Pathophysiology
Clinical meaning
Schizophrenia is a chronic neurodevelopmental disorder characterized by positive symptoms (hallucinations, delusions, disorganized thought), negative symptoms (anhedonia, avolition, alogia, flat affect, social withdrawal), and cognitive impairment (executive dysfunction, working memory deficits, attention impairment). The dopamine hypothesis remains the foundational model: (1) Mesolimbic pathway hyperactivity โ excessive dopamine in the ventral tegmental area (VTA) to nucleus accumbens projection causes positive symptoms; ALL effective antipsychotics block D2 receptors in this pathway; (2) Mesocortical pathway hypoactivity โ insufficient dopamine in the VTA to prefrontal cortex projection causes negative symptoms and cognitive deficits; traditional antipsychotics (which globally block D2) worsen these symptoms; atypical antipsychotics with 5-HT2A antagonism partially restore prefrontal dopamine release. The glutamate hypothesis explains aspects the dopamine theory cannot: NMDA receptor hypofunction (supported by the observation that PCP and ketamine, NMDA antagonists, produce schizophrenia-like symptoms including negative symptoms) leads to cortical disinhibition and downstream mesolimbic dopamine excess. Structural brain changes include: enlarged lateral ventricles, decreased cortical gray matter volume (progressive loss, especially prefrontal and temporal cortex), and hippocampal volume reduction. These changes begin before symptom onset and progress throughout the illness. First-episode...