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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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Effects of individual AP drugs on gene expression are shown with fold change and 95% confidence intervals. These genes show differential expression profiles in the liver by the individual AP drugs. Values are expressed as fold changes compared to the unaffected controls. Red: significant from the controls (FDR p < 0.05). RIS, risperidone; PHE, phenothiazines; OLA, olanzapine; HAL, haloperidol.
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Figure 5: Effects of individual AP drugs on gene expression are shown with fold change and 95% confidence intervals. These genes show differential expression profiles in the liver by the individual AP drugs. Values are expressed as fold changes compared to the unaffected controls. Red: significant from the controls (FDR p < 0.05). RIS, risperidone; PHE, phenothiazines; OLA, olanzapine; HAL, haloperidol.

Mentions: Following the AP class analyses, we analyzed individual AP drug effects on gene expression in the liver. Individual AP drug analysis including haloperidol, phenothiazines, olanzapine, risperidone and the unaffected controls revealed 158 transcripts (FDR p < 0.05) that are differentially regulated among the four AP drug groups. We then compared this result with the previous results from AP class comparisons (typical AP vs. control and atypical AP vs. control). Among the 158 transcripts, we identified 151 transcripts that are common in the typical AP class comparison and 20 transcripts that are common in the atypical AP class comparison. This confirms that typical APs, not atypical APs, exert robust effects on gene expression in the liver. Among those 151 transcripts, 26 transcripts are associated with response to stress based on the functional annotation analysis (adj. p = 0.001, fold enrichment = 3.21). Figure 5 illustrates four example genes that are differentially regulated by individual AP drugs. For instance, C-reactive protein (CRP) expression (FDR p = 0.0002) and interleukin receptor 1 antagonist (IL1RN) expression (FDR p = 0.0004) are selectively increased by the phenothiazines. In contrast, transglutaminase 2 (TGM2) expression is increased by all four AP drugs as compared to the controls (FDR p < 0.0001). A catalase (CAT) gene expression is decreased by phenothiazines, haloperidol, and olanzapine, but not by risperidone (FDR p < 0.01). Detailed information on the 151 genes is shown in Additional File 4.


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)

Effects of individual AP drugs on gene expression are shown with fold change and 95% confidence intervals. These genes show differential expression profiles in the liver by the individual AP drugs. Values are expressed as fold changes compared to the unaffected controls. Red: significant from the controls (FDR p < 0.05). RIS, risperidone; PHE, phenothiazines; OLA, olanzapine; HAL, haloperidol.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Effects of individual AP drugs on gene expression are shown with fold change and 95% confidence intervals. These genes show differential expression profiles in the liver by the individual AP drugs. Values are expressed as fold changes compared to the unaffected controls. Red: significant from the controls (FDR p < 0.05). RIS, risperidone; PHE, phenothiazines; OLA, olanzapine; HAL, haloperidol.
Mentions: Following the AP class analyses, we analyzed individual AP drug effects on gene expression in the liver. Individual AP drug analysis including haloperidol, phenothiazines, olanzapine, risperidone and the unaffected controls revealed 158 transcripts (FDR p < 0.05) that are differentially regulated among the four AP drug groups. We then compared this result with the previous results from AP class comparisons (typical AP vs. control and atypical AP vs. control). Among the 158 transcripts, we identified 151 transcripts that are common in the typical AP class comparison and 20 transcripts that are common in the atypical AP class comparison. This confirms that typical APs, not atypical APs, exert robust effects on gene expression in the liver. Among those 151 transcripts, 26 transcripts are associated with response to stress based on the functional annotation analysis (adj. p = 0.001, fold enrichment = 3.21). Figure 5 illustrates four example genes that are differentially regulated by individual AP drugs. For instance, C-reactive protein (CRP) expression (FDR p = 0.0002) and interleukin receptor 1 antagonist (IL1RN) expression (FDR p = 0.0004) are selectively increased by the phenothiazines. In contrast, transglutaminase 2 (TGM2) expression is increased by all four AP drugs as compared to the controls (FDR p < 0.0001). A catalase (CAT) gene expression is decreased by phenothiazines, haloperidol, and olanzapine, but not by risperidone (FDR p < 0.01). Detailed information on the 151 genes is shown in Additional File 4.

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