Thalamic dopamine D2-receptor availability in schizophrenia: a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis

Pontus Plavén-Sigray,Simon Cervenka,Ingrid Agartz,Helena Fatouros-Bergman,Carl M Sellgren,Maria Lee,Karin Collste,Lars Farde,Granville J Matheson,Pauliina Ikonen Victorsson,Alexander Santillo,Sophie Erhardt,Christer Halldin

doi:10.1038/s41380-021-01349-x

Abstract

Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [11C]FLB457. The main outcome was D2-R binding potential (BPND) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen’s dz = −0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BPND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen’s dz = −0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen’s d = −0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity.

Highlights

The dopamine system has for several decades been of central importance for research on the pathophysiology and treatment of schizophrenia
Molecular imaging studies have shown a slight increase in striatal D2 receptors (D2-R) in psychosis and schizophrenia patients compared with controls, this was not significant in the subsample of antipsychotic-naive firstepisode patients [4]
By using the Bayes Factor (BF) we evaluated whether the collected data are more consistent with the hypothesis of decreases in thalamic D2-R binding in psychosis and schizophrenia patients (H1), or with the null hypothesis of no effect (H0)

Summary

Introduction

The dopamine system has for several decades been of central importance for research on the pathophysiology and treatment of schizophrenia. Well over one hundred molecular imaging studies have investigated the in vivo effects of antipsychotic treatments, showing that all currently licensed antipsychotic drugs block dopamine D2 receptors (D2-R) [1, 2]. Molecular imaging studies have shown a slight increase in striatal D2-R in psychosis and schizophrenia patients compared with controls, this was not significant in the subsample of antipsychotic-naive firstepisode patients [4]. Several other brain regions have been considered more important in generating the diversity of symptoms observed in schizophrenia. Further investigations of dopaminergic function outside of the striatum is needed in order to understand the pathophysiology of the disorder

Objectives

Results

Conclusion