Since GLP-1 drugs like Novo Nordisk’s semaglutide and Eli Lilly’s tirzepatide took the world by storm for their potent treatment of diabetes and obesity, they have also been plagued by a clinical conundrum. In some studies, the peptides seem to possess antidepressant effects, while in others they’ve been linked to worse mental health and even increased suicidality.
Now, a team of researchers in China has found evidence that the key to solving this puzzle lives not in the brain, but in the gut. Mice treated with GLP-1s liraglutide and semaglutide saw bacteria called Lactobacillus delbrueckii flourish in their guts, with the microbes churning out a compound that alleviates symptoms of depression.
The results were published today in Cell Host & Microbe.
“We conducted this study to resolve a clinical paradox and ended up uncovering an entirely new gut–brain pathway through which a metabolic drug can influence mood,” Honghong Yao, Ph.D., chair of pharmacology at Southeast University in Jiangsu and leader of the study, told Fierce Biotech.
By analyzing blood from patients with major depressive disorder and healthy controls, the researchers found that natural levels of GLP-1s were lower in those with depression. When they explored further by injecting liraglutide into depressed mice, they found the peptide built up in the intestine rather than the brain, Yao said.
Further experiments confirmed that daily injections of liraglutide restored the rodents’ taste for sugar, a sign that the classic depression symptom anhedonia was diminished, and also improved their performance on a pair of stress tests.
Treated mice had much higher levels of L. delbrueckii in their feces, and the researchers linked the proliferation of the bacteria to the GLP-1s. L. delbrueckii supports the synthesis of a cannabis-like molecule called 2-arachidonoylglycerol or 2-AG, which Yao and colleagues reason has a soothing effect on the brain.
When depressed mice were fed L. delbrueckii, or had 2-AG injected directly into their brains, their symptoms also improved.
“Liraglutide boosts L. delbrueckii, which provides a precursor that the body turns into 2-AG, calming stress circuits in the brain,” Yao summarized.
This pathway has nothing to do with the GLP-1 receptor, she added, which may explain why different studies have come to different conclusions about the effect GLP-1 drugs have on mental health.
“GLP-1 analogs can activate central GLP-1 receptors in brain regions involved in stress and anxiety,” Yao said. “The net effect on mood may depend on the balance between opposing mechanisms.”
The study does point to a “new pathway by which GLP-1 receptor agonists could exert beneficial effects to the brain including potential antidepressant actions,” Nora Volkow, M.D., a psychiatrist and director of the National Institute on Drug Abuse who has researched GLP-1s and mental health but was not involved with the new study, told Fierce in a statement.
However, Volkow cautioned, “this was a preclinical study in mice, and further research is needed to examine how GLP-1 medications affect brain function and psychiatric conditions in people.”
Yao has not yet reached out to GLP-1 leaders Novo Nordisk or Eli Lilly about the results, she said, but is “happy to discuss with them if they’re interested in the gut‑microbiome pathway.”
Responding to requests for comment from Fierce, both Novo and Lilly stressed the safety of their approved GLP-1 products. The FDA recently requested for the pharmas to remove the risk of suicidal ideation and behavior from the labels of Novo’s Saxenda (liraglutide) and Wegovy (semaglutide) and Lilly’s Zepbound (tirzepatide) after an agency analysis found no connection between the medicines and suicidality.
“We are happy to see the FDA’s recommendation to remove the warning,” a Novo spokesperson said to Fierce in a statement. “We prioritize patient safety and will continue to collaborate closely with the FDA and other regulatory authorities to monitor the safety of all our GLP-1 receptor agonist medicines.”
Patient safety is the “top priority” for Lilly, too, a spokesperson for the Indianapolis drugmaker told Fierce. “If someone is experiencing side effects while taking any Lilly medication, we encourage them to speak with their healthcare provider.”
While Novo declined to add whether the company intends to pursue the use of its GLP-1 medicines for depression or other mental health conditions, an investigator-initiated trial at Denmark’s Nordsjaellands Hospital is testing semaglutide’s potential at treating major depressive disorder in patients also with overweight or obesity.
Lilly, on the other hand, was not shy about sharing its plans.
“Lilly has initiated a phase 3 study to evaluate the efficacy and safety of brenipatide—a dual GLP-1/GIP—when administered along with antidepressant therapy in delaying time to relapse in adult participants with major depressive disorder,” the spokesperson said. “We have also started two phase 2 studies evaluating brenipatide as adjunctive treatment for bipolar disorder and schizophrenia.”
It’ll take further study to determine if other GLP-1s aside from liraglutide and semaglutide also serve as a boon for L. delbrueckii, Yao told Fierce, and whether other gut bacteria can play a role too remains to be seen.
Yao’s primary focus now is on further unpacking the biology behind the microbe’s antidepressive effect, and on marching ahead with further translational work. The current study only used male mice, she said, but with depression more prevalent in women than in men, “we urgently need to validate whether this mechanism holds true in female animals.”
Following more animal testing, Yao hopes to probe whether bestowing L. delbrueckii or its chemical products on people with depression can help treat their disease.
“This will require small-scale proof-of-concept clinical trials,” she said.