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

Psilocybin linked to reduction in depression

In continuation of my update on Psilocybin  

A study of 19 patients with treatment-resistant depression treated with psilocybin in Switzerland found psilocybin was associated with a significant reduction in depression symptoms. The study is published in The Lancet Regional Health—Europe.

Psilocybin—a naturally occurring psychedelic compound found in some species of mushrooms—has demonstrated promising antidepressant effects in depression and treatment-resistant depression in controlled clinical trials. However, its effectiveness and safety in real-world treatment settings remain largely unknown.

This study analyzed the medical records of 19 patients who received one to four clinical dosing sessions of psilocybin at the Psychiatric University Hospital Zurich as treatment for treatment-resistant mild to severe depression.

On average, the clinician-reported depression rating scores decreased from approximately 31/60 before psilocybin treatment to 20/60 within 42 days after the final dosing session. The patient-reported depression scores decreased from an average of 32/63 to 23/63. Side effects were reported in 30/40 psilocybin dosing sessions, with the most common being fatigue, headache, and tearfulness, but no serious or sustained side effects were documented.

The authors say their findings suggest that results from clinical trials may translate into routine clinical practice, although outcomes appear smaller in scale. They highlight that the small sample size of this study limits generalizability and, as there was no longer-term follow-up, it is not known if the improvements in depression symptoms were maintained. They call for larger real-world studies.

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

A single dose of magic mushroom compound reduces anxiety and depression among cancer patients

In continuation of my update on psilocybin

Magic mushrooms are wild or cultivated mushrooms containing psilocybin, which is a naturally occurring hallucinogenic and psychoactive compound. A single dose of psilocybin provides long-term relief of anxiety and depression in cancer patients, a new study found.

A team of researchers at the New York University Grossman School of Medicine has found that a one-time, single dose of psilocybin, the compound found in psychedelic mushroom or magic mushroom, combined with psychotherapy, has been linked to a marked improvement in existential and emotional distress in patients with cancer. The drug’s effect has persisted for nearly five years after administration.

The study, published in the Journal of Psychopharmacology, highlights the efficacy of psilocybin in reducing anxiety levels and depression in cancer patients. Patients with cancer who received the compound reported reductions in anxiety, depression, demoralization, hopelessness, and death anxiety nearly five years after receiving a single dose of the drug and psychotherapy.

Psilocybin effects

Psilocybin is a known hallucinogenic substance commonly found in mushrooms growing in South America, Mexico, Europe, and the United States. A schedule-I controlled substance, the compound has a high potential for abuse. However, people use it as a recreational drug, and over the past years, studies have analyzed its potential for medical purposes.

The compound has both positive and negative effects. It has been studied to relieve symptoms of anxiety and depression but has been known to trigger psychotic episodes. The drug has long been used recreationally due to its hallucinogenic effects, which work by altering a person’s perception, thoughts, and feelings.

Promising results

In the current study, the researchers conducted a long-term within-subjects follow-up analysis of self-reported symptomatology among 15 participants, who agreed to participate at an average of 3.2 to 4.5 years, following the administration of psilocybin.

The researchers noted that among the participants, about 60 to 80 percent of them had met the criteria for clinically significant anxiolytic or antidepressant responses after 4.5 years after receiving the drug. Further, 71 to 100 percent attributed positive life changes, thanks to the combination of psilocybin and psychotherapy treatment, rating it among the most spiritually significant and personally-meaningful experiences in their lifetime.

“These findings suggest that psilocybin-assisted psychotherapy holds promise in promoting long-term relief from cancer-related psychiatric distress. Limited conclusions, however, can be drawn regarding the efficacy of this therapy due to the crossover design of the parent study,” the researchers wrote on the paper.

“Nonetheless, the present study adds to the emerging literature base suggesting that psilocybin-facilitated therapy may enhance the psychological, emotional, and spiritual well-being of patients with life-threatening cancer,” they added.

