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

Scientists discover strange link between vitamin D and pain

In continuation of my update on Vitamin D

Women with low vitamin D levels may face a more painful recovery after breast cancer surgery and could require significantly more opioid medication afterward, according to research published online in the journal Regional Anesthesia & Pain Medicine.

The findings suggest that breast cancer patients with vitamin D deficiency (below 30 nmol/L) might benefit from taking vitamin D supplements before undergoing a radical mastectomy.

Researchers say growing evidence points to vitamin D playing an important role in how the body senses and regulates pain. Scientists believe this may be connected to the vitamin's anti inflammatory properties and its effects on the immune system. Vitamin D deficiency is also frequently seen in people with breast cancer.

Study Examined Pain After Breast Cancer Surgery

To explore the connection, researchers carried out a prospective observational study at Fayoum University Hospital in Egypt between September 2024 and April 2025.

The study included 184 women with breast cancer who were preparing to have surgery to remove one breast. Half of the participants had vitamin D deficiency (below 30 nmol/L), while the other half had vitamin D levels above 30 nmol/L. The two groups were otherwise similar, with average ages of 44 and 42.

Doctors and nurses caring for the patients did not know their vitamin D status. All participants received the hospital's standard treatment before, during, and after surgery.

During the operation, patients were given fentanyl to control acute pain. After surgery, everyone received intravenous paracetamol every eight hours. Patients were also able to self administer tramadol, another opioid pain medication, by pressing a control button.

Patients With Low Vitamin D Needed More Opioids

Pain levels were recorded immediately after surgery and again at 6, 12, 18, and 24 hours later. Researchers also tracked nausea, vomiting, sedation levels, and length of hospital stay.

Patients with vitamin D deficiency were three times more likely to experience moderate to severe pain during the first 24 hours after surgery compared with patients who had adequate vitamin D levels.

Researchers noted that none of the patients in either group reported severe pain of 7 or higher on the standard 0 to 10 pain scale. The difference was entirely related to a higher number of patients experiencing moderate pain levels between 4 and 6.

The vitamin D deficient group also required more opioid medication. On average, these patients received 8 μg more fentanyl during surgery, which researchers described as a modest increase.

However, after surgery, the difference became much larger. Patients with low vitamin D used an average of 112mg more tramadol than those with sufficient vitamin D levels. The medication was patient controlled, with doses capped at 50mg per hour.

Vitamin D and Recovery Complications

Opioid medications can lead to side effects such as nausea, vomiting, drowsiness, and confusion. They also carry risks of dependence and addiction.

The study found postoperative nausea occurred more often among patients with vitamin D deficiency. Vomiting was only reported in the deficient group, although researchers said the difference was too small to be considered statistically significant.

The researchers acknowledged several limitations. Because the study was observational and conducted at a single medical center, it cannot prove that low vitamin D directly caused the increase in pain. The team also did not measure inflammatory markers that might explain how vitamin D influences pain. In addition, information about anxiety, depression, cancer stage, previous treatments, and sleep problems before surgery was not collected.

Even with those limitations, the researchers concluded, "Vitamin D deficiency is associated with a higher occurrence of moderate to severe postoperative pain and increased opioid consumption in patients undergoing unilateral modified radical mastectomy."

They added, "Preoperative vitamin D supplementation in breast cancer patients with vitamin D levels below 30 nmol/L may have a role in modulating postoperative pain."

https://rapm.bmj.com/content/early/2026/05/04/rapm-2025-107495

Scientists discover strange link between vitamin D and pain 

Scientists discover strange link between vitamin D and pain

In continuation of my update on Vitamin D 

Women with low vitamin D levels may face a more painful recovery after breast cancer surgery and could require significantly more opioid medication afterward, according to research published online in the journal Regional Anesthesia & Pain Medicine.

The findings suggest that breast cancer patients with vitamin D deficiency (below 30 nmol/L) might benefit from taking vitamin D supplements before undergoing a radical mastectomy.

Researchers say growing evidence points to vitamin D playing an important role in how the body senses and regulates pain. Scientists believe this may be connected to the vitamin's anti inflammatory properties and its effects on the immune system. Vitamin D deficiency is also frequently seen in people with breast cancer.

Study Examined Pain After Breast Cancer Surgery

To explore the connection, researchers carried out a prospective observational study at Fayoum University Hospital in Egypt between September 2024 and April 2025.

The study included 184 women with breast cancer who were preparing to have surgery to remove one breast. Half of the participants had vitamin D deficiency (below 30 nmol/L), while the other half had vitamin D levels above 30 nmol/L. The two groups were otherwise similar, with average ages of 44 and 42.

Doctors and nurses caring for the patients did not know their vitamin D status. All participants received the hospital's standard treatment before, during, and after surgery.

During the operation, patients were given fentanyl to control acute pain. After surgery, everyone received intravenous paracetamol every eight hours. Patients were also able to self administer tramadol, another opioid pain medication, by pressing a control button.

