Study links semaglutide and tirzepatide to fewer anxiety and depression diagnoses in obesity care

IN CONTINUATION OF MY UPDATE ON semaglutide and tirzepatide 

In a recent study published in the journal Communications Medicine, a group of researchers examined associations between initiation of tirzepatide or semaglutide and incident neuropsychiatric diagnoses in adults with obesity, compared with other weight-loss treatments, with separate analyses for individuals with and without type 2 diabetes.

Background

Currently, obesity affects more than 650 million adults globally, with implications for physical and mental well-being. People with obesity are more likely to suffer from psychiatric conditions, including anxiety and depression, than people without obesity. Moreover, mental illness can increase the chances of developing obesity. Newer incretin-based medications like semaglutide and tirzepatide have changed obesity treatment by producing substantial weight loss, but their effects on neuropsychiatric health remain uncertain in routine clinical practice. 

About the study

Researchers conducted a retrospective cohort study using de-identified electronic health records from the TriNetX United States Collaborative Network between January 2020 and November 2025. Adults meeting the study’s obesity criteria, who newly initiated tirzepatide or semaglutide, were identified and compared with matched individuals who started naltrexone-bupropion, phentermine, or phentermine-topiramate. The study included two separate analyses based on whether or not the participants had type 2 diabetes, and bariatric surgery recipients and a non-pharmacological weight-loss cohort were also evaluated as contextual comparison groups.

To increase comparability between treatment groups, propensity score matching was performed using demographic features, body mass index (BMI), glycated hemoglobin (HbA1c), medical history, co-existing treatments, healthcare utilization, and results of laboratory investigations. Patients with type 1 diabetes, prior bariatric surgery, history of organ transplantation, human immunodeficiency virus (HIV) infection, and end-stage renal disease were not included. Patients were monitored for a maximum of 24 months from treatment initiation until the initial diagnosis of a neuropsychiatric outcome, death, loss to follow-up, or end of study.

The primary outcome was a new diagnosis of anxiety disorder. Secondary outcomes included diagnoses of depression, mood disorder, insomnia, broadly defined cognitive deficits, nerve disorders, peripheral neuropathy, and substance-related disorders. Hazard ratios with 95% confidence intervals (CIs) were obtained using Cox proportional hazards models, adjusted for possible confounders, and various sensitivity analyses were also performed.

Study results

Before matching, individuals initiating incretin-based therapies differed considerably from comparator groups, particularly regarding psychiatric illnesses and psychotropic medication use. After matching on propensity scores, the groups had very similar baseline demographic characteristics, cardiometabolic health issues, laboratory measures, and health care use, allowing for more reliable comparisons between the treatment groups.

 

Individuals receiving semaglutide and tirzepatide generally had lower hazards of several recorded neuropsychiatric diagnoses when compared to bariatric surgery recipients.

Among individuals with obesity and type 2 diabetes, both medications were associated with lower hazards of anxiety disorders, broadly defined cognitive deficits, mood disorders, and depression. Similar results were seen for individuals without type 2 diabetes, but the neurological outcomes were less consistent between the groups. 

Semaglutide was associated with a higher hazard of nerve disorders in participants without diabetes, while tirzepatide showed lower hazards of substance-related disorders and peripheral neuropathy compared with bariatric surgery. The negative control analyses did not find any clinically meaningful differences, providing some reassurance about the analytical approach.

Compared with naltrexone-bupropion, semaglutide was associated with lower hazards of anxiety disorders, depression, cognitive deficits, and insomnia in adults with type 2 diabetes. Tirzepatide also showed lower hazards of anxiety disorders, depression, mood disorders, and cognitive deficits within this group.

Similar reductions were observed among adults without diabetes, indicating that both medications were consistently associated with lower rates of several recorded psychiatric diagnoses than this comparator.

