Weight loss drug GLP-1 may have potential to treat depression, improve motivation, new study suggests

The blockbuster GLP-1 drugs taken by many Americans for diabetes and to aid in weight loss may also have potential for treating major depression, a new study finds.

A paper published this week in JAMA Psychiatry found semaglutide, the active ingredient in GLP-1 drugs like Ozempic and Wegovy, "significantly improved" motivation in patients with major depressive disorder, or MDD — a promising finding because lack of motivation and related disruptions to the brain’s reward pathways play a critical role in many other psychiatric conditions as well.

It follows other studies suggesting possible uses of the drugs for alcohol and drug use disorder and appears to be the first randomized clinical trial on semaglutide and motivation in people with severe depression.

The study followed 72 people whose body mass index made them overweight or obese who also met the clinical criteria for MDD, characterized by symptoms including depressed mood and loss of interest or pleasure in most activities. Roughly half of the participants took semaglutide and half took a placebo.

At the start of the study and at its end 16 weeks later, the participants took a series of repeated trials in which they could earn money by performing a "hard" task, which involved typing with their nondominant hand, or an "easy" one typing with their dominant hand. Completing either task gave them a chance to win money, and they could win more money by doing "hard" tasks than "easy" ones.

While the findings did not address any possible changes to the participants’ mood, researchers found people who took semaglutide were significantly more willing to exert effort by choosing the "hard" task. The drug caused them to value the rewards more and perceive the tasks to be less difficult.

"The idea of the drug is that it activates the GLP-1 receptors in the brain, which leads to reduction in appetite and weight loss," said Dr. Rodrigo Mansur, the study’s lead author, staff psychiatrist at the University Health Network in Toronto and an assistant professor in the Department of Psychiatry at the University of Toronto. "This makes psychiatrists like me interested in what else activation of these receptors can do, and one of the main areas of interest is motivation."

Mansur called motivation a "key clinical problem in depression, which is not only feeling low and sad, it’s as much about losing motivation and interest in things." Existing treatments for depression do not address that combination, he said. Motivational issues "affect people with other diagnoses" than depression including bipolar disorder, schizophrenia, Parkinson’s and Alzheimer’s disease, he said.

Other studies, however, have found little benefit from the drug for some of these conditions.

Dina Hirsch, Northwell Health’s clinical director of bariatric psychology and behavioral weight management, said in an email GLP-1 drugs, which work to reduce weight in part by quieting repetitive thoughts about eating, may have "neuroprotective and anti-inflammatory effects" that make them effective treatments for depression.

"Since neuroinflammation is a known driver of depression, 'cooling down' the brain's inflammatory response may directly lift depressive symptoms," she said.

Dr. J. John Mann, co-director of the Center for the Prevention and Treatment of Depression at Columbia University, said in an interview the study marked a significant advance over earlier work that suggested GLP-1’s can improve depression: "What’s been missing is randomized clinical control studies ... This is the beginning and this is interesting, but now we need to replicate these findings."

But few experts are ready to get behind widespread off-label use of GLP-1 drugs. Until recently, it was thought they could, in rare cases, cause suicidal thoughts or actions for some people, though in 2024, the FDA conducted a preliminary but broad review that found no evidence that was true. More common side effects include nausea.

In an email, Genna Hymowitz, director of metabolic and bariatric psychology and a clinical associate professor at Stony Brook Medicine, said more research was needed "before we prescribe GLP-1s to people who are not overweight, and we need to better understand the long term risks of GLP-1s. Some studies have demonstrated an increased risk of depression and anxiety in individuals taking GLP-1s, and, anecdotally, some patients report experiencing emotional numbing when taking GLP-1 medications."

And, she warned, the drugs could exacerbate disordered eating for some people.

By Nicholas Spangler

nicholas.spangler@newsday.comspanglernewsday

Nicholas Spangler is a general assignment reporter and has worked at Newsday since 2010.