Patients With Low Vitamin D Needed More Opioids

Pain levels were recorded immediately after surgery and again at 6, 12, 18, and 24 hours later. Researchers also tracked nausea, vomiting, sedation levels, and length of hospital stay.

Patients with vitamin D deficiency were three times more likely to experience moderate to severe pain during the first 24 hours after surgery compared with patients who had adequate vitamin D levels.

Researchers noted that none of the patients in either group reported severe pain of 7 or higher on the standard 0 to 10 pain scale. The difference was entirely related to a higher number of patients experiencing moderate pain levels between 4 and 6.

The vitamin D deficient group also required more opioid medication. On average, these patients received 8 μg more fentanyl during surgery, which researchers described as a modest increase.

However, after surgery, the difference became much larger. Patients with low vitamin D used an average of 112mg more tramadol than those with sufficient vitamin D levels. The medication was patient controlled, with doses capped at 50mg per hour.

Vitamin D and Recovery Complications

Opioid medications can lead to side effects such as nausea, vomiting, drowsiness, and confusion. They also carry risks of dependence and addiction.

The study found postoperative nausea occurred more often among patients with vitamin D deficiency. Vomiting was only reported in the deficient group, although researchers said the difference was too small to be considered statistically significant.

The researchers acknowledged several limitations. Because the study was observational and conducted at a single medical center, it cannot prove that low vitamin D directly caused the increase in pain. The team also did not measure inflammatory markers that might explain how vitamin D influences pain. In addition, information about anxiety, depression, cancer stage, previous treatments, and sleep problems before surgery was not collected.

Even with those limitations, the researchers concluded, "Vitamin D deficiency is associated with a higher occurrence of moderate to severe postoperative pain and increased opioid consumption in patients undergoing unilateral modified radical mastectomy."

They added, "Preoperative vitamin D supplementation in breast cancer patients with vitamin D levels below 30 nmol/L may have a role in modulating postoperative pain.

https://rapm.bmj.com/content/early/2026/05/04/rapm-2025-107495

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

Scientists discover strange link between vitamin D and pain | ScienceDaily

Methamphetamine impairs dopamine uptake by targeting a protein modification

In continuation of my update on Methamphetamine

Dopamine brings on a surge of pleasure, but too much dopamine in a synapse can ultimately lead to mood disorders and addiction. A recent preclinical study published in The FASEB Journal suggests that methamphetamine boosts dopamine levels by reversibly reducing the amount of a modification on the dopamine transporter. Loss of the modification decreases the transporter's ability to remove the neurotransmitter from synapses.

The findings shed new light on how the transporter works and could help researchers develop new treatments for addiction and neurological disorders, such as depression and schizophrenia.

The neurotransmitter dopamine is involved in many processes, such as movement, reward, motivation, learning, and memory. When triggered, special neurons in the brain release dopamine into the gaps between neurons, called synapses, making a person experience happiness and euphoria. Low levels, however, can make a person feel depressed.

Because inappropriate amounts can lead to psychological disorders or addiction, levels of the neurotransmitter are regulated by dopamine transporters (DATs) that remove excess dopamine from synapses. Protein modifications can modulate DAT activity. Palmitoylation enhances DAT reuptake of dopamine, whereas phosphorylation by the enzyme protein kinase C decreases reuptake.

Methamphetamine can slow reuptake by stimulating phosphorylation, but Roxanne Vaughan, James Foster, and colleagues at the University of North Dakota wanted to see whether the drug also affects DAT palmitoylation.

In a rat model and in in vitro experiments, methamphetamine rapidly reduced DAT palmitoylation and DAT transporter activity. Palmitoylation returned to normal levels much more quickly than transporter activity, which suggests that additional processes are involved in keeping DAT activity suppressed after palmitoylation recovers.

The methamphetamine effects were specific—cocaine did not impact palmitoylation. In vitro experiments revealed that protein kinase C was necessary for the reduction in palmitoylation. Additional experiments with DAT mutated at a position where half of the palmitoylation typically occurs reduced palmitoylation to about half of wild-type levels, and the mutant took up even less dopamine in methamphetamine-treated cells.

"By revealing that methamphetamine suppresses dopamine transporter palmitoylation, this study identifies a previously unknown mechanism through which the drug alters dopamine signaling," says Vaughan. "Understanding this process could guide the development of treatments aimed at stabilizing or restoring transporter regulation, potentially reducing the long-term dopamine imbalances and neurochemical damage linked to methamphetamine addiction."

