Clinical meaning
Schizophrenia is a chronic neurodevelopmental disorder involving dysregulated dopaminergic, glutamatergic, and GABAergic neurotransmission across distinct neural circuits. The dopamine hypothesis (revised) proposes: (1) Mesolimbic dopamine hyperactivity causes positive symptoms (hallucinations, delusions, disorganized speech/behavior) — this is the target of all antipsychotics through D2 receptor blockade; (2) Mesocortical dopamine hypoactivity in the prefrontal cortex causes negative symptoms (affective flattening, alogia, avolition, anhedonia, asociality) and cognitive deficits (working memory, executive function impairment) — unfortunately worsened by D2 blockade of first-generation antipsychotics; (3) Tuberoinfundibular D2 blockade causes hyperprolactinemia; (4) Nigrostriatal D2 blockade causes extrapyramidal symptoms (EPS). The glutamate hypofunction hypothesis adds that NMDA receptor dysfunction on GABAergic interneurons disinhibits glutamate release, contributing to both positive and negative symptoms (supported by PCP/ketamine psychosis models). Neurodevelopmental abnormalities include enlarged lateral ventricles, reduced cortical gray matter volume, and disrupted cortical connectivity. First-generation antipsychotics (haloperidol, chlorpromazine) primarily block D2 receptors with high EPS risk; second-generation antipsychotics (risperidone, olanzapine, quetiapine, clozapine) additionally block 5-HT2A receptors, partially restoring mesocortical dopamine and reducing EPS, but cause metabolic syndrome (weight gain, diabetes, dyslipidemia) through H1 and 5-HT2C antagonism.