Is Ozempic An Antidepressant? Preliminary Studies Suggest It Could Be

Early last month, medical records company Epic found a curious relationship lurking within the charts of individuals taking weight loss drugs like Ozempic and Mounjaro. Diabetics, for whom these drugs were initially designed, were less likely to be diagnosed with depression and anxiety. Even non-diabetics, specifically those taking semaglutide (known by its brand names Ozempic and Wegovy), also had a lower likelihood of depression and anxiety.

It may seem out of left field for a drug meant to trick your brain into thinking it's satiated to have such an unintended effect. Yet, as Ozempic, Wegovy, and the latest installment of these injectables, Zepbound, find themselves increasingly in mainstream use, the unexpected — from conjuring bizarre dreams to curbing addiction and inflammation — seem to be increasing.

In a study published Wednesday in the journal Brain and Behavior, one group of scientists in China may be approaching an answer as to what makes these drugs capable of mitigating depression and anxiety, at least in mice. They found that dulaglutide, from the same chemical family as semaglutide, may be reversing metabolic damage incurred in the brain from chronic stress. In mice exposed to a stressful environment and activities for four weeks, following that up with three weeks of dulaglutide treatment improved metabolic pathways associated with how mousy brains processed lipids (aka fats), amino acids (the basic building blocks of proteins), and the body’s primary energy molecule adenosine triphosphate (also known as ATP).

“These primary data provide a new perspective for understanding the antidepressant-like effects of dulaglutide and may facilitate the use of dulaglutide as a potential therapeutic strategy for depression,” the researchers write in their paper.

What exactly is dulaglutide?

Like its close chemical relative semaglutide, dulaglutide is a glucagon-like pepetide 1 (or GLP-1) agonist. These are chemicals that mimic GLP-1, a hormone naturally produced by our bodies in response to eating food. GLP-1 is typically produced by cells in the gut — there’s some evidence it’s produced in the brain as well — and travels to the brain, where it acts on areas involved in appetite. This interaction, and other effects like slowing down the rate your stomach empties itself, convinces your body to believe it’s full. Additionally, for people with diabetes, GLP-1 agonists help with regulating blood sugar levels by telling the body to make insulin.

As experts have previously told Inverse, GLP-1 agonists also affect appetite neural pathways associated with the reward and pleasure aspects of eating, which is likely how these drugs can have secondary cognitive effects like curbing addictive behaviors.

For depression and anxiety, some studies in animals have found that GLP-1 agonists may exert neuroprotective effects by counteracting metabolic missteps that can affect brain health and cognitive functioning. For instance, one 2023 study found that giving dulaglutide to rats with vascular dementia, a common form of dementia caused by decreased blood flow to the brain, appeared to alleviate brain tissue damage and inflammation by tweaking metabolic pathways involved in cell survival and waste management. Another 2015 study found that liraglutide improved anxiety depression and anxiety-like behaviors in rats by encouraging neuroplasticity, the brain’s innate ability to reorganize itself, which is crucial for learning and memory.

Finetuning the metabolism of mental health

In the new study, the researchers wanted to catalog the kinds of metabolic changes dulaglutide was capable of, particularly within the hippocampus, a region of the brain consistently linked with depression.

Sixty mice, around seven weeks old, were divided into a control and experimental group, the latter further subdivided into three groups that were exposed to stressful situations meant to make the animals depressed and anxious. Some of these stressors included being deprived of food or water for 12 hours, having their cages unstable and tilted for 24 hours, reversing their periods of darkness and light for 24 hours, and forcing them into crowded cages, also for 24 hours.

After four weeks of stress, the mice were offered either a biweekly injection of high or low doses of dulaglutide (0.6 and 0.3 milligrams per kilogram, respectively) or, as a control, an injection of saline.

During the three weeks of treatment with the drug, the researchers did several different behavioral tests (which were also conducted before the experiment) to assess the animals’ emotional responses. Samples of their hippocampi were collected and the multitude of molecules simmering within the folds of neural tissue were analyzed. The same was done for the control mice who weren’t subjected to any stressors and their counterparts who were but didn’t get any dulaglutide.

The researchers identified, in total, about 64 different chemicals associated with four different metabolic pathways that dulaglutide was adjusting to offset depressive and anxiety symptoms seen in the stressed mice. They noticed that for lipids involved in neuronal function, dulaglutide appeared to be nudging their levels, which were thrown into disarray due to the stress the mice experienced, back toward a healthier balance in the hippocampus. For amino acids, dulaglutide upped levels of aspartic acid, glutamic acid, and arginine, which some studies have shown to be decreased in animal models of depression. The researchers also noticed levels of other molecules involved in ATP production, the cell’s “battery” providing its primary energy source, was also increased, indicating dulaglutide was reversing the damage caused by stress through this pathway as well.

Lastly, the weight loss drug increased levels of niacinamide, also known as vitamin B3 with purported antidepressant effects, and picolinic acid, a derivative of tryptophan (a molecule that can go on to make the feel-good chemical serotonin) that may be decreased in individuals with major depression.

Future concerns

These results offer a fascinating snapshot of how multipurpose weight loss drugs like GLP-1 agonists could open up new avenues to mental health treatment. This comes at a time as rates of depression in the U.S. are skyrocketing: 29 percent of U.S. adults report being diagnosed with depression at some point during their lifetime, nearly 10 percent higher compared to 2015, according to a May 2023 Gallup poll.

Despite the promise, findings that dulaglutide helps depressed and anxious mice don’t necessitate the same observation in humans. For one, modeling in lab animals is far more simple and might not capture the full picture and complexity of depression and anxiety in humans. There’s also the issue of long-term safety, such as side effects of stomach paralysis reported among Ozempic users and concerns with organ failure. Currently, GLP-1 agonists are approved for the treatment of type 2 diabetes, and some, like Eli Lilly’s Zepbound, which contains tirzepatide, specifically for weight loss.

It’s too soon to say whether GLP-1 agonists and their ilk are antidepressant wunderkind mental health care needs — only time, and further research, will tell.