Among adults without type 2 diabetes, a direct comparison between tirzepatide and semaglutide showed that tirzepatide was associated with higher hazards of anxiety disorders and insomnia than semaglutide, while no consistent differences were observed for most neurological outcomes after statistical adjustment. However, the authors noted that absolute and relative estimates differed for anxiety and insomnia in this head-to-head comparison, so these small differences should be interpreted cautiously.

Absolute risk differences indicated larger reductions in anxiety disorders among individuals with type 2 diabetes than among those without diabetes when tirzepatide or semaglutide was compared with naltrexone-bupropion.

Sensitivity analyses generally supported the primary findings. Per-protocol and as-treated analyses showed similar directions of association for anxiety and depression, although the strength of some associations varied depending on treatment persistence. Lower use of psychiatric medications, particularly selective serotonin reuptake inhibitors (SSRIs), was also observed among incretin-based therapy recipients compared with matched comparator groups.

Subgroup analyses suggested that the associations were generally consistent across age, BMI, and clinical characteristics, with some stronger associations observed among older adults and individuals with severe obesity.

Exploratory analyses generally showed greater reductions in body weight and HbA1c over 24 months in the incretin-based therapy groups than in the conventional anti-obesity medication groups, although some comparisons varied by diabetes status and outcome measure.

Additional sensitivity analyses using stricter outcome definitions and alternative cohort criteria yielded findings that were directionally similar, though some estimates became less precise due to smaller sample sizes. Importantly, cognitive findings were sensitive to outcome definition, and the broad cognitive endpoint included codes that could reflect acute or transient altered mental status rather than dementia or progressive cognitive decline.

Conclusion

The findings suggest that initiation of tirzepatide and semaglutide is associated with different neuropsychiatric outcome patterns depending on the comparator treatment and the presence of type 2 diabetes. Compared with naltrexone-bupropion, both medications were generally associated with lower hazards of anxiety and depression. In contrast, tirzepatide showed higher hazards of anxiety and insomnia than semaglutide among adults without type 2 diabetes.

These findings provide clinicians and patients with important real-world evidence to inform treatment decisions, while underscoring the need for continued patient monitoring. However, the results should not be interpreted as evidence that these medications prevent dementia, progressive cognitive decline, or psychiatric disease, because the study relied on diagnosis codes and remains vulnerable to residual confounding and misclassification.

In addition, as this study was observational, prospective studies with standardized neuropsychiatric assessments are needed to confirm these associations. Further research is needed to understand how these medications may influence mental health outcomes across different patient populations.

Study links semaglutide and tirzepatide to fewer anxiety and depression diagnoses in obesity care

FDA Proposes to Exclude Semaglutide, Tirzepatide, and Liraglutide on 503B Bulks List.

The U.S. Food and Drug Administration announced the  proposal  to exclude semaglutide, tirzepatide, and liraglutide on the 503B bulks list, finding no clinical need for outsourcing facilities to compound these drugs from bulk substances. 

The 503B bulks list identifies bulk drug substances that outsourcing facilities may use in compounding under the conditions of section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act). In most cases, outsourcing facilities cannot compound drugs using bulk drug substances unless the substance appears on the 503B bulks list, or the compounded drug is on the FDA’s drug shortage list at the time of compounding, distribution, and dispensing. 

After evaluating the nominations for these three substances, the FDA did not identify a clinical need for outsourcing facilities to compound semaglutide, tirzepatide, and liraglutide from bulk drug substances. 

“When FDA-approved drugs are available, outsourcing facilities cannot lawfully compound using bulk drug substances unless there is a clear clinical need,” said FDA Commissioner Marty Makary, M.D., M.P.H. “This action reflects our responsibility to protect patients and preserve the integrity of the drug approval process while continuing to provide a transparent, science-based pathway for public input.”

The FDA carefully reviewed the nominations it received and did not identify sufficient evidence to include semaglutide, tirzepatide and liraglutide on the 503B bulks list. A determination of clinical need is based on patient safety and medical necessity under the law. 