The authors said psilocybin shows promise as an important tool for enhancing psychotherapy’s efficacy and eventually, providing relief for symptoms of anxiety and depression.  While the exact mechanism on how psilocybin works are not fully understood, the researchers believe the drug makes the brain more receptive to new thought patterns and ideas.

It is also believed that the compound targets a brain network, called the default mode network, which becomes activated when individuals perform mind wandering and self-reflection. These activities aid in making sense of oneself and a sense of coherent narrative identity.

In most people with anxiety and depression, the said network becomes excessively active and has been tied to feelings of worry, rigid thinking, and rumination. The compound appears to work to shift the activity in the network, allowing people to have a broader perspective of their lives and behaviors.

The team plans to further conduct additional studies with bigger trials in patients who belong to diverse ethnic and socioeconomic populations. Also, they hope to conduct more studies on patients with advanced cancer-related psychiatric and existential distress.

https://journals.sagepub.com/doi/abs/10.1177/0269881119897615?journalCode=jopa&

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

Researchers find clues that depression may speed brain aging

In continuation of my updates on depression and its causes

Memory and thinking skills naturally slow with age but now scientists are peeking inside living brains to tell if depression might worsen that decline—and finding some worrisome clues. Depression has long been linked to certain cognitive problems, and depression late in life even may be a risk factor for the development of Alzheimer's. Yet how depression might harm cognition isn't clear.

One possibility: Brain cells communicate by firing messages across connections called synapses. Generally, good cognition is linked to more and stronger synapses. With cognitive impairment, those junctions gradually shrink and die off. But until recently, scientists could count synapses only in brain tissue collected after death.

Yale University scientists used a new technique to scan the brains of living people—and discovered that patients with depression had a lower density of synapses than healthy people the same age.

The lower the density, the more severe the depression symptoms, particularly problems with attention and loss of interest in previously pleasurable activities, Yale neuroscientist Irina Esterlis said Thursday at a meeting of the American Association for the Advancement of Science. She wasn't studying just seniors but a range of ages including people too young for any cognitive changes to be obvious outside of a brain scan—on the theory that early damage can build up.

"We think depression might be accelerating the normal aging," she said.

Her studies so far are small. To prove if depression really worsens that decline would require tracking synaptic density in larger numbers of people as they get older, to see if and how it fluctuates over time in those with and without depression, cautioned Jovier Evans, a staff scientist at the National Institute on Mental Health.

Esterlis is planning a larger study to do that. It's delicate research. Volunteers are injected with a radioactive substance that binds to a protein in the vesicles, or storage bins, used by synapses. Then during a PET scan, areas with synapses light up, allowing researchers to see how many are in different regions of the brain.

Esterlis said there are no medications that specifically target the underlying synapse damage.

But other brain experts said the preliminary findings are a reminder of how important it is to treat depression promptly, so people don't spend years suffering.

"If your mood isn't enough to make you go and get treated, then hopefully your cognition is," said Dr. Mary Sano, who directs the Mount Sinai Alzheimer's Disease Research Center in New York and wasn't involved in the new research.

Still, she cautioned that normal cognitive aging is a complicated process that involves other health problems, such as heart disease that slows blood flow in the brain. It might be that depression, rather than worsening synaptic decline, just makes it more obvious, Sano noted.

With depression "at any age, there's a hit on the brain. At an older age the hit may be more visible because there may already be some loss," she explained.

Indeed, another way the brain ages: The blood-brain barrier, which normally protects against infiltration of damaging substances, gradually breaks down, Daniela Kaufer of the University of California, Berkeley, told the AAAS meeting. That triggers inflammation, setting off a cascade that can cause cognitive impairment. Her lab found a specific molecular culprit and is developing, in studies with mice, a way to block the inflammatory damage.

The University of Toronto's Etienne Sibille is developing a compound to target yet another piece of the puzzle, brain receptors that are impaired with both aging and depression. Mouse studies showed it could reverse stress-induced memory loss, he said. Any human testing is at least several years away.

