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Effects of typical and atypical antipsychotic drugs on gene expression profiles in the liver of schizophrenia subjects.

Choi KH, Higgs BW, Weis S, Song J, Llenos IC, Dulay JR, Yolken RH, Webster MJ - BMC Psychiatry (2009)

Bottom Line: Comparison between typical antipsychotics and atypical antipsychotics further identified genes associated with lipid metabolism and mitochondrial function.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Stanley Laboratory of Brain Research, Rockville, MD 20850, USA. choik@stanleyresearch.org

ABSTRACT

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.

Conclusion: 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.

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Related in: MedlinePlus

Genes associated with the golgi/endoplasmic reticulum transport are up-regulated in the atypical AP group compared to the control group. Each gene is plotted with fold change and 95% confidence intervals. Green: p < 0.001 and red: p < 0.0001
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Figure 3: Genes associated with the golgi/endoplasmic reticulum transport are up-regulated in the atypical AP group compared to the control group. Each gene is plotted with fold change and 95% confidence intervals. Green: p < 0.001 and red: p < 0.0001

Mentions: Figure 3 illustrates the genes associated with the golgi/endoplasmic reticulum are consistently up-regulated in the atypical AP group compared to the controls. However, most of the genes show moderate fold changes between 1.3 and 2 compared to the fold changes observed between the typical AP group and the controls. Increased gene expression associated with the golgi/endoplasmic reticulum suggest that atypical APs affect post-translational modifications, rather than the genes involved in direct transcriptional modifications in the nucleus of the cells.


Effects of typical and atypical antipsychotic drugs on gene expression profiles in the liver of schizophrenia subjects.

Choi KH, Higgs BW, Weis S, Song J, Llenos IC, Dulay JR, Yolken RH, Webster MJ - BMC Psychiatry (2009)

Genes associated with the golgi/endoplasmic reticulum transport are up-regulated in the atypical AP group compared to the control group. Each gene is plotted with fold change and 95% confidence intervals. Green: p < 0.001 and red: p < 0.0001
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2749837&req=5

Figure 3: Genes associated with the golgi/endoplasmic reticulum transport are up-regulated in the atypical AP group compared to the control group. Each gene is plotted with fold change and 95% confidence intervals. Green: p < 0.001 and red: p < 0.0001
Mentions: Figure 3 illustrates the genes associated with the golgi/endoplasmic reticulum are consistently up-regulated in the atypical AP group compared to the controls. However, most of the genes show moderate fold changes between 1.3 and 2 compared to the fold changes observed between the typical AP group and the controls. Increased gene expression associated with the golgi/endoplasmic reticulum suggest that atypical APs affect post-translational modifications, rather than the genes involved in direct transcriptional modifications in the nucleus of the cells.

Bottom Line: Comparison between typical antipsychotics and atypical antipsychotics further identified genes associated with lipid metabolism and mitochondrial function.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Stanley Laboratory of Brain Research, Rockville, MD 20850, USA. choik@stanleyresearch.org

ABSTRACT

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus