Mechanism of Action of Antipsychotic Drugs

Antipsychotic drugs (APDs) are typically classified as typical or atypical. Treatment with typical APDs such as haloperidol is accompanied by extrapyramidal (parkinsonian) side effects. Atypical APDs, such as clozapine, display a much lower or absent incidence of extrapyramidal side effects (EPS), are more effective in treating negative symptoms, and offer therapeutic benefit to patients who are refractory to other APDs. However, many atypical and some typical APDs have other side effects, such as weight gain and cardiac conduction changes. Considerable attention has been devoted to uncovering the factors that contribute to the differences between typical and atypical APDs, both in terms of therapeutic and side affects.

The striatum is thought to be the site at which typical APDs, by virtue of D2 receptor blockade, result in EPS. Two compartments in the striatum, the patch (striosome) and matrix, have been defined on the basis of histochemical markers and afferent innervations. The DA innervation of the matrix is preferentially lost in Parkinson's disease, while the patch compartment has been suggested to subserve certain cognitive functions. We recently found that atypical APDs have a significantly greater effect on the patch compartment (as reflected by the ratio of Fos-li neurons in the two compartments) than do typical APDs. Particularly striking is the complete lack of overlap in the patch:matrix ratio between typical and atypical APDs.

We have also recently found that those APDs with significant weight gain liability activate orexin-containing neurons of the hypothalamus. Orexin is a peptide transmitter that regulates arousal and elicits food intake. Interestingly, the appetite suppressor amphetamine also activates orexin neurons. We have found that APDs with weight gain liability specifically activate orexin neurons that project to the prefrontal cortex, but amphetamine does not target this cell population. This observation may explain why the weight gain seen with APDs is correlated with a better therapeutic outcome.