Apoptosis in schizophrenia: pathophysiologic and therapeutic considerations

A role for apoptosis in schizophrenia has long been hypothesized, but only recently have studies begun to examine this issue. This paper will review studies of apoptotic regulatory proteins, DNA fragmentation, and gene microarrays to highlight the potential role of apoptosis in the pathophysiology and treatment of schizophrenia.

Although several studies indicate a possible increase in apoptotic susceptibility, accumulating evidence suggests that apoptotic activity may actually be downregulated in chronic schizophrenia. Furthermore, antipsychotics produce complex effects on apoptotic regulation in the central nervous system, activating both proapoptotic and antiapoptotic signaling pathways.

Somewhat paradoxically, apoptosis appears to be downregulated in cortex of patients with chronic schizophrenia. This could reflect either a pathophysiological failure to mount an effective response to an apoptotic insult or an appropriate compensatory response to an earlier insult. The former could account for evidence indicating reduced neuronal viability without large-scale neuronal death in schizophrenia. The latter could reflect an earlier period of increased apoptotic activity in response to one or more proapoptotic insults. Antipsychotic treatment can modify the apoptotic response. This suggests implications for treatment, especially if future studies indicate that gray matter loss occurs via apoptotic mechanisms.