Psychiatric Imaging

Psychotic illnesses such as schizophrenia are common and amongst the top ten greatest causes of adult disability in the world. We urgently need new and better treatments. However, a major limit on developing better treatments is that we dont understand what leads to psychosis. The brain chemical messenger, dopamine, is known to be abnormal in the condition. It is also known that cannabis use, and some forms of social stress, increase the risk of psychosis. We aim to study how these risk factors affect the dopamine system, and see if differences in dopamine function explain why some vulnerable people develop psychosis and others do not. We also know that current treatments act down-stream of the dopamine abnormality, but it is not clear whether they make this abnormality better or worse. We will test whether the dopamine system is different in patients who do not respond to treatment, and if treatment increases the dopamine abnormality. Finally we will also test whether we can counter the dopamine abnormality by targeting its control mechanisms. These studies will help predict and prevent psychosis, and develop better treatments.

Psychotic disorders such as schizophrenia are amongst the top ten causes of disability in adults- accounting for one in every ten hospital beds used in the UK. The main treatments, the antipsychotic drugs, were discovered over fifty years ago. Since then there has been limited progress as: i) the medications are still based on the same old principle (dopamine (DA) receptor blockade), ii) there are no good predictors of response so treatment proceeds by trial-and-error, and iii) current treatments are ineffective for one in three patients. A major limit for the development of new, rational treatments has been the lack of a defined etiology and limited knowledge of the pathophysiology of schizophrenia. As a result most drug development in the last fifty years has simply sought to emulate aspects of existing antipsychotics and/or has used empirical animal models (e.g.: conditioned avoidance response or PCP-induced locomotion) that were developed prior to clear knowledge of the pathophysiology.|However, there is now evidence of a defined neurochemical pathophysiology in psychosis. Over fifteen in vivo studies in the last decade point to one central fact: presynaptic DA dysfunction is the final common pathway leading to psychosis (data reviewed and synthesized in: Howes et al, B J Psuch, 2007 & Lyon et al. Schiz. Bull. doi:10.1093, 2009). For this reason understanding the causes and implications of presynaptic DA dysfunction is critical to the pathophysiology of psychosis and provides a framework for understanding risk factors, predicting onset and delivering new treatments as set out in a recent review of the area (Howes and Kapur, Schiz Bulletin, 2009). The programme is divided into four sections: (a) Risk factors to pathophysiology; (b) Predicting illness onset; (c) Pathophysiology to therapeutics; (d) Targets beyond dopamine.|The first section will investigate the effects of the two major environmental risk factors for psychosis - cannabis use and social stress/defeat - on DA function using F-DOPA and raclopride positron emission tomography (PET) in individuals exposed to these risk factors. Section 2 addresses the ultimate aim in therapeutics of psychosis - predicting and preventing its onset using PET and magnetic resonance imaging (MRI) to identify biomarkers and pathoetiological changes underlying the development of psychosis. One third of patients with established psychosis fail to respond to treatment. Section 3 will investigate the determinants and predictors of treatment response using PET and MR spectroscopy of dopamine and glutamate markers respectively. Section 4 investigates upstream modulators of DA to identify novel non-D2 targets for drug discovery using agents that act at DA autoreceptors and glutamatergic and other regulatory mechanisms.|These studies have the potential to identify prognostic markers for psychosis and new therapeutic avenues to treat established illness.|