Researchers at the University of Nebraska Medical Center and Vanderbilt University in Nashville, Tenn., have found that two commonly used medications for treatment of mental illness might cause a health risk to a subset of individuals based on their genetic makeup.
The findings were published in the September issue of the Journal of Lipid Research, a publication of the American Society for Biochemistry and Molecular Biology. The research is funded by a five-year, $3.2 million National Institute of Mental Health grant.
The research findings center around the gene 7-dehydrocholesterol reductase (DHCR7), which produces the enzyme responsible for the final step in cholesterol production. Cholesterol is essential for the normal function of all cells of the body. Many different cell types synthesize cholesterol, including the brain, as the nervous system cannot use the cholesterol from food intake.
Two defective copies of the gene cause the developmental disorder Smith-Lemli-Opitz syndrome (SLOS), characterized by an elevation of a toxic cholesterol precursor, 7-DHC. SLOS affects one in 20,000 to 60,000 newborns, with symptoms ranging from mild learning and behavioral problems to profound mental and physical challenges. It also is noteworthy that three in four children with SLOS have an autism spectrum disorder.
In contrast, individuals with a single defective copy of the DHCR7 gene, so called "carriers," are considered healthy. However, the latest research showed that if those individuals take either aripiprazole (marketed as Abilify) or trazodone (marketed as Oleptro), they might have an unwanted physiological response to the treatment.
Aripiprazole typically is used to treat biopolar disorder, schizophrenia, depression and irritability associated with autism, while trazodone is used to treat depression. Patients often continue to use these medications during pregnancy.
"A single copy of the defective DHCR7 gene leads to a slight elevation of 7-DHC. Similarly, the two medications we studied also mildly elevate 7-DHC levels even when the two copies of the DHCR7 genes are fully functional," said lead author Zeljka Korade, D.V.M., Ph.D., a professor of pediatrics, biochemistry and molecular biology at UNMC. "However, when a single copy of the defective DHCR7 gene is combined with the aripiprazole or trazodone treatment in adults, the 7-DHC levels are markedly elevated into a range of that seen in SLOS patients."
The health consequences of this strong 7-DHC elevation in adulthood remain unknown to date. The study was performed on human skin cells donated by individuals who carry a single copy of the defective DHCR7 gene, but the authors believe that a similar process takes place in all tissues affected by the defective DHCR7 gene, including the brain.
"These medications are perfectly safe in 99 percent of the people who take them, but this might not be so for the approximately 1 percent of people who have a single defective copy of the DHCR7 gene," said Karoly Mirnics, M.D., Ph.D., director of the Munroe-Meyer Institute for Genetics and Rehabilitation at UNMC and co-author. "This might be especially important during pregnancy, when the mother is taking one of these medications, and either the mother or the child has a single copy of the defective DHCR7 gene. This interaction has a potential to adversely affect the developing brain of the unborn child, leading to a chemically induced SLOS, and this should be investigated."
"Our ongoing research is testing these and similar gene-drug interactions in pregnant transgenic mouse models, and we might be able to answer this very important question in the near future," Dr. Korade said. "This is a perfect example of precision medicine, where the genetic makeup of the patients might be critical to choose an optimal and personalized treatment."
Individuals who are prescribed one of these medications and are considering pregnancy should consult with their physician about getting a genetic test to determine if they are a carrier of the defective gene, she said. Likewise, people who are known carriers or who have a family history of SLOS in their family and are prescribed either aripiprazole or trazodone, should talk to their physician about a potential risk to their health.
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