The FDA is now inviting interested parties to submit comments electronically through the docket by June 29, 2026. The agency will consider submitted comments before making a final determination. 

https://en.wikipedia.org/wiki/Liraglutide

https://en.wikipedia.org/wiki/Tirzepatide

https://en.wikipedia.org/wiki/Semaglutide

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FDA Proposes to Exclude Semaglutide, Tirzepatide, and Liraglutide on 503B Bulks List | FDA

FDA Approves Zepbound (tirzepatide) for Chronic Weight Management

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• The U.S. Food and Drug Administration (FDA) approved Eli Lilly and Company's (NYSE: LLY) Zepbound™ (tirzepatide) injection, the first and only obesity treatment of its kind that activates both GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) hormone receptors. Zepbound is indicated for adults with obesity (with a BMI of 30 kg/m2 or greater), or those who are overweight (with a BMI of 27 kg/m2 or greater) and also have weight-related medical problems such as hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease, to lose weight and keep it off. It should be used with a reduced-calorie diet and increased physical activity. Zepbound should not be used with other tirzepatide-containing products or any GLP-1 receptor agonist medicines, and it has not been studied in patients with a history of pancreatitis, or with severe gastrointestinal disease, including severe gastroparesis.
• "Obesity is a chronic disease that can result in serious health complications, including heart disease, stroke and diabetes. Despite our knowledge of obesity as a treatable, chronic disease, people living with obesity still face many challenges in their health and weight management journey," said Joe Nadglowski, president and chief executive officer of the Obesity Action Coalition. "New treatment options bring hope to the many people with obesity who struggle with this disease and are seeking better options for weight management."
• The approval was based on results from the phase 3 SURMOUNT-1 and SURMOUNT-2 trials. In SURMOUNT-1, a study in 2,539 adults with obesity, or excess weight and weight-related medical problems not including diabetes, people taking Zepbound as an adjunct to diet and exercise experienced substantial weight loss compared with placebo at 72 weeks. At the highest dose (15 mg), people taking Zepbound lost on average 48 lb., while at the lowest dose (5 mg), people lost on average 34 lb. (compared to 7 lb. on placebo).
• Additionally, 1 in 3 patients taking Zepbound at the highest dose lost over 58 lb. (25% of body weight), compared to 1.5% on placebo, according to data not controlled for type 1 error. The average starting weight was 231 lb.
• While not approved to treat these conditions, in a clinical trial, people who dieted, exercised and took Zepbound for the treatment of obesity or overweight with weight-related medical problems observed changes in cholesterol and reductions in blood pressure and waist size.
• "Unfortunately, despite scientific evidence to the contrary, obesity is often seen as a lifestyle choice – something that people should manage themselves," said Dr. Leonard Glass, senior vice president global medical affairs, Lilly Diabetes and Obesity. "For decades, diet and exercise have been a go-to, but it's not uncommon for a person to have tried 20-30 times to lose weight with this approach. Research now shows that the body may respond to a calorie-deficit diet by increasing hunger and reducing feelings of fullness, making weight loss more difficult. Lilly is aiming to eliminate misperceptions about this disease and transform how it can be managed."
• Zepbound use may be associated with gastrointestinal adverse reactions, sometimes severe. The most commonly reported adverse events (observed in ≥ 5% of clinical trial participants) were nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection-site reactions, fatigue, hypersensitivity reactions, eructation, hair loss and gastroesophageal reflux disease.1 In studies, most nausea, diarrhea and vomiting occurred when people increased their dose – but the effects generally decreased over time. In studies, gastrointestinal side effects were more common in people taking Zepbound than people taking placebo, and people taking Zepbound were more likely than those on placebo to stop treatment because of these side effects. The label for Zepbound includes a Boxed Warning regarding thyroid C-cell tumors. Zepbound is contraindicated in patients with a personal or family history of medullary thyroid carcinoma, in patients with Multiple Endocrine Neoplasia syndrome type 2, and in patients with known serious hypersensitivity to tirzepatide or any of the excipients in Zepbound. See Important Safety Information below and full Prescribing Information and Medication Guide.
• "Far too many hurdles continue to prevent people living with obesity from accessing obesity treatments that could lead to significant weight loss," said Mike Mason, executive vice president and president, Lilly Diabetes and Obesity. "Broader access to these medicines is critical, which is why Lilly is committed to working with healthcare, government and industry partners to ensure people who may benefit from Zepbound can access it."
• Zepbound is expected to be available in the U.S. by the end of the year in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) at a list price of $1,059.87, which is approximately 20% lower than semaglutide 2.4 mg injection for weight loss. List price does not reflect the typical out-of-pocket cost to patients given insurance coverage and discounts. Lilly is putting a commercial savings card program in place that will help people who may benefit from Zepbound better access it.

