Researchers Look to Unlock GLP-1 Drugs’ Potential in Psychiatry

Researchers are exploring the potential of glucagon-like peptide 1 (GLP-1) receptor agonists to treat neuropsychiatric disorders such as cognitive dysfunction and alcohol use disorder, according to a panel held last week at the American Society of Clinical Psychopharmacology’s annual meeting in Phoenix.

GLP-1 receptor agonists such as semaglutide and tirzepatide mimic the effects of GLP-1, a peptide produced in the intestinal mucosa, and are known for leading to remarkable weight loss in both the general population and individuals with antipsychotic-induced weight gain.

GLP-1 medications do not increase resting metabolic rate or promote physical activity, but “they do have a very robust signal in reducing caloric intake,” explained Rodrigo Mansur, M.D., Ph.D., research scientist, psychiatrist at the University Health Network, and assistant professor of psychiatry at the University of Toronto. “Patients tell us, ‘They reduce feelings of hunger, they promote feelings of satiety.’”

These medications are believed to modulate the rewarding aspects of food—and potentially other substances. A recent Phase 2 trial found that weekly low-dose semaglutide significantly reduced the amount of alcohol consumed by adults with alcohol use disorder during a self-administration task taken after four weeks of treatment, according to panelist Christian Hendershot, Ph.D., a professor of population and public health sciences at Keck School of Medicine at the University of Southern California, who conducted the trial with colleagues.

Research on GLP-1 medications in animal models suggest the compounds also have neuroprotective and anti-inflammatory actions, which has led to expanded research on their potential to treat neuropsychiatric disorders, said Greg Nigel, Ph.D., chief of the drug design and development section at the Intramural Research Program at the National Institute on Aging. GLP-1 receptors are found throughout the brain, and studies are showing they may prove valuable in a host of neurodegenerative disorders that are prevalent in late life, such as Parkinson’s and Alzheimer’s disease.

Mansur discussed a recent randomized trial that he and colleagues undertook to explore semaglutide’s potential for improving executive function in individuals with major depressive disorder (MDD), 80% of whom had a lifetime history of suicidality. Over the 16-week trial, Mansur and colleagues found no difference in executive function scores between the semaglutide and placebo groups. However, the researchers did find a statistical improvement in global cognition for semaglutide compared with placebo—suggesting it may work in other cognitive domains.

For related information, see the Psychiatric News article “Award Winner Describes Efforts to Improve Cognition in People With Bipolar Disorder.”

(Image: Getty Images/iStock/zimmytws)

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Diabetes Medication Shows Promise at Reducing Sleep Apnea Severity

The antidiabetic tirzepatide reduces the frequency of breathing interruptions and other sleep-related symptoms in adults with obstructive sleep apnea (OSA), according to findings from two placebo-controlled clinical trials published today in the New England Journal of Medicine. Adults who took tirzepatide also exhibited reductions in risk factors associated with sleep apnea like body weight and blood pressure compared with those who took placebo.

“Historically, treating OSA meant using devices during sleep, like a CPAP [continuous positive airway pressure] machine, to alleviate breathing difficulties and symptoms,” said lead investigator Atul Malhotra, M.D., of the University of California, San Diego, in a press release. “However, its effectiveness relies on consistent use. This new drug treatment offers a more accessible alternative for individuals who cannot tolerate or adhere to existing therapies.”

Malhotra and colleagues enrolled 469 adults diagnosed with clinical obesity and moderate-to-severe OSA; the participants were equally divided into two groups: Group one consisted of those who were not using CPAP devices to manage their sleep apnea and group two consisted of those who were.

In each CPAP group, the participants were randomly assigned to a subcutaneous injection of 10-15 mg of tirzepatide or a placebo weekly for 52 weeks. At the end of one year, the investigators assessed the change in participants’ apnea–hypopnea index (AHI, the number of breathing pauses per hour of sleep) relative to baseline. Other symptoms assessed included hypoxic burden (percentage decrease in blood oxygen levels), patient-reported sleep impairment, body weight, and systolic blood pressure.

At baseline, the participants had an average AHI of around 50 events an hour. After 52 weeks, the AHI among adults in group one who took tirzepatide dropped by 25.3 events an hour versus 5.3 events an hour in the placebo group. Among adults in group two, AHI dropped by 29.3 events an hour versus 5.5 events an hour in the placebo group. In addition, the participants taking tirzepatide lost around 18% (group one) and 20% (group two) of their baseline body weight and had greater improvements than the placebo group for all other sleep and metabolic symptoms assessed.

The most common tirzepatide-associated side effects were gastrointestinal issues such as diarrhea, nausea, or vomiting; 7.5% of the participants reported serious adverse events, with similar rates in the tirzepatide and placebo groups.

In an accompanying NEJM editorial, Sanjay R. Patel, M.D., of the University of Pittsburgh said these study findings were promising but noted that whether “tirzepatide improves patient-centered outcomes in obstructive sleep apnea remains unclear because a change in the AHI has not been validated as a surrogate marker of clinically relevant end points.” Though patient-reported sleep impairment also improved with tirzepatide, Patel said important outcomes like daytime sleepiness and overall functioning need to be assessed.

These trials were funded by Eli Lilly, manufacturer of tirzepatide; Malhotra is a consultant for Eli Lilly.

(Image: Getty Images/iStock/Askolds)

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