New research conducted at the University of Pittsburgh suggests a possible way to lower the risk of diabetes linked to commonly used antipsychotic medications. The study provides initial evidence supporting the idea of combining antipsychotic drugs that block dopamine receptors in the brain with drugs that prevent these same receptors from being blocked in the pancreas. This strategy may help minimize the metabolic side effects, such as impaired blood sugar control or dysglycemia. This research offers a new perspective on managing the potential risks associated with antipsychotic medication use.
The study provides initial support for combining antipsychotic medications that block dopamine receptors in the brain with drugs that prevent those same receptors from being blocked in the pancreas. This approach, outlined in the latest issue of Diabetes, could help reduce metabolic side effects such as impaired blood sugar control, or dysglycemia. The research also suggests that weight control medications like Wegovy and Ozempic may not be as effective in managing dysglycemia caused by antipsychotic drugs. Patients who are dealing with the weight gain caused by antipsychotic medications might consider taking new drugs to control their appetite, but they could be overlooking an important underlying cause of the drug-induced dysglycemia. “Antipsychotic medications don’t just stop working below the neck,” said Zachary Freyberg, M.D., Ph.D., associate professor of psychiatry and cell biology at Pitt’s School of Medicine. “Maintaining glucose metabolism requires the brain to be in constant communication with the rest of the body, and vice versa. Next-generation antipsychotic drugs can be modified as a new strategy to control dysglycemia.”The majority of prescribed antipsychotic drugs function by inhibiting the brain receptors that interact with dopamine, a crucial neurotransmitter involved in the brain’s reward system and movement control. It is important to note that the dopamine D2 receptors, which are targeted by antipsychotic medications, are not limited to the brain. Previous research by Freyberg has demonstrated that these medications also block D2 receptors in the pancreas.
Freyberg’s groundbreaking finding challenges traditional beliefs and emphasizes the significance of pancreatic dopamine in regulating blood sugar levels and potentially contributing to diabetes.Blood sugar is regulated by D2 receptors on pancreatic cells that control the production and secretion of insulin and glucagon hormones. Antipsychotic medications can disrupt this balance, leading to dysglycemia and diabetes. However, researchers have developed a molecule that can prevent antipsychotic drugs from blocking D2 receptors in organs like the pancreas, allowing for potential therapeutic benefits of peripheral dopamine signaling. This collaboration was with the National Institute on Drug Abuse (NIH NIDA).Bromocriptine methiodide, also known as BrMel, is a molecule that is similar in structure to bromocriptine, which is a drug approved by the FDA for treating type 2 diabetes. However, BrMel has been modified in a way that reduces its ability to pass through the brain-blood barrier when given systemically. This means that its effects are limited to the body’s periphery, rather than affecting the brain. Early studies in mice have indicated that the effects of dopamine on glucose metabolism require communication between the brain and peripheral organs, including the pancreas. Experiments have shown that when bromocriptine is administered systemically, it improves glucose metabolism.In the study of insulin-resistant mice, drugs like BrMeI, which target peripheral areas, were not effective. However, using bromocriptine directly to the brain may be helpful in preventing or reversing dysglycemia. Freyberg and his team at Pitt are conducting a safety clinical trial to see if antipsychotic drugs can still be effective when used alongside bromocriptine, which is already approved by the FDA. They plan to move on to a larger trial to test the effectiveness of this combination.
Research suggests that there is great potential for BrMel and similar molecules to help manage dysglycemia in the coming years.
According to Freyberg, the need for both the brain and the body to regulate stable glycemic control brings a new perspective to understanding neuropsychiatry and allows for the integration of knowledge from different organ systems.
Freyberg also pointed out that the majority of psychiatric medications are prescribed by general practitioners rather than psychiatrists. He hopes that their research will raise awareness about the importance of communication between the brain and the body in maintaining physiological functions.The study also advises healthcare providers to consider the potential for drugs that target the brain, such as psychiatric medications, to have effects outside the brain when prescribing medications.”
Additional contributors to the study include Zachary Farino, M.S., Despoina Aslanoglou, Ph.D., and José Mantilla-Rivas, M.D., from the University of Pittsburgh; Alessandro Bonifazi, Ph.D., Michael Ellenberger, J.D., Comfort Boateng, Ph.D., and Amy Hauck Newman, Ph.D., from the National Institute on Drug Abuse (NIDA); Rana Rais, Ph.D., and Barbara Slusher, Ph.D., from Johns Hopkins University; and Sandra Pereira, Ph.D., and Margaret Hahn, M.D., Ph.D., from the University.The authors of the article are from the University of Toronto, Oregon Health & Science University, and Albert Einstein College of Medicine. The content of the article is the responsibility of the authors and may not represent the official views of the National Institutes of Health.
