Project description:Antipsychotic drugs are commonly used to treat psychosis, mood disorders, and anxiety. While there is indirect evidence that some component of the antipsychotic effect of these drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects via epigenetic modulation. Here we tested the effect of an antipsychotic, olanzapine, on the methylation status of genes following chronic treatment. These effects have been revealed through significantly increased (p<0.01) DNA methylation of genes involved in dopaminergic and non-dopaminergic pathways including the glutamatergic, GABAergic, cholinergic, neuregulin and ErbB signaling pathways. The affected genes included GLS in hippocampus, NR1 in cerebellum and GLUD1 and NR2B in liver. Further, from a set of genes in the 22q11.2 micro-deletions that has been previously implicated in psychosis, 22 genes showed increased methylation following olanzapine treatment. Ingenuity Pathway Analysis (IPA) revealed that chronic olanzapine treatment significantly affected several important pathways such as CREB and CDK5 signaling (p=1.4E-05). Also, DNA replication, recombination and repair, cellular movement and cell cycle have been identified as the top networks affected by olanzapine. The results suggest that these downstream effects, aside from D2 blockade, may play a critical role in the biological actions of antipsychotics. These include altered expressions of relevant genes involved in GABAergic, glutamatergic, cholinergic, neuregulin and ErbB signaling pathways. Epigenetic mechanisms involving changes in DNA methylation could, therefore, explain the delay and individualized non-specificity of biological effects of olanzapine. The results also suggest that DNA methylation may play a role in the process of therapeutic efficacy of olanzapine by altering the transcriptome via tissue-specific methylation of genes involved in schizophrenia signaling pathways.

Project description:Antipsychotic drugs are commonly used to treat psychosis, mood disorders, and anxiety. While there is indirect evidence that some component of the antipsychotic effect of these drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects via epigenetic modulation. Here we tested the effect of an antipsychotic, olanzapine, on the methylation status of genes following chronic treatment. These effects have been revealed through significantly increased (p<0.01) DNA methylation of genes involved in dopaminergic and non-dopaminergic pathways including the glutamatergic, GABAergic, cholinergic, neuregulin and ErbB signaling pathways. The affected genes included GLS in hippocampus, NR1 in cerebellum and GLUD1 and NR2B in liver. Further, from a set of genes in the 22q11.2 micro-deletions that has been previously implicated in psychosis, 22 genes showed increased methylation following olanzapine treatment. Ingenuity Pathway Analysis (IPA) revealed that chronic olanzapine treatment significantly affected several important pathways such as CREB and CDK5 signaling (p=1.4E-05). Also, DNA replication, recombination and repair, cellular movement and cell cycle have been identified as the top networks affected by olanzapine. The results suggest that these downstream effects, aside from D2 blockade, may play a critical role in the biological actions of antipsychotics. These include altered expressions of relevant genes involved in GABAergic, glutamatergic, cholinergic, neuregulin and ErbB signaling pathways. Epigenetic mechanisms involving changes in DNA methylation could, therefore, explain the delay and individualized non-specificity of biological effects of olanzapine. The results also suggest that DNA methylation may play a role in the process of therapeutic efficacy of olanzapine by altering the transcriptome via tissue-specific methylation of genes involved in schizophrenia signaling pathways. comparison of olanzapine treated rats vs. control rats for genome-wide DNA methylation changes

Project description:This resident physician-led quality improvement project was conducted with aims to improve the health of youth prescribed atypical antipsychotic medications by increasing physician monitoring for metabolic side effects, while simultaneously educating trainees in quality improvement methodology. The plan, do, study, act quality improvement framework was utilized. Baseline metabolic monitoring rates of patients prescribed atypical antipsychotic medications in the two psychiatry resident outpatient clinics were obtained. Rates were stratified based on time on medication (<1 year, ?1 year) and parameter monitored. Metabolic monitoring rates subsequent to targeted changes were obtained. Problem solving with residents revealed barriers to monitoring, such as limited awareness of specific guideline recommendations and lack of convenient access to medical equipment (calibrated scales). Residents received education about atypical antipsychotic monitoring guidelines and side effect treatment. Residents were provided with calibrated scales. Atypical antipsychotic monitoring templates were introduced. Online surveys using were conducted to determine self-reported baseline-monitoring rates and comfort with guidelines following targeted change. The baseline metabolic monitoring rates of patients prescribed atypical antipsychotic medications was 9% (range: 0 to 17.6%) for youth in their first year taking an atypical antipsychotic medication and 58.9% (range: 29% to 100%) in subsequent years on medication. The results of relatively easy changes resulted in modest improvement in monitoring rates. The metabolic monitoring rate of a patient initiated on an atypical antipsychotic medication was 29% after targeted quality improvement measures were employed. Following quality improvement changes, residents reported increased knowledge about guidelines and increased monitoring for side effects. Use of a standardized data collection instrument to track monitoring of patients increased from 0% to 70% (range: 30% to 90%). Quality improvement projects provide an avenue with which to improve atypical antipsychotic monitoring rates. Through active participation in quality improvement projects, psychiatry residents may be taught to employ quality improvement methodology.

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Gene-microRNA interactions associated with antipsychotic mechanisms and the metabolic side effects of olanzapine.

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