Abstract
Childhood trauma is a risk factor for psychosis. Amphetamine increases synaptic striatal dopamine levels and can induce positive psychotic symptoms in healthy individuals and patients with schizophrenia. Socio-developmental hypotheses of psychosis propose that childhood trauma and other environmental risk factors sensitize the dopamine system to increase the risk of psychotic symptoms, but this remains to be tested in humans. We used [11C]-(+)-PHNO positron emission tomography to measure striatal dopamine-2/3 receptor (D2/3R) availability and ventral striatal dexamphetamine-induced dopamine release in healthy participants (n = 24). The relationships between dexamphetamine-induced dopamine release, dexamphetamine-induced positive psychotic symptoms using the Positive and Negative Syndrome Scale (PANSS), and childhood trauma using the Childhood Trauma Questionnaire (CTQ) were assessed using linear regression and mediation analyses, with childhood trauma as the independent variable, dexamphetamine-induced dopamine release as the mediator variable, and dexamphetamine-induced symptoms as the dependent variable. There was a significant interaction between childhood trauma and ventral striatal dopamine release in predicting dexamphetamine-induced positive psychotic symptoms (standardized β = 1.83, p = 0.003), but a mediation analysis was not significant (standardized β = −0.18, p = 0.158). There were no significant effects of dopamine release and childhood trauma on change in negative (p = 0.280) or general PANSS symptoms (p = 0.061), and there was no relationship between ventral striatal baseline D2/3R availability and positive symptoms (p = 0.368). This indicates childhood trauma and dopamine release interact to influence the induction of positive psychotic symptoms. This is not consistent with a simple sensitization hypothesis, but suggests that childhood trauma moderates the cognitive response to dopamine release to make psychotic experiences more likely.
Highlights
Schizophrenia is among the leading causes of global disease burden and is associated with high mortality and morbidity[1,2,3]
Seven of eight imaging studies found that schizophrenia is associated with increased striatal dopamine release induced by amphetamine[16,17,18,19,20,21,22,23], and a further study found greater striatal dopamine release induced by acute stress exposure[24]
In order to examine whether the relationship between childhood trauma and positive psychotic symptoms is mediated by dopamine release, we performed a mediation analysis with childhood trauma as the independent variable, ventral striatal dexamphetamineinduced dopamine release as the mediator variable, and dexamphetamine-induced positive symptoms as the dependent variable, using the ‘Model 4’ template implemented in the PROCESS Statistical Package for the Social Sciences (SPSS) package[72]
Summary
We investigated whether the interaction between these two variables was a significant predictor of positive psychotic symptoms, by running a linear regression model, which included dexamphetamine-induced change in positive psychotic symptoms as the dependent variable, and the following predictor (independent) variables: ventral striatum dopamine release capacity (ΔBPND), childhood trauma (CTQ score), and the interaction between these variables (ΔBPND × CTQ score). In order to examine whether the relationship between childhood trauma and positive psychotic symptoms is mediated by dopamine release, we performed a mediation analysis with childhood trauma as the independent variable, ventral striatal dexamphetamineinduced dopamine release as the mediator variable, and dexamphetamine-induced positive symptoms as the dependent variable, using the ‘Model 4’ template implemented in the PROCESS (version 3) SPSS package (http:// www.processmacro.org/index.html)[72]. Mediation was deemed to be significant if 0 was not contained within the 95% bootstrap confidence intervals of the indirect effect, testing the combined effects of paths a (CTQ to dexamphetamine-induced dopamine release) and b (dexamphetamine-induced dopamine release to dexamphetamine-induced positive psychotic symptoms)
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