Scientists may have uncovered the reason critical medications for schizophrenia and bipolar disorder cause weight gain and diabetes -- findings they hope will lead to better drugs.
The medications, known as antipsychotics, help control the hallucinations, delusions and confused thoughts that plague people with schizophrenia. They can also help stabilize extreme mood swings in those with bipolar disorder.
The drugs, which include clozapine, olanzapine, ziprasidone and many others, "serve an important purpose," said Dr. Zachary Freyberg, the senior researcher on the new study.
"In many cases," he added, "they can be life-saving."
The problem is their "metabolic" side effects, said Freyberg, an assistant professor of psychiatry and cell biology at the University of Pittsburgh School of Medicine.
Antipsychotics often trigger weight gain, cholesterol spikes and elevations in blood sugar that can lead to type 2 diabetes.
In fact, those side effects commonly drive patients to stop taking the drugs, said Dr. Ken Duckworth, chief medical officer of the nonprofit National Alliance on Mental Illness.
Duckworth, who was not involved in the new research, said it's important to understand why those adverse effects occur.
These findings, he said, "begin to unravel" the issue.
Specifically, the Pitt researchers zeroed in on dopamine, a chemical that transmits messages between cells by interacting with receptors on their surfaces. In the brain, dopamine plays a role in pleasure, motivation and learning.
While there are many antipsychotic drugs, they all work in a similar way: blocking certain dopamine receptors, known as D2-like receptors.
If those receptors only existed in the brain, that might be well and good.
In reality, Freyberg explained, the body actually has more dopamine receptors outside the brain than within it.
"It's naive to think [antipsychotics] only work from the neck up," he said.
Critically, there are D2-like receptors on cells in the pancreas, too. Certain pancreatic cells produce hormones that either raise blood sugar (glucagon) or lower it (insulin).
In lab experiments with pancreatic cells, Freyberg's team found that dopamine influenced the production of both glucagon and insulin. And the cells themselves were actually capable of churning out their own dopamine, confirming the importance of the chemical outside the brain, the study authors said.
Then, when the researchers used antipsychotic medications to block the pancreatic cells' D2-like receptors, that ramped up the production of both glucagon and insulin.
In the body, unchecked release of those hormones could quickly lead to a loss in insulin sensitivity and chronically high blood sugar levels.
The good news, Freyberg said, is that understanding the "why" might now allow researchers to develop antipsychotic medications that avert metabolic side effects.
"This makes it all less of a black box," Duckworth said.
In addition, researchers are working on medications that do not target dopamine at all. Last year, an early trial found that an experimental medication, dubbed SEP-363856, eased an array of symptoms in people with schizophrenia. They included not only hallucinations and delusions, but problems such as flattened emotions and social withdrawal.
The drug leaves D2-like receptors alone.
The takeaway, both Duckworth and Freyberg said, is that patients' difficulties with current antipsychotics are being heard.
"Scientists are working on this," Duckworth said.
For now, the challenge for patients is to manage the side effects the best they can. The first step is being aware that they can happen, Duckworth noted, since people being newly prescribed an antipsychotic are not necessarily able to process all the information they're receiving.
To help limit weight gain, many people need to change the way they eat, Duckworth said, trading "family-style" eating for portion control.
Physical activity is also key. Duckworth suggested people try to make exercise a way to connect socially as well, by going to the local Y, for instance.
For their part, Duckworth said, doctors should be monitoring patients' weight, blood sugar and cholesterol, to catch unhealthy changes.
The study was published online Tuesday in the journal Translational Psychiatry.More information
The National Alliance on Mental Illness has more on psychiatric medications.
SOURCES: Zachary Freyberg, MD, PhD, assistant professor, psychiatry and cell biology, University of Pittsburgh School of Medicine; Ken Duckworth, MD, chief medical officer, National Alliance on Mental Illness, Arlington, Va.; Translational Psychiatry, Feb. 16, 2021, online
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