Dopamine Synthesis Capacity and GABA and Glutamate Levels Separate Antipsychotic-Naïve Patients With First-Episode Psychosis From Healthy Control Subjects in a Multimodal Prediction Model

Abstract

Background Disturbances in presynaptic dopamine activity and levels of gamma-aminobutyric acid (GABA) and glutamate plus glutamine (Glx) collectively may have a role in the pathophysiology of psychosis, although separately they are poor diagnostic markers. We tested whether these neurotransmitters in combination improve the distinction of antipsychotic-naïve first episode psychotic patients from healthy controls. Methods We included 23 patients (mean age 22.3 years, nine males) and 20 controls (mean age 22.4 years, eight males). We determined dopamine metabolism in nucleus accumbens (NAcc) and striatum from 18F-FDOPA positron emission tomography. We measured GABA levels in anterior cingulate cortex (ACC) and Glx levels in ACC and left thalamus with 3 Tesla 1H-MRS. We used binominal logistic regression for unimodal prediction when we modelled neurotransmitters individually, and for multimodal prediction when we combined the three neurotransmitters. We selected the best combination based on Akaike information criterion. Results Individual neurotransmitters failed to predict group. Three triple neurotransmitter combinations significantly predicted group after Benjamini-Hochberg correction. The best model (Akaike information criterion 48.5) carried 93.5% of the cumulative model weight. It reached a classification accuracy of 83.7% (p=0.003) and included dopamine synthesis capacity (Ki 4p) in NAcc (p=0.664), GABA levels in ACC (p=0.019), Glx levels in thalamus (p=0.678), and the interaction-term Ki 4pxGABA (p=0.016). Conclusion Our multimodal approach proved superior classification accuracy implying that the pathophysiology of patients represents a combination of neurotransmitter disturbances rather than aberrations in a single neurotransmitter. Particularly aberrant interrelations between Ki 4p in NAcc and GABA values in ACC appeared to contribute diagnostic information.Background: Disturbances in presynaptic dopamine activity and levels of GABA (gamma-aminobutyric acid) and glutamate plus glutamine collectively may have a role in the pathophysiology of psychosis, although separately they are poor diagnostic markers. We tested whether these neurotransmitters in combination improve the distinction of antipsychotic-naïve patients with first-episode psychosis from healthy control subjects. Methods: We included 23 patients (mean age 22.3 years, 9 male) and 20 control subjects (mean age 22.4 years, 8 male). We determined dopamine metabolism in the nucleus accumbens and striatum from 18F-fluorodopa ( 18F-FDOPA) positron emission tomography. We measured GABA levels in the anterior cingulate cortex (ACC) and glutamate plus glutamine levels in the ACC and left thalamus with 3T proton magnetic resonance spectroscopy. We used binominal logistic regression for unimodal prediction when we modeled neurotransmitters individually and for multimodal prediction when we combined the 3 neurotransmitters. We selected the best combination based on Akaike information criterion. Results: Individual neurotransmitters failed to predict group. Three triple neurotransmitter combinations significantly predicted group after Benjamini-Hochberg correction. The best model (Akaike information criterion 48.5) carried 93.5% of the cumulative model weight. It reached a classification accuracy of 83.7% (p = .003) and included dopamine synthesis capacity (K i 4p) in the nucleus accumbens (p = .664), GABA levels in the ACC (p = .019), glutamate plus glutamine levels in the thalamus (p = .678), and the interaction term K i 4p × GABA (p = .016). Conclusions: Our multimodal approach proved superior classification accuracy, implying that the pathophysiology of patients represents a combination of neurotransmitter disturbances rather than aberrations in a single neurotransmitter. Particularly aberrant interrelations between K i 4p in the nucleus accumbens and GABA values in the ACC appeared to contribute diagnostic information.</p