Extrapyramidal Side Effects, Tardive Dyskinesia, and the Concept of Atypicality

The most frequent problems associated with the older generation of antipsychotic agents are extrapyramidalside effects (EPS) and tardive dyskinesia. Neuroleptic-induced EPS are thought to becaused by blockade of nigrostriatal dopamine tracts resulting in a relative increase in cholinergic activity;tardive dyskinesia is less well understood but is thought to be a supersensitivity response tochronic dopamine blockade. The leading hypothesis for the mechanism of action of the newer generationof atypical antipsychotics is the presence of a high serotonin-to-dopamine receptor blockade ratioin the brain. When serotonergic activity is blocked—as is the case with atypical antipsychotics—dopamine release increases and balances out the dopamine blockade effect at postsynaptic receptorsites, which results in few or no EPS. Prospective data indicate that the risk of tardive dyskinesia inpatients taking atypical antipsychotics is less than that for those taking typical antipsychotics. Thisarticle reviews the mechanisms of neuroleptic-induced EPS and tardive dyskinesia and discusses therelationship between these movement disorders and atypical antipsychotic agents.