Dopamine and glutamate in individuals at high risk for psychosis: a meta‐analysis of in vivo imaging findings and their variability compared to controls

Abstract

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. Fortyeight 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 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.

Circuit-Based Approaches to Understanding Corticostriatothalamic Dysfunction Across the Psychosis Continuum

“…Human neuroimaging studies are partially consistent with these models, suggesting that disrupted corticostriatal and hippocampal-striatal FC are apparent across the psychosis spectrum and may thus represent a vulnerability marker for psychosis, with midbrain dysfunction emerging when symptoms require some level of clinical attention. However, both ventral and dorsal CST dysconnectivity is found across the continuum, with elevated markers of dopamine function being more robustly identified in the latter system (117,(119)(120)(121)(122), consistent with the increasing prominence of dorsal circuitry in the primate brain (112)(113)(114). These findings therefore suggest that dysfunction of distinct elements of the ventral and dorsal systems may emerge contemporaneously and may influence different aspects of psychosis, with the ventral system driving aberrant salience signaling and the dorsal system contributing to the development of persistent thought patterns (16,22,(162)(163)(164)187).…”

“…Such findings challenge the mesolimbic, ventral CST focus of preclinical models and suggest that the dorsal CST may play a more prominent role in disease pathophysiology. Of particular note, positron emission tomography (PET) studies using the tracer L-3,4-Dihydroxy-6-[ 18 F]fluorophenylalanine ( 18 F-DOPA) have consistently reported increased dopamine synthesis capacity in the dorsal striatum of ARMS and other high-risk individuals, particularly those who later transition to psychosis (117,(119)(120)(121)(122).…”

“…This trend suggests that midbrain dysfunction may be a trait marker of genetic risk and/or clinically significant symptoms. Accordingly, PET studies have not found evidence for elevated striatal 18 F-DOPA in healthy people with subthreshold psychosis symptoms or in ARMS individuals that do not transition to psychosis (121,157,158). Thus, the fMRI and PET findings converge to indicate that dysregulation of midbrain dopaminergic afferents to the striatum is closely linked to the emergence of clinically significant symptoms.…”

Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance

“…Elevated striatal dopamine synthesis and release capacity has also been found in people at genetic and/or clinical high risk for schizophrenia in some (100,104,105), although not in all studies; potentially because not all patients are actually in the prodrome to schizophrenia (106). Notwithstanding this issue, dopaminergic elevations were most marked in striatal regions innervated by frontal cortical projections, J o u r n a l P r e -p r o o f as with schizophrenia, and greater elevation here is associated with more severe prodromal-type symptoms (95,107).…”

Variability and Magnitude of Brain Glutamate Levels in Schizophrenia: A Meta And Mega-Analysis

“…1H-MRS studies reporting glutamate, glutamine, or Glx values for a schizophrenia patient group in comparison with a healthy volunteer group were included in the analysis. Studies in clinical high risk or genetic high risk cohorts have been summarised elsewhere (31) and were excluded from the current analysis on individuals meeting diagnostic criteria. In the case of longitudinal studies, only the values for the rst time point were included.…”