Clozapine is the only medication indicated for treating
refractory schizophrenia, due to its superior efficacy among all
antipsychotic agents, but its mechanism of action is poorly understood. To date, no studies of human postmortem brain have characterized the gene expression response to
clozapine. Therefore, we addressed this question by analyzing expression data extracted from published microarray studies involving brains of patients on
antipsychotic therapy. We first performed a systematic review and identified four microarray studies of postmortem brains from
antipsychotic-treated patients, then extracted the expression data. We then performed generalized linear model analysis on each study separately, and identified the genes differentially expressed in response to
clozapine compared to other atypical
antipsychotic medications, as well as their associated canonical pathways. We also found a number of genes common to all four studies that we analyzed: GCLM, ZNF652, and GYPC. In addition, pathway analysis highlighted the following processes in all four studies:
clathrin-mediated endocytosis, SAPK/JNK signaling, 3-phosphoinositide synthesis, and
paxillin signaling. Our analysis yielded the first comprehensive compendium of genes and pathways differentially expressed upon
clozapine treatment in the human brain, which may provide insight into the mechanism and unique efficacy of
clozapine, as well as the pathophysiology of
schizophrenia.