Interrelations between dopaminergic-, gabaergic- and glutamatergic neurotransmitters in antipsychotic-naïve psychosis patients and the association to initial treatment response

Preclinical evidence points to disturbances in neural networks in psychosis involving interrelations between dopaminergic-, GABAergic- and glutamatergic neurotransmitter systems. In support, we have previously shown that aberrant interrelations between these neurotransmitters, in contrast to individual transmitter systems, can separate antipsychotic-naïve first-episode psychotic patients (AN-FEP) from healthy controls (HC). Here, we characterized neurotransmitter interrelations, examined their association with treatment response, and explored the effect of treatment on the interrelations. Sixty participants (29 AN-FEP and 31 HC) underwent dynamic [18F]-DOPA PET with arterial blood sampling to measure dopamine synthesis (DS) (k₃) in nucleus accumbens (NAcc) and magnetic resonance spectroscopy (MRS) to estimate levels of glutamate (Glu) in anterior cingulate cortex (ACC) and thalamus, and gamma-aminobutyric-acid (GABA) in ACC. A subgroup of the patients was re-scanned after six weeks antipsychotic monotherapy with aripiprazole (PET: 10 AN-FEP; MRS: 27 AN-FEP; 30 HC). Psychopathology was assessed at both visits. Multiple linear regression models and linear mixed models were used to analyze data. We found a negative association between k₃ (dependent variable) and GABA in HC (β = -0.15, p = 0.03) and a positive association in patients (β = 0.15, p = 0.04). The aberrant relationship between k₃ and GABA was driven by the group-GABA interaction (p = 0.002) and related to treatment response (p = 0.02). No significant group interactions were found for the interrelations between k₃ and Glu, but a positive association was found between k₃ and Glu in thalamus (p = 0.04) in both groups and the association decreased after treatment in AN-FEP (p = 0.01). The data show that DS in NAcc and GABA levels in ACC are inversely interrelated in AN-FEP, and that the degree of abnormality predicts treatment effect. Moreover, antipsychotic treatment alters the relationship between dopaminergic activity in NAcc and Glu levels in thalamus. The findings suggest that combined instead of single neurotransmitter disturbances should be considered when novel therapeutics are developed for schizophrenia. Clinical trial registration: The Pan European Collaboration on Antipsychotic Naïve Schizophrenia II (PECANSII) study, ClinicalTrials.gov Identifier: NCT02339844. https://www.clinicaltrials.gov/study/NCT02339844 .