Untreated bipolar disorder has severe consequences for the mother and there is increasing utilization of atypical antipsychotics as mood stabilizers and adjuncts to antidepressant therapy, with an associated increase in fetal exposure to these medications. Because of large differences in the pharmacokinetics of many drugs between humans and rodents, we have demonstrated that "behaviorally active" doses of many psychiatric drugs in laboratory animals do not reflect/model actual human clinical exposure and we have published on the need for clinically relevant and sustained drug administration in animal studies to mimic human exposures. Using a rat model, this study provides rigorous control of clinically relevant fetal exposure and will assess behavioral, gene expression and epigenomic changes in the offspring with an outcome that can inform clinical risks as well as identifying which medication may be the most appropriate clinical choice.
Specific Aim 1 will provide animals with clinically relevant and verified drug exposure throughout gestation for the most commonly utilized atypical antipsychotics in the Emory University Women's Mental Health Program: quetiapine/norquetiapine, olanzapine, and risperidone/paliperidone.
Specific Aim 2 will provide a behavioral assessment of development (motor and cognitive) prior to weaning and as juveniles (postnatal days 23-35) with the hypothesis that prenatal exposure to atypical antipsychotic drugs alters normal development compared to vehicle controls.
Specific Aim 3 will utilize our skills in gene expression (transcriptome) and epigenetic analysis (whole genome methylation patterns) in two brain regions (frontal cortex and hippocampus) likely to be important targets for healthy neurobiological functioning and relevant to the behavioral studies in specific aim 2. We will also assay leukocytes collected from these offspring which might provide biomarkers as "windows" into the brain. These data will provide important basic science information regarding medication effects on the developing brain which can translate, based upon known function(s) of specific genes, into areas of clinical assessment that may be most closely watched by pediatricians following these children. The focus of these studies on a single class of medications, with generally similar clinical efficacy, may directly guide physicians and patients in determining which medication may provide the least risk.

Public Health Relevance

Untreated bipolar disorder during pregnancy has severe consequences for the mother and there is increasing utilization of atypical antipsychotic medications as pharmacotherapy throughout the country with an associated increase in fetal exposure to these medications. My lab has argued that behaviorally active doses of many psychiatric drugs in laboratory animals may have little to do with actual human clinical exposure and have published on the need for clinically relevant and sustained drug administration in animal studies. This study provides rigorous control of clinically relevant fetal exposure and will assess behavioral, gene expression and epigenomic changes in the offspring with an outcome that can inform clinicians and parents about potential risks as well as identifying which medication may be the most appropriate choice.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD074486-01
Application #
8411507
Study Section
Special Emphasis Panel (ZRG1-EMNR-R (55))
Program Officer
Ren, Zhaoxia
Project Start
2013-06-15
Project End
2018-05-31
Budget Start
2013-06-15
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$329,834
Indirect Cost
$118,402
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322