Proteome effects of antipsychotic drugs: Learning from preclinical models

Proteome-wide expression analyses are performed in the brain of schizophrenia patients to understand the biological basis of the disease and discover molecular paths for new clinical interventions. A major issue with postmortem analysis is the lack of tools to discern molecular modulation related to the disease from dysregulation due to medications. We review available proteome-wide analysis of antipsychotic treatment in rodents, highlighting shared dysregulated pathways that may contribute to an extended view of molecular processes underlying their pharmacological activity. Fourteen proteomic studies conducted with typical and atypical antipsychotic treatments were examined; hypothesis-based approaches are also briefly discussed. Treatment with antipsychotics mainly affects proteins belonging to metabolic pathways involved in energy generation, both in glycolytic and oxidative phosphorylation pathways, suggesting antipsychotics-induced impairments in metabolism. Nevertheless, schizophrenic patients show impaired glucose metabolism and mitochondrial dysfunctions independent of therapy. Other antipsychotics-induced changes shared by different studies implicate cytoskeletal and synaptic function proteins. The mechanism can be related to the reorganization of dendritic spines resulting from neural plasticity events induced by treatments affecting neurotransmitter circuitry. However, metabolic and plasticity pathways activated by antipsychotics can also play an authentic role in the etiopathological basis of schizophrenia.