.   

Brain Mechanisms underlying Illness and its treatment: As well as looking at the causes of illness, is important to understand the biological mechanisms through which the above factors influence the brain to result in symptoms. So we examined how PET and MRI studies have clarified he role of neurotransmitters in bipolar disorder and schizophrenia and also the effects of antipsychotic medications on the brain..  We carried out a meta-analysis showing the important role of brain glutamate and its relationship with dopamine in early psychosis and how it changed following antipsychotics. We also showed that antipsychotics cause reversible structural brain changes within one week.

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Summary:  These studies show that the genetic factors predisposing to serious mental illness and that some of the environmental risk factors are also in common. However others such as exposure to early brain hazards and life events are more specific, the former to schizophrenia and the latter to the affective psychoses

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