Clinical meaning
Schizophrenia is a chronic psychotic disorder characterized by positive symptoms (hallucinations, delusions, disorganized speech/behavior), negative symptoms (flat affect, alogia, avolition, anhedonia, asociality), and cognitive impairment (working memory, attention, executive function deficits). The dopamine hypothesis remains central: mesolimbic pathway hyperactivity (excess dopamine) produces positive symptoms, while mesocortical pathway hypoactivity (insufficient dopamine) produces negative and cognitive symptoms. This dual dysfunction explains why typical antipsychotics (which globally block D2 receptors) improve positive symptoms but may worsen negative symptoms. The glutamate hypothesis proposes NMDA receptor hypofunction leads to disrupted glutamate-GABA balance and downstream dopamine dysregulation. Serotonin dysregulation also contributes, explaining why atypical antipsychotics (which block 5-HT2A in addition to D2) are more effective for negative symptoms. Neurodevelopmental factors are important: prenatal complications (viral infection, malnutrition, hypoxia), genetic vulnerability (polygenic, hundreds of risk genes), and structural brain changes (enlarged ventricles, reduced hippocampal and prefrontal cortex volume, progressive gray matter loss) suggest schizophrenia begins as a neurodevelopmental disruption that manifests clinically in late adolescence/early adulthood.