TY - JOUR
T1 - Dopamine and glutamate in individuals at high risk for psychosis
T2 - a meta-analysis of in vivo imaging findings and their variability compared to controls
AU - McCutcheon, Robert A.
AU - Merritt, Kate
AU - Howes, Oliver D.
N1 - Funding Information:
R.A. McCutcheon's work is funded by a Wellcome Trust grant (no. 200102/Z/15/Z) and UK National Institute for Health Research (NIHR) fellowships. K. Merritt is funded by a UK Medical Research Council grant (no. MR/S003436/1). O.D. Howes is funded by the UK Medical Research Council and the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the funding bodies. R.A. McCutcheon and K. Merritt contributed equally to this paper. Supplementary information on the study is available at https://doi.org/10.5281/zenodo.4739435 .
Publisher Copyright:
© 2021 World Psychiatric Association
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/10
Y1 - 2021/10
N2 - Dopaminergic and glutamatergic dysfunction is believed to play a central role in the pathophysiology of schizophrenia. However, it is unclear if abnormalities predate the onset of schizophrenia in individuals at high clinical or genetic risk for the disorder. We systematically reviewed and meta-analyzed studies that have used neuroimaging to investigate dopamine and glutamate function in individuals at increased clinical or genetic risk for psychosis. EMBASE, PsycINFO and Medline were searched form January 1, 1960 to November 26, 2020. Inclusion criteria were molecular imaging measures of striatal presynaptic dopaminergic function, striatal dopamine receptor availability, or glutamate function. Separate meta-analyses were conducted for genetic high-risk and clinical high-risk individuals. We calculated standardized mean differences between high-risk individuals and controls, and investigated whether the variability of these measures differed between the two groups. Forty-eight eligible studies were identified, including 1,288 high-risk individuals and 1,187 controls. Genetic high-risk individuals showed evidence of increased thalamic glutamate + glutamine (Glx) concentrations (Hedges’ g=0.36, 95% CI: 0.12-0.61, p=0.003). There were no significant differences between high-risk individuals and controls in striatal presynaptic dopaminergic function, striatal D2/D3 receptor availability, prefrontal cortex glutamate or Glx, hippocampal glutamate or Glx, or basal ganglia Glx. In the meta-analysis of variability, genetic high-risk individuals showed reduced variability of striatal D2/D3 receptor availability compared to controls (log coefficient of variation ratio, CVR=–0.24, 95% CI: –0.46 to –0.02, p=0.03). Meta-regressions of publication year against effect size demonstrated that the magnitude of differences between clinical high-risk individuals and controls in presynaptic dopaminergic function has decreased over time (estimate=–0.06, 95% CI: –0.11 to –0.007, p=0.025). Thus, other than thalamic glutamate concentrations, no neurochemical measures were significantly different between individuals at risk for psychosis and controls. There was also no evidence of increased variability of dopamine or glutamate measures in high-risk individuals compared to controls. Significant heterogeneity, however, exists between studies, which does not allow to rule out the existence of clinically meaningful differences.
AB - Dopaminergic and glutamatergic dysfunction is believed to play a central role in the pathophysiology of schizophrenia. However, it is unclear if abnormalities predate the onset of schizophrenia in individuals at high clinical or genetic risk for the disorder. We systematically reviewed and meta-analyzed studies that have used neuroimaging to investigate dopamine and glutamate function in individuals at increased clinical or genetic risk for psychosis. EMBASE, PsycINFO and Medline were searched form January 1, 1960 to November 26, 2020. Inclusion criteria were molecular imaging measures of striatal presynaptic dopaminergic function, striatal dopamine receptor availability, or glutamate function. Separate meta-analyses were conducted for genetic high-risk and clinical high-risk individuals. We calculated standardized mean differences between high-risk individuals and controls, and investigated whether the variability of these measures differed between the two groups. Forty-eight eligible studies were identified, including 1,288 high-risk individuals and 1,187 controls. Genetic high-risk individuals showed evidence of increased thalamic glutamate + glutamine (Glx) concentrations (Hedges’ g=0.36, 95% CI: 0.12-0.61, p=0.003). There were no significant differences between high-risk individuals and controls in striatal presynaptic dopaminergic function, striatal D2/D3 receptor availability, prefrontal cortex glutamate or Glx, hippocampal glutamate or Glx, or basal ganglia Glx. In the meta-analysis of variability, genetic high-risk individuals showed reduced variability of striatal D2/D3 receptor availability compared to controls (log coefficient of variation ratio, CVR=–0.24, 95% CI: –0.46 to –0.02, p=0.03). Meta-regressions of publication year against effect size demonstrated that the magnitude of differences between clinical high-risk individuals and controls in presynaptic dopaminergic function has decreased over time (estimate=–0.06, 95% CI: –0.11 to –0.007, p=0.025). Thus, other than thalamic glutamate concentrations, no neurochemical measures were significantly different between individuals at risk for psychosis and controls. There was also no evidence of increased variability of dopamine or glutamate measures in high-risk individuals compared to controls. Significant heterogeneity, however, exists between studies, which does not allow to rule out the existence of clinically meaningful differences.
KW - clinical high risk
KW - dopamine receptor availability
KW - dopaminergic dysfunction
KW - genetic high risk
KW - glutamatergic dysfunction
KW - presynaptic dopaminergic function
KW - Schizophrenia
KW - thalamic glutamate
UR - http://www.scopus.com/inward/record.url?scp=85114711027&partnerID=8YFLogxK
U2 - 10.1002/wps.20893
DO - 10.1002/wps.20893
M3 - Article
AN - SCOPUS:85114711027
SN - 1723-8617
VL - 20
SP - 405
EP - 416
JO - World Psychiatry
JF - World Psychiatry
IS - 3
ER -