5-HT2A receptor density is decreased in the at-risk mental state

Rationale Current perspectives on the pathophysiology of schizophrenia direct attention to serotonergic (serotonin, 5-HT) dysregulation in the prodrome or at-risk mental state (ARMS). Objective To study the cerebral 5-HT2A receptor (5-HT2AR) in the ARMS with [F-18]altanserin positron emission tomography (PET) and a bolus-infusion paradigm. Materials and methods We quantified the spatial distribution of 5-HT2AR binding potential (BP1') in never-medicated subjects assigned to early (n=6) and late (n=8) prodromal states of schizophrenia relative to healthy controls (n=21). Five single nucleotide polymorphisms (SNPs) in the 5-HT2AR-encoding gene (HTR2A; 13q14-21) were genotyped to control for a potential bias in BP1' due to between-group differences in genotype distributions. Results Group comparisons of partial-volume corrected PET data by statistical parametric mapping and confirmatory volume of interest analysis yielded a dissemination of BP1' decreases consistent with increasing levels of risk. An additional decrease in caudate BP1' was present in subjects who subsequently converted to first-episode psychosis (n=5), but absent in non-converters (n=9). Between-group differences were not confounded by a differential distribution of SNP genotypes. Conclusion These results suggest a progressive reduction of cortical 5-HT2AR density as a surrogate biological measure of increased risk for schizophrenia, irrespective of conversion. Progressive reductions of subcortical 5-HT2AR density could provide an indicator of illness activity and help to predict imminent conversion to schizophrenia. Moreover, our findings substantiate the rationale for establishing a phase-specific psychopharmacological intervention in the ARMS that addresses the serotonergic component of vulnerability to schizophrenia.