Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT...

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.