Is neuroleptic dysphoria a variant of drug-induced extrapyramidal side effects?

Neuroleptic drugs induce psychological side effects such as dysphoria, cognitive impairment, and loss of motivation. These side effects were largely underrecognized and trivialized in the past as variants of extrapyramidal side effects (EPSEs). We review the recent literature on the subject and clarify the relation between neuroleptic-induced dysphoria and EPSEs.

We critically examined clinical, interventional, neuroimaging, and basic science studies published in the past 10 years, delineating the temporal, phenomenological, biochemical, and neuroanatomical relation between dysphoria and EPSEs.

Subjective responses occur within 4 to 6 hours of neuroleptic use, whereas acute dystonia is often observed within 24 hours and parkinsonian syndrome after 5 to 7 days. Neuroleptic-induced dopaminergic blockade mediates both dysphoria and EPSEs. However, impaired dopamine function in the nucleus accumbens seems to give rise to dysphoria, whereas blockade of D2 receptors in the nigrostriatal system is responsible for EPSEs.

The earlier notion that neuroleptic dysphoria is a variant of EPSEs was simplistic and speculative. Exploring the differences rather than dwelling on the similarities will likely enhance our understanding of dopamine's role in the origin of varied side effects and in their distinctive characteristics.