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Objective-Whilst there is robust evidence of elevated dopamine synthesis capacity once a psychotic disorder has developed, little is known about whether it is altered prior to the first episode of frank illness. We addressed this issue by measuring dopamine synthesis capacity in subjects at ultra high risk of psychosis, and then following them to determine their clinical outcome.Method-This prospective study included thirty subjects who met standard criteria for being at ultra high risk of psychosis and twenty-nine healthy volunteers. Subjects were scanned using [18F]-DOPA positron emission tomography. The ultra high risk subjects were scanned at presentation and followed-up for at least three years to determine their clinical outcome. Six subjects had co-morbid schizotypal personality disorder and were excluded from the analysis (data are provided for comparison). Of the remaining subjects, nine developed a psychotic disorder subsequent to scanning (psychotic transition group), and 15 did not (non-transition group).Results-There was a significant effect of group on striatal dopamine synthesis capacity (p=0.006). The psychotic transition group had greater dopamine synthesis capacity in the striatum (p=0.004, effect size=1.18) and its associative subdivision (p=0.015, effect size=1.24) than controls, and showed a positive correlation between dopamine synthesis capacity and symptom severity. Dopamine synthesis capacity was also significantly greater in the psychotic transition than the non-transition group (p=0.036).Conclusions-These findings provide evidence that the onset of frank psychosis is preceded by presynaptic dopaminergic dysfunction. Further work is required to determine the specificity of elevated dopamine synthesis capacity to particular psychotic disorders.

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Schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential.

Molecular imaging studies have generated important in vivo insights into the etiology of schizophrenia and treatment response. This article first reviews the PET and SPECT evidence implicating dopaminergic dysfunction, especially presynaptic dysregulation, as a mechanism for psychosis. Second, it summarises the neurochemical imaging studies of antipsychotic action, focussing on D2/3 receptors. These studies show that all currently licensed antipsychotic drugs block striatal D2/3 receptors in vivo- a site downstream of the likely principal dopaminergic pathophysiology in schizophrenia- and that D2/3 occupancy above a threshold is required for antipsychotic treatment response. However, adverse events, such as extra-pyramidal side-effects or hyperprolactinemia, become much more likely at higher occupancy levels, which indicates there is an optimal 'therapeutic window' for D2/3 occupancy, and questions the use of high doses of antipsychotic treatment in clinical practice and trials. Adequate D2/3 blockade by antipsychotic drugs is necessary but not always sufficient for antipsychotic response. Molecular imaging studies of clozapine, the one antipsychotic licensed for treatment resistant schizophrenia, have provided insights into the mechanisms underlying its unique efficacy. To link this pharmacology to the phenomenology of the illness, we discuss the role of dopamine in motivational salience and show how i) psychosis could be viewed as a process of aberrant salience, and ii) antipsychotics might provide symptomatic relief by blocking this aberrant salience. Finally, we discuss the implications of these PET and SPECT findings for new avenues of drug development.