Study suggests tools to prevent diabetes from psychiatric meds

A recent study from the University of Pittsburgh offers a promising approach to mitigate the risk of diabetes linked with commonly prescribed antipsychotic medications. This investigation provides preliminary evidence supporting the concurrent administration of antipsychotics that inhibit dopamine receptors in the brain along with drugs that prevent these medications from blocking dopamine receptors in the pancreas. Published in Diabetes, this strategy could alleviate metabolic side effects, such as dysglycemia, which is a condition characterized by improper blood sugar regulation.

The research also sheds light on why weight control medications, including new neuropeptide drugs like Wegovy and Ozempic, may not effectively manage dysglycemia induced by antipsychotic drugs. Patients experiencing weight gain from antipsychotic medications might opt for these new drugs to control their appetite, potentially overlooking a crucial underlying cause of drug-induced dysglycemia.

"Antipsychotic medications don't just stop working below the neck," explained senior author Zachary Freyberg, M.D., Ph.D., an associate professor of psychiatry and cell biology at the University of Pittsburgh's School of Medicine. He emphasized the critical role of constant communication between the brain and the rest of the body in maintaining glucose metabolism. Modifying next-generation antipsychotic drugs could offer a new strategy to manage dysglycemia and diabetes.

Most antipsychotic medications function by blocking dopamine receptors in the brain, which are essential for the brain's reward system and movement control. However, the specific dopamine receptors affected by these drugs, known as dopamine D2 receptors, are not confined to the brain. Freyberg's previous research demonstrated that antipsychotic medications also block D2 receptors in the pancreas.

This groundbreaking discovery highlighted the importance of pancreatic dopamine in controlling blood sugar by interacting with D2 receptors on pancreatic cells responsible for producing and secreting insulin and glucagon. When the balance between these glucose-regulating hormones is disrupted by antipsychotic medications, it can lead to dysglycemia and diabetes.

However, peripheral dopamine signaling holds therapeutic potential. Collaborating with researchers at the National Institute on Drug Abuse (NIDA), Freyberg's team developed a molecule, bromocriptine methiodide (BrMel), that can prevent antipsychotic drugs from blocking D2 receptors in organs like the pancreas while sparing the brain. Structurally similar to bromocriptine, an FDA-approved drug for type 2 diabetes, BrMel has been modified to reduce its ability to cross the blood-brain barrier, thereby limiting its activity to peripheral organs.

Early studies in mice suggest that effective glucose metabolism requires communication between the brain and peripheral organs, including the pancreas. Experiments showed that systemically administered bromocriptine improved glucose metabolism in insulin-resistant mice, whereas BrMel or bromocriptine delivered directly to the brain did not show similar improvements. These findings suggest that BrMel-like drugs, which prevent antipsychotic medications from acting on peripheral targets, could be useful in preventing or even reversing dysglycemia.

Freyberg and his colleagues at the University of Pittsburgh are currently conducting a preliminary safety clinical trial to ensure the therapeutic effects of antipsychotic drugs are retained when co-administered with bromocriptine. They plan to initiate a larger trial in the coming years to test the efficacy of BrMel and similar molecules in limiting dysglycemia.

"The fact that both the brain and the body are required to maintain stable glycemic control provides a novel dimension in understanding neuropsychiatry," said Freyberg. "This begins to integrate disparate pieces of knowledge about different organ systems into a coherent whole."

Freyberg also noted that most psychiatric medications are prescribed by general practitioners rather than psychiatrists. He hopes this research will raise awareness about the importance of brain-body communication in maintaining physiological functions and remind clinicians to consider the potential actions of psychiatric medications outside the brain when making prescription recommendations.