Proposed integrated model of schizophrenia

It has been proposed that the nigrostriatal dopaminergic abnormalities arise secondary to dysfunction in cortical circuits; this proposes that lower cortical glutamate and NMDA receptor levels lead to reduced activation of cortical GABA interneurons regulating glutamatergic projection neurons into the striatum, as shown in the figure.^1,2

Imaging studies indicate higher striatal dopamine, which has been linked to psychotic symptoms.²

Lower cortical levels of glutamate and GABA underpin an excitation/inhibition imbalance, which has been linked to both cognitive deficits and negative symptoms.²

This helps explain why dopamine-targeting treatments improve psychosis but often have limited effects on negative symptoms and cognition, as these are likely reflecting upstream cortical glutamatergic, and GABAergic dysfunction.²

GABA=gamma-aminobutyric acid; NDMA=N-methyl-D-aspartate