5-HT2 antagonism and EPS benefits: is there a causal connection?

This article examines the hypothesis that 5-HT₂ antagonism ameliorates extrapyramidal side effects (EPS) induced by the blockade of D₂ dopamine receptors by antipsychotics. Neuroanatomical and neurophysiological data confirm the existence of pathways whereby 5-HT₂ antagonism may influence EPS. The experimental data in rodents is marginally positive, but shows that the net effect of 5-HT₂ antagonism is dependent upon the precise conditions under which catalepsy is induced. The data in monkeys are mainly negative. Studies in patients who have received adjunct 5-HT₂ antagonists in addition to typical neuroleptics lend some support the the hypothesis, but are not conclusive. It is reasoned that 5-HT₂ antagonism plays no role in clozapine's freedom from EPS, but it may be responsible for risperidone's decreased propensity to cause EPS. The article concludes that there is support for a conditional role of 5-HT₂ in decreasing EPS: 5-HT₂ antagonists may delay the onset and decrease the severity of EPS but cannot totally eliminate its occurrence. The implications of these findings for the next generation of combined 5-HT₂/D₂ antagonists are discussed.