A new study that found the annual number of children prescribed antipsychotic drugs jumped fivefold between 1995 and 2002 to an estimated 2.5 million children, is giving new urgency to the work of Marilyn Ader, associate professor of physiology and biophysics at the Keck School of Medicine.

Ader, along with her colleague Richard Bergman, chair of physiology and biophysics at the Keck School and the Keck Chair in Medicine, studied two of the six medications in this class of drugs. Their study, published in the February 2005 issue of the journal Diabetes, noted that these drugs can have serious side effects.

In their six-week study, animals given the antipsychotic drugs “virtually doubled their body fat, becoming obese in a short period of time,” said Ader. In addition, the researchers found the functioning of the pancreas was severely impaired.

“When obesity impairs the ability of insulin to lower the blood sugar [‘insulin resistance”], a normal, healthy pancreas will sense that the insulin isn’t working, and compensate by releasing more insulin. It’s a normal function, called compensatory hyperinsulinemia,” said Ader.

However, in the animals that became obese and insulin resistant after receiving certain antipsychotic medications, “we were surprised to find that they were unable to release more insulin. Their pancreatic secretory function was seriously impaired,” she said. Since reduced secretory function of the pancreas presages type 2 (adult-type) diabetes, the findings of Ader’s group provide an important clue to the link between antipsychotic drugs and the development of diabetes.

Since the publication of the first study, Ader has been awarded a five-year grant from the National Institutes of Health to further study this group of antipsychotic drugs to help determine the risk factors critical in the development of these complications. Current studies are also aimed at identifying the mechanisms by which these drugs may cause increased fat mass and damage to pancreatic function.

“We know antipsychotic drugs work on the brain for treatment of psychiatric illnesses,” Ader notes. “But when a patient also develops obesity or problems with insulin secretion, is that because the drugs are affecting the fat tissue or the pancreas, or are these side effects mediated by some central mechanism of the drugs on the brain?,” she asks. “We need to answer these questions to figure out how to design a drug without the side effects, or to determine how you can block the bad effects with a different medication.”

While pharmacologists focus their attention on how antipsychotics interact with receptors on cells to explain these drug side effects, Ader said she and her colleagues “take a systems biology approach, rather than focusing on a single tissue or organ of the body.”

As an example, she said, “we examine whether antipsychotic medications may interfere with how the brain may ‘talk’ to the pancreas, or how the pancreas ‘talks’ to the liver or muscle. It’s an incredibly orchestrated system.”

What is truly amazing, she added, “is that this study of antipsychotic drugs now gives us some clues to how ‘garden variety’ diabetes may develop. It raises the possibility that the brain may somehow communicate with the pancreas to increase secretion of insulin when insulin resistance develops. This suggests that the pathogenesis of Type 2 diabetes may develop in part because these brain processes are interrupted.”

Ader is quick to note that the drugs can be very effective in treating the devastating symptoms of schizophrenia, bipolar disorder and a number of serious mental illnesses.

“Patients who otherwise couldn’t function are often able to perform normal tasks and live more normal lives with these medications,” she said. “The reason this issue of antipsychotic-associated diabetes has become alarming is that these drugs are being used to treat more and more conditions, like dementia or anxiety or, as this recent study found, pediatric populations.”

Indeed, the new study from Vanderbilt’s Children’s Hospital found more than half the antipsychotic drug prescriptions for children were for attention deficit disorder and other non-psychotic conditions.