Antipsychotic-associated neuronal changes in the brain: Toxic, therapeutic, or irrelevant to the long-term outcome of schizophrenia?

The increasingly wide-spread use of antipsychotics in both adults and children calls for a detailed examination of antipsychotic-associated neuronal changes in the brain, and whether these changes are toxic, therapeutic, or perhaps irrelevant to the outcome of major psychiatric disorders, especially schizophrenia. In this review we will examine the extensive evidence demonstrating both acute and longer-term antipsychotic-associated neurotoxicity and neuroplasticity, as well as the more specific cellular changes that appear to underlie these phenomena. These include changes in proteins affecting cell survival, impairment of the mitochondrial respiratory chain, increases in DNA fragmentation, injury to dendritic microtubules, increases in dopamine-generated reactive oxygen species, changes in cell morphology, and rapid induction of apoptosis. We shall also examine the correlation between these changes and alterations in gross brain structure. There appears to be a disjunction between the widespread cellular and gross structural brain changes in schizophrenia, and the duration of illness, expression of symptoms, and response to treatment. We shall explore possible explanations for this apparent paradox.