• People who are commercially insured with coverage for Zepbound may be eligible to pay as low as $25 for a 1-month or 3-month prescription.
• People who are commercially insured without coverage for Zepbound may be eligible to pay as low as $550 for a 1-month prescription of Zepbound, approximately 50% lower than the list price.
• People may begin using the savings card program in the days following product availability at U.S. pharmacies. To learn more about these programs, or to sign up to receive the latest news, please visit www.Zepbound.lilly.com. Terms and conditions apply.
• Tirzepatide is also under regulatory review for weight management in Europe, China, the United Kingdom and several additional markets.

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FDA Approves Zepbound (tirzepatide) for Chronic Weight Management

FDA Approves Mounjaro (tirzepatide) Injection for the Treatment of Adults with Type 2 Diabetes

The U.S. Food and Drug Administration (FDA) has approved Mounjaro (tirzepatide) injection, Eli Lilly and Company's (NYSE: LLY) new once-weekly GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Mounjaro has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes mellitus.

As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body's receptors for GIP and GLP-1, which are natural incretin hormones.1

"Mounjaro delivered superior and consistent A1C reductions against all of the comparators throughout the SURPASS program, which was designed to assess Mounjaro's efficacy and safety in a broad range of adults with type 2 diabetes who could be treated in clinical practice. The approval of Mounjaro is an exciting step forward for people living with type 2 diabetes given the results seen in these clinical trials," said Juan Pablo Frías, M.D., Medical Director, National Research Institute and Investigator in the SURPASS program.

Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly's well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

The approval was based on results from the phase 3 SURPASS program, which included active comparators of injectable semaglutide 1 mg, insulin glargine and insulin degludec. Efficacy was evaluated for Mounjaro 5 mg, 10 mg and 15 mg used alone or in combination with commonly prescribed diabetes medications, including metformin, SGLT2 inhibitors, sulfonylureas and insulin glargine. Participants in the SURPASS program achieved average A1C reductions between 1.8% and 2.1% for Mounjaro 5 mg and between 1.7% and 2.4% for both Mounjaro 10 mg and Mounjaro 15 mg. While not indicated for weight loss, mean change in body weight was a key secondary endpoint in all SURPASS studies. Participants treated with Mounjaro lost between 12 lb. (5 mg) and 25 lb. (15 mg) on average.1

Side effects reported in at least 5% of patients treated with Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion (dyspepsia), and stomach (abdominal) pain. The labeling for Mounjaro contains a Boxed Warning regarding thyroid C-cell tumors. Mounjaro is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.1

"Lilly has a nearly 100-year heritage of advancing care for people living with diabetes – never settling for current outcomes. We're not satisfied knowing that half of the more than 30 million Americans living with type 2 diabetes are not reaching their target blood glucose levels," said Mike Mason, president, Lilly Diabetes. "We are thrilled to introduce Mounjaro, which represents the first new class of type 2 diabetes medication introduced in almost a decade and embodies our mission to bring innovative new therapies to the diabetes community."

More at 

https://www.rxlist.com/mounjaro-drug.htm