466. Neurotransmitter disturbances and relationship to short- and long-term outcome in initially antipsychotic-naïve patients with first-episode psychosis

Abstract

Abstract Background Rodent models of schizophrenia suggest that combined dopaminergic, glutamatergic and GABAergic neurotransmitter disturbances play a key role in the illness pathophysiology, but whether this translates to patient samples is unknown. Furthermore, non-dopaminergic neurotransmitter disturbances may be more pronounced in patients not responding sufficiently to antipsychotic treatment. Aims & Objectives To investigate this, we assessed cerebral levels of glutamate and GABA as well as striatal dopamine synthesis (DS) in antipsychotic-naïve first-episode patients with psychosis (FEP) and related findings to short- and long-term clinical outcome over the first two years of illness. Method We recruited 57 initially antipsychotic-naïve patients with FEP (22.6±5.0 years, 58% females) and 55 healthy controls (HCs) (22.2±4.3 years, 62% females) and assessed glutamate and GABA levels in dorsal anterior cortex, and glutamate levels in left thalamus after 6 weeks (FEP: 48; HC: 53), 6 months (FEP: 37; HC: 49), and 2 years (FEP: 35; HC: 45) using magnetic resonance spectroscopy (1H-MRS). A subsample of participants underwent 18F-DOPA-PET at baseline (FEP: 29; HC: 31) to measure dopamine synthesis (k3) in nucleus accumbens (NAc). Psychopathology and cognitive function were assessed at all visits. Results In the antipsychotic-naïve state, FEP revealed abnormal high thalamic glutamate and too low GABA and glutamate levels in anterior cingulate cortex (ACC), whereas striatal dopamine synthesis did not differ from HC. A favorable short-term response to antipsychotic treatment was seen in FEP with higher striatal dopaminergic activity. On the other hand, higher thalamic glutamate and lower GABA levels in ACC at illness onset were associated with both poor short-term and long-term treatment response. Moreover, lower glutamate levels in ACC were associated with a higher degree of cognitive deficits at all visits over the two years. Last, the association between GABA levels in ACC and striatal dopaminergic activity was abnormal in antipsychotic-naïve FEP compared with HC, and the degree of abnormality was related to short-term outcome in FEP. Discussion & Conclusions The results support combined dopaminergic, glutamatergic and GABAergic neurotransmitter disturbances in initially antipsychotic-naïve FEP and suggest non-dopaminergic and combined neurotransmitter disturbances as novel treatment targets in first-episode psychosis patients with poor treatment response.