Years ago, during his clinical residency, University of Pittsburgh psychiatrist and cell biologist Zachary Freyberg noticed that many of his patients taking antipsychotics gained substantial weight, had trouble controlling their blood sugar, and ultimately developed diabetes. “There's a tendency to think that if you're treating someone psychiatrically, you're focusing on the brain and the mind,” he said. “One of the important lessons that I've learned over time is that these [medications] don't know they have to [stop working] at the neck.”

An important clue about why antipsychotic drugs cause side effects is their dopamine-blocking ability, which targets the pancreas and other organs in addition to the brain. Freyberg wondered whether drugs that stimulated pancreatic dopamine receptors could compete with dopamine-blocking antipsychotic drugs in the pancreas and keep the effects of antipsychotics confined to the brain. To test out this theory, Freyberg modified bromocriptine, a dopamine agonist that stimulates pancreatic dopamine, such that it stayed away from the brain. In a recent study published in Diabetes, Freyberg’s group reported that modified bromocriptine entered the brain more slowly and stayed in the body longer than its unmodified version. The modified drug is thus a useful tool to separate the effects of dopamine in the brain versus the periphery. 

“To try to understand the relative contributions between the central and peripheral effects of dopamine is really novel,” said Jacob Ballon, a psychiatrist at Stanford University who was not involved in the study. “If you're looking for more selective medications, you need to know what the relative contributions in different areas are.”

To develop a form of bromocriptine that would stimulate pancreatic, but not neuronal, dopamine receptors, Freyberg teamed up with chemist Amy Newman at the National Institutes of Health. “Most chemists aim to create drugs that penetrate the brain efficiently, but I asked if she could make one that didn't,” said Freyberg. Together, they devised a strategy to modify bromocriptine by incorporating iodine to add more charges. Consistent with its Food and Drug Administration (FDA)-approved use for type 2 diabetes, unmodified bromocriptine improved glucose tolerance, lowered fasting blood glucose , and enhanced insulin sensitivity in a mouse model of diet-induced dysglycemia. The modified version showed limited effectiveness, suggesting that both brain and peripheral receptors need to work together for proper metabolic control. Future studies will focus on enhancing modified bromocriptine’s effects on metabolism. “This is just the first generation. We can hopefully make even better drugs down the line,” Freyberg said.

His group plans to do a safety trial to test both bromocriptine and an improved modified version alongside antipsychotic drugs. Given that bromocriptine is a generic drug, its affordability and accessibility could significantly benefit people on antipsychotic medications. 

Freyberg thinks it’s essential to raise awareness that medications targeting the brain may have systemic effects throughout the body, and that healthcare providers should consider overall physical health in addition to psychiatric symptoms. “Such comprehensive care can lead to improved long-term outcomes,” he said. Ballon agreed. “I hope this study helps to continue the conversation around the relationship between dopamine and blood sugar and weight, and to push forward the possibility of treatments that may help modify some of these areas of risk,” he said. 

 Reference

1. Bonifazi, A. et al. Development of novel tools for dissection of central versus peripheral dopamine D₂-like receptor signaling in dysglycemia. Diabetes  73, 1411-1425 (2024).