There are 4 main dopamine pathways in the brain:

1. Nigro-Striatal: substantial nigra to basal ganglia, involved in movement (what gets affected to cause EPS: tardive dyskinesia, akatisia)
2. Meso-Limbic: VTA to nucleus accumbens, “reward” pathway (causes the positive symptoms of schizophrenia)
3. Meso-Cortical: VTA to cortex, motivation and emotional response (thought to cause the negative symptoms of schizophrenia)
4. Tubulo-Infundibular: hypothalamus to posterior pituitary (hypoprolactinemia in untreated individuals, but D2 blockade with antipsychotics can cause a hyperprolactenemia)

Antipsychotic medication can be divided into 2 classes

1. Typical/First Generation
2. Atypical/Second Generation

Typicals are characterized by strong D2 antagonism in the mess-limbic and meso-cortical pathways. This can also lead to significant extrapyramidal symptoms (EPS). They also have strong CYP-450 metabolism (which means lots of interactions with other drugs and grapefruits).

• High-potency typicals: only slightly anticholinergic & minimally sedating but have more weight gain and a higher risk of EPS
• Low-potency typicals: more quite sedating and more anticholinergic (bradycardia, GI upset) but have a lower risk of EPS

Atypicals have less risk for EPS, but carry a higher risk for metabolic side-effects and weight gain. While they bind to D2 receptors (like typicals), atypicals have higher affinity for serotonin (5HT) receptors.

Clozapine is a little different from the other atypicals in that is has been shown to have a shorter half-life, which is thought to be why it doesn’t produce as many EPS. However it has the very specific (and serious) risk of agranulocytosis.