Antipsychotic medications don’t just stop labor

PITTSBURGH, June 13, 2024 – New research from the University of Pittsburgh reveals a potential approach to reducing the risk of diabetes associated with widely prescribed antipsychotic medications.

The study presents the first evidence to support the co-administration of antipsychotic drugs that block dopamine receptors in the brain, as well as drugs that prevent antipsychotics from blocking these same receptors in the pancreas. This approach, published today in Diabetes, could limit metabolic side effects, including impaired blood glucose control or dysglycemia.

This research may also explain why medications aimed at weight control, including the new neuropeptide drugs Wegovy and Ozempic, may not be as effective as hoped in controlling dysglycemia caused by antipsychotic medications. Patients who experience weight gain associated with antipsychotic medications may be tempted to take these new medications to control satiety – but they may be missing an important underlying cause of drug-induced deglycation.

“Antipsychotic medications don’t just stop working below the neck,” said lead author Zachary Freyberg, MD, Ph.D., associate professor of psychiatry and cell biology at Pitt School of Medicine. “Maintaining glucose metabolism requires the brain to be in constant communication with the rest of the body, and vice versa. New generation antipsychotic medications can be modified as a new strategy to control dysglycemia and diabetes.

Most prescription antipsychotic medications work by blocking the class of brain receptors that respond to a neurotransmitter called dopamine – a fundamental molecule of the brain’s reward system and control of brain-directed movements. However, the subtype of dopamine receptors that respond to antipsychotic medications, called dopamine D₂ receptors, are not exclusive to the brain. As Freyberg’s previous research has shown, antipsychotic medications also block D.₂ receptors in the pancreas.

Freyberg’s revolutionary discovery demonstrated that pancreatic dopamine plays a key role in blood sugar control by interacting with D.₂ receptors on the surface of pancreatic cells that control the production and secretion of the hormones insulin and glucagon. When the delicate balance between glucose-raising and glucose-lowering hormones is destabilized by antipsychotic medications, dysglycemia and diabetes can result.

However, peripheral dopamine signaling can be exploited for therapeutic purposes. Working with researchers at the National Institute on Drug Abuse (NIH NIDA) at the National Institutes of Health, the team created a molecule that can limit D’s blockade of antipsychotic medications.₂ receptors in organs like the pancreas, but not in the brain. This molecule, called bromocriptine methiodide, or BrMel, is structurally similar to bromocriptine – a drug approved by the FDA to treat type 2 diabetes – but has a modification that makes it less likely to cross the blood-brain barrier if it is administered systemically, thus limiting its activity to the periphery.

Early studies in mice suggest that dopamine’s effects on glucose metabolism require communication between the brain and peripheral organs, including the pancreas. Experiments showed that, unlike systemically administered bromocriptine which improved the glucose profile of insulin-resistant mice, peripherally restricted BrMeI or bromocriptine administered directly to the brain did not show improvement. Drugs like BrMeI, which can prevent antipsychotic medications from acting on peripheral targets, may therefore be useful in preventing or even reversing dysglycemia.

Freyberg and colleagues at Pitt are in the early stages of a safety clinical trial aimed at ensuring that the therapeutic effects of antipsychotic drugs are preserved when these psychiatric drugs are administered in tandem with bromocriptine since it is already approved by the FDA . They hope to launch a larger trial to test the effectiveness of BrMel and similar molecules in limiting dysglycemia in the coming years.

“The fact that the brain and body must maintain stable glycemic control offers a new dimension in the understanding of neuropsychiatry and begins to integrate disparate pieces of knowledge about different organ systems into a coherent whole,” Freyberg said.

“The majority of psychiatric medications are prescribed by general practitioners and not psychiatrists,” he added. “We hope that our research will raise awareness of the importance of communication between the brain and the rest of the body in maintaining physiological functions and remind clinicians that they must also consider that drugs designed to act on brain targets , like psychiatric medications, may also have significant actions outside of the brain when making prescribing recommendations.

Other authors of this research are Zachary Farino, MS, Despoina Aslanoglou, Ph.D., and José Mantilla-Rivas, MD, all of Pitt; Alessandro Bonifazi, Ph.D., Michael Ellenberger, JD, Comfort Boateng, Ph.D., and Amy Hauck Newman, Ph.D., all of NIDA; Rana Rais, Ph.D., and Barbara Slusher, Ph.D., both of Johns Hopkins University; Sandra Pereira, Ph.D., and Margaret Hahn, MD, Ph.D., both of the University of Toronto; Amy Eshleman, Ph.D., and Aaron Janowsky, Ph.D., both of Oregon Health and Science University; and Gary Schwartz, Ph.D., of the Albert Einstein College of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.