The Second Revision of the Dopamine Theory of Schizophrenia: Implications for Treatment and Drug Development

Abstract

In this edition of Biological Psychiatry, Egerton et al. (1) from the Institute of Psychiatry at King’s College in London published the results of an imaging study measuring dopamine (DA) synthesis capacity in subjects presenting potentially prodromal symptoms of schizophrenia. Subjects fulfilled clinical criteria associated with a 20% to 40% risk of presenting a psychotic episode within 1 to 3 years (2), a condition labeled as ultra-high risk (UHR). Compared with matched control subjects, striatal DA synthesis capacity (measured with positron emission tomography as the uptake of [F]DOPA) was increased in UHR subjects. Analysis of striatal functional subdivisions showed that the [F] DOPA uptake was increased in the associative striatum (AST) and not in the ventral striatum (VST). This outcome confirms an earlier result from the same group in a smaller cohort (3) and suggests that abnormalities of DA function in the AST precede the emergence of psychotic symptoms in UHR subjects. The authors should be complimented for having submitted their initial findings to the rigor of replication in an independent cohort. As pointed out by the authors, replication of a clinical finding by the same investigators does carry less weight than independent replication. Nonetheless, replication studies are extremely important and might not be given enough attention and credit in the field. Given that the recruitment criteria, clinical evaluation, and imaging technique were maintained between the two studies, the data can be pooled, and this combined analysis will be especially important for the follow-up studies. Based on the UHR criteria, it is anticipated that 20% to 40% of these subjects will present a psychotic episode within 2 years and that this episode might be the first psychotic manifestation of a chronic psychotic disorder such as schizophrenia. In the follow-up of the first cohort, the authors observed that increased [F]DOPA uptake at baseline was associated with higher risk of psychotic transition within 3 years. It will be very important to ascertain if the prognostic value of elevated [F]DOPA uptake in the AST is replicated in this larger cohort. This result provides an important contribution to a large body of imaging work performed over the last decade that generated a remarkably consistent picture of alteration of DA function in schizophrenia [reviewed in (4,5)]. Using either [F]DOPA uptake or competition studies between endogenous DA and DA D2 receptor ligands, several groups have documented that schizophrenia is associated with increases in striatal presynaptic DA function, at least during the period of psychotic exacerbation, and that this increase is associated with the severity and acuity of psychotic symptoms. This DA dysregulation does not appear to be a