Social adversity, dopamine, cognition and psychosis (response to the neurobiological basis of mental health highlight)

Psychotic illnesses, such as schizophrenia, are common devastating conditions. Individuals with psychosis experience delusions, hallucinations and difficulties with thinking and planning. The cause of psychosis is not known. However, research shows that levels of the chemical messenger, dopamine, are increased in the brain. Other research indicates that patients have particular difficulty with planning and thinking, and this appears to be related to malfunction in the prefrontal part of the brain. Finally, the risk of developing psychosis is significantly increased in people who have been exposed to long-term social stressors. Until now, these factors have mainly been studied separately. A key aim of this project is to put information on dopamine, prefrontal brain function and social stressors in psychosis together and clarify the relationship between them. We plan to do this by measuring dopamine function and prefrontal activity using brain scanning, and measuring social stressors with specific research interviews. We will do this in people who are very vulnerable to psychosis, and have a high risk of developing the illness in the near future. We will assess these individuals at the start of the study and again after 12 months, then follow them up to find out who subsequently develops a psychotic illness. This will allow us to find which factors indicate that someone is at high risk of psychosis, and how changes in these factors over time are linked to the development of psychosis. This will help with the early identification of individuals who are vulnerable to psychosis and the development of new treatments designed to prevent the later onset of psychosis in people who are at high risk.

The pathophysiological mechanisms leading to psychosis are poorly understood. Elevated striatal dopamine synthesis and release, impaired performance on tasks involving prefrontal cortex, and abnormal prefrontal activation during these tasks have been consistently reported in people with psychotic disroders, including medication na?ve patients at the onset of illness. The incidence of psychosis has been strongly associated with environmental factors such as belonging to an ethnic minority or immigrant group and living in an urban area. These factors are associated with social adversity and it has been suggested that their cumulative effect is a state of social defeat. Central dopamine activity and prefrontal cortical function are normally inter-related, and animal studies indicate that social stress and defeat can elevate both striatal and prefrontal dopamine levels. However, to date, dopaminergic function, cognitive processing and social factors in psychosis have largely been investigated separately. The aim of the present proposal is to integrate data from these different domains by studying each of them in the same individuals using PET, fMRI and social measures. These will be examined in a longitudinal study of people with an At Risk Mental State (ARMS). Around a third of this group are likely to subsequently develop psychosis, a third remain stable and a third will improve. Participants will be assessed at baseline and after 12 months. Cross-sectional comparison of the ARMS group with controls will reveal the extent to which social factors, dopaminergic activity, and prefrontal function are abnormal in people at high risk of psychosis. Further, the prospective study of this group over its divergent clinical course, with repetition of the baseline assessments, will indicate the relationship between the longitudinal trajectory of these abnormalities and clinical outcome. Our hypothesis is that these abnormalities progress in the subgroup of subjects that goes on to develop the illness, but not in these at risk subjects who do not become psychotic. This work will help to identify factors that are critical to the onset of psychosis, and may therefore inform the development of interventions designed to prevent the the onset of psychosis in people who are vulnerable to the disorder.