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Researchers find clues that depression may speed brain aging

New version of obesity drug could help people reduce weight without experiencing anxiety, depression

In continuation of my update on Rimonabant

A new version of an obesity drug that caused serious psychiatric side effects could help people lose pounds without experiencing the anxiety, depression and suicidal thoughts previously associated with it. The research, published in Bioorganic and Medicinal Chemistry, shows that the new version of the drug can still work without reaching the brain in rats, avoiding the side effects.

The researchers behind the study, from RTI International in the US, say this means the new version of the drug could be used in the future for treating obesity. And their approach could also support the development of drugs to tackle liver disease, metabolic conditions and high blood cholesterol.

In our bodies we have cannabinoid receptors that control appetite, mood, memory and pain. The obesity drug Rimonabant stops these receptors from working. But the drug was found to have serious psychiatric side effects in a small number of the people who took it. Because of this, the drug was never approved in the US and manufacturer Sanofi-Aventis pulled from the European market voluntarily.

In the new study, the researchers altered the drug so it no longer gets into the brain, which stops it from having psychiatric side effects.

Study author Dr. Rangan Maitra, from RTI International in the US, explained: "There is a real need for new medicines to treat metabolic conditions like obesity. We are working with chemists to alter the drug Rimonabant and create compounds that cannot get into the brain. We hope this will help create drugs that can treat people with these conditions, without them having to suffer the side effects."

Dr. Maitra and colleagues modified the original Rimonabant compound by changing its weight, polarity and other properties to try to stop it from getting into the brain.

Tests in rats found that one of the versions, called 8c, blocks the target receptor and is much less likely than the original drug to get into the brain and affect the central nervous system.

The researchers found that 8c mostly stays in the blood and works on cannabinoid receptors found in parts of the body other than the brain. In comparison, more than half of the original drug Rimonabant entered the brain.

It's early days for the research, and the new version of the drug will need to go through testing before it can be used to treat people, but the researchers say it's a step in the right direction. Their study also outlines how scientists can test drugs designed to target cannabinoid receptors to make sure they are working outside the brain.

"Drug development is a long and arduous process," said Dr. George Amato, co-author of the study. "You have to develop hundreds, if not thousands, of compounds before you get the right one. The challenge is that some medicines that are absorbed in the gut also get into the brain. We set out to find compounds that absorb across the gut barrier but not the brain barrier. We've identified some, and they'll now serve as lead structures for further refinement."

New version of obesity drug could help people reduce weight without experiencing anxiety, depression

Antidepressant could do double duty as diabetes drug, study shows

We know that, Paroxetine (also known by the trade names Aropax, Paxil, Pexeva, Seroxat, Sereupin) is an antidepressant drug of the SSRItype. Paroxetine is used to treat major depression, obsessive-compulsive disorder, panic disorder, social anxiety, posttraumatic stress disorder and generalized anxiety disorder in adult outpatients.

Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline. Genericformulations have been available since 2003 when the patent expired.

In adults, the efficacy of paroxetine for depression is comparable to that of older tricyclic antidepressants, with fewer side effects and lower toxicity.  Differences with newer antidepressants are subtler and mostly confined to side effects. It shares the common side effects and contraindications of other SSRIs, with high rates of nausea, somnolence, and sexual side effects. Paroxetine is associated with clinically significant weight gain. Pediatric trials of paroxetine for depression did not demonstrate statistical efficacy better than placebo.

Now University of Texas Medical Branch at Galveston researchers have  discovered that the commonly used antidepressant drug paroxetine could also become a therapy for the vascular complications of diabetes...

"The future potential of this study is that we may be able to 'repurpose' paroxetine for the experimental therapy of diabetic cardiac complications," Szabo said. "We'll need to carefully characterize its safety profile in diabetic patients, but I think there's definite potential here."

Ref : http://diabetes.diabetesjournals.org/content/early/2012/12/03/db12-0789
Antidepressant could do double duty as diabetes drug, study shows