Glutamate Hypofunction, Serotonin Dysregulation, and Dopamine Hyperactivation in Psychosis

The pathophysiology of psychosis implicates interacting disturbances across multiple neurotransmitter systems. Classical dopamine-centric frameworks are increasingly complementedby models emphasising glutamatergic NMDA receptor hypofunction and serotonergic 5-HT2Areceptor dysregulation. This review synthesises preclinical, pharmacological, neuroimaging,and postmortem evidence that links cortical NMDA hypofunction and aberrant 5-HT2Asignalling to mesolimbic D2 receptor hyperactivation. We present a mechanistic cascade inwhich NMDA hypofunction reduces inhibitory control by parvalbumin-positive interneurons,producing cortical disinhibition and abnormal glutamatergic drive to midbrain dopamineneurons; concurrent 5-HT2A dysregulation amplifies this process by facilitating excitatorycortical output. Clinical and therapeutic implications for schizophrenia, substance-inducedpsychosis, and affective psychosis are discussed, and avenues for multi-target interventionsand biomarker development are proposed.