Effects of typical and atypical antipsychotic drugs on gene expression profiles in the liver of schizophrenia subjects.
BACKGROUND
Although much progress has been made on antipsychotic drug development, precise mechanisms behind the action of typical and atypical antipsychotics are poorly understood.


METHODS
We performed genome-wide expression profiling to study effects of typical antipsychotics and atypical antipsychotics in the postmortem liver of schizophrenia patients using microarrays (Affymetrix U133 plus2.0). We classified the subjects into typical antipsychotics (n = 24) or atypical antipsychotics (n = 26) based on their medication history, and compared gene expression profiles with unaffected controls (n = 34). We further analyzed individual antipsychotic effects on gene expression by sub-classifying the subjects into four major antipsychotic groups including haloperidol, phenothiazines, olanzapine and risperidone.


RESULTS
Typical antipsychotics affected genes associated with nuclear protein, stress responses and phosphorylation, whereas atypical antipsychotics affected genes associated with golgi/endoplasmic reticulum and cytoplasm transport. Comparison between typical antipsychotics and atypical antipsychotics further identified genes associated with lipid metabolism and mitochondrial function. Analyses on individual antipsychotics revealed a set of genes (151 transcripts, FDR adjusted p < 0.05) that are differentially regulated by four antipsychotics, particularly by phenothiazines, in the liver of schizophrenia patients.


CONCLUSIONS
Typical antipsychotics and atypical antipsychotics affect different genes and biological function in the liver. Typical antipsychotic phenothiazines exert robust effects on gene expression in the liver that may lead to liver toxicity. The genes found in the current study may benefit antipsychotic drug development with better therapeutic and side effect profiles.
Choi
Kwang H
KH
Stanley Laboratory of Brain Research, Rockville, MD 20850, USA. choik@stanleyresearch.org
Higgs
Brandon W
BW
Weis
Serge
S
Song
Jonathan
J
Llenos
Ida C
IC
Dulay
Jeannette R
JR
Yolken
Robert H
RH
Webster
Maree J
MJ
D000328:Adult; D014150:Antipsychotic Agents / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use*; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000187:drug effects / Q000235:genetics; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics; D010597:Pharmacogenetics; D010640:Phenothiazines / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D014150:Antipsychotic Agents; D009687:Nuclear Proteins; D010640:Phenothiazines