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-HT 2A receptor (5-HT 2A R) in the ARMS with [ 18 F]altanserin positron emission tomography (PET) and a bolus-infusion paradigm. Materials and methods We quantified the spatial distribution of 5-HT 2A R binding potential (BP 1 ′) 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-HT 2A R-encoding gene (HTR2A; 13q14-21) were genotyped to control for a potential bias in BP 1 ′ 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 BP 1 ′ decreases consistent with increasing levels of risk. An additional decrease in caudate BP 1 ′ 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-HT 2A R density as a surrogate biological measure of increased risk for schizophrenia, irrespective of conversion. Progressive reductions of subcortical 5-HT 2A R 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.