5-HT2A receptor density is decreased in the at-risk mental state
Current perspectives on the pathophysiology of schizophrenia direct attention to serotonergic (serotonin, 5-HT) dysregulation in the prodrome or at-risk mental state (ARMS).
To study the cerebral 5-HT2A receptor (5-HT2AR) in the ARMS with [18F]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.
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.
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.
KeywordsSchizophrenia Psychosis Prodrome At-risk Serotonin 5-HT 5-HT2A Receptor PET
R.H. and A.M. contributed equally to this study. The authors gratefully acknowledge the fruitful discussions with J. Ermert and K. Hamacher as well as the excellent assistance of S. Grafmuller, M. Lang, B. Palm, S. Rehbein, E. Wabbals (Institute of Nuclear Chemistry), M. Cremer, M. Vogeling (Molecular Neuroimaging Group), H. Herzog, S. Schaden, L. Tellmann, E. Theelen (PET Instrumentation Group), B. Elghahwagi, P. Engels, G. Oefler, J. N. Shah (MRI Instrumentation Group, Research Center Juelich), and C. Hanses (Department of Psychiatry, University of Bonn). The present project is part of the German Research Network on Schizophrenia (GRNS) and the Brain Imaging Center West (BICW) supported by the German Federal Ministry for Education and Research (BMBF; grants 01 GI9934), the Deutsche Forschungsgemeinschaft (DFG; Klinische Forschergruppe 112 to A.B.), and the International Consortium for Brain Mapping (ICBM). W.M. received project funding from Eli Lilly. The authors have no conflicts of interest to report, nor any involvement to disclose, financial or otherwise, that may bias the conduct, interpretation or presentation of this work.
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