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

Methamphetamine impairs dopamine uptake by targeting a protein modification

FDA Approves Jascayd (nerandomilast) to Treat Idiopathic Pulmonary Fibrosis

Boehringer Ingelheim’s Jascayd (nerandomilast) tablets has been approved by the U.S. Food and Drug Administration (FDA) as an oral treatment option for idiopathic pulmonary fibrosis (IPF) in adult patients.2 Jascayd is the first and only preferential inhibitor of phosphodiesterase 4B (PDE4B) to be approved in this indication. This represents a novel mechanism of action that exerts both antifibrotic and immunomodulatory effects, thereby slowing the decline in lung function in IPF patients.2,3

“This milestone represents a new era in the treatment of IPF, a rare and debilitating chronic condition that worsens lung function. Nerandomilast has proven to slow lung function decline in IPF,” said Toby Maher, M.D., Ph.D., Professor of Clinical Medicine, Keck School of Medicine, USC Los Angeles. “Nerandomilast is a welcome new treatment option with a well-tolerated safety profile for physicians to consider for appropriate patients.”

The FDA approval is based on data from two clinical trials: FIBRONEER™-IPF (NCT05321069) and Trial 2 (NCT04419506). The primary endpoint in FIBRONEER™-IPF was the absolute change from baseline in Forced Vital Capacity (FVC), a measure of lung function,4 in mL at week 52.2,3 Nerandomilast demonstrated a significantly smaller FVC decline compared to placebo.2,3 Specifically, the adjusted mean decline in patients receiving 18 mg or 9 mg nerandomilast was -106 mL and -122 mL, respectively, versus -170 mL in the placebo group.2 Additionally, a treatment effect was shown as early as week two with nerandomilast 18 mg compared to placebo, with changes from baseline in FVC continuing to diverge over time to week 52.2,3

“The FDA approval of nerandomilast is a pivotal moment for people living with IPF as this marks the first time in over 10 years that the treatment landscape is evolving,” said Shashank Deshpande, Chairman of the Board of Managing Directors and Head of Human Pharma at Boehringer Ingelheim. “This new step forward, driven by the compelling results of the FIBRONEER™-IPF trial, underscores our unwavering commitment to change the way we treat IPF by delivering innovative therapies like nerandomilast.”

The most common (≥5%) adverse reactions reported in patients treated with nerandomilast and more frequently than the placebo group were as follows for nerandomilast 18 mg, 9 mg and placebo, respectively: diarrhea (42%, 31%, 17%), COVID-19 (13%, 16%, 12%), upper respiratory tract infection (13%, 11%, 10%), depression (12%, 11%, 10%), weight decreased (11%, 10%, 8%), decreased appetite (9%, 9%, 5%), nausea (8%, 9%, 7%), fatigue (7%, 8%, 6%), headache (7%, 6%, 5%), vomiting (6%, 5%, 5%), back pain (6%, 5%, 4%) and dizziness (5%, 6%, 5%).2

Discontinuation due to adverse reactions occurred more frequently in patients treated with nerandomilast (with or without background antifibrotic treatment) 18 mg (15%) and 9 mg (12%) compared to placebo (11%).2 The most frequent adverse reaction leading to discontinuation of nerandomilast 18 mg and 9 mg was diarrhea (6% and 2%, respectively).2

There is no ‘Warnings and Precautions’ section in the FDA approved product label.2

“The FDA approval of nerandomilast is exciting news for people living with idiopathic pulmonary fibrosis and their caregivers,” said Scott Staszak, President and CEO of the Pulmonary Fibrosis Foundation. “There has been a long-standing need for new treatment options for IPF within our community and nerandomilast provides an important addition to the care landscape.”

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

FDA Approves Jascayd (nerandomilast) to Treat Idiopathic Pulmonary Fibrosis

FDA Approves Caplyta (lumateperone) as an Adjunctive Therapy for the Treatment of Major Depressive Disorder (MDD) in Adults

In continuation of my update on lumateperone

Johnson & Johnson (NYSE: JNJ) announced the U.S. Food and Drug Administration (FDA) approval of  Caplyta® (lumateperone) as an adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults. The approval – the first under J&J leadership following its acquisition of Intra-Cellular Therapies, Inc. – provides patients with a safe and effective new treatment option that can enable a path to remission. Caplyta® makes it easy to start and stay on treatment without the need for titration. Weight gain and other metabolic side effects that typically lead to discontinuation of care were similar to placebo. This approval marks the fourth indication for Caplyta®, the first and only FDA-approved treatment for bipolar I and II depression in adults, as an adjunctive and monotherapy; also approved for the treatment of schizophrenia in adults.

MDD, or clinical depression, is one of the most common psychiatric disorders, affecting about 22 million American adults.4,5 While oral antidepressants may offer relief for some, 2 in 3 people living with MDD continue to experience residual symptoms despite treatment, significantly impacting their overall quality of life.6 Beyond its toll on patients’ wellbeing, MDD has a substantial economic burden and is the leading cause of disability in the U.S.7

“Depression is a complex disorder that affects each person differently, underscoring the urgent need for a range of effective and well-tolerated treatment options,” said Roger S. McIntyre, M.D., FRCPC, Professor of Psychiatry and Pharmacology, University of Toronto.a “For people who are still experiencing lingering depressive symptoms while on an antidepressant, adding Caplyta® to a patient’s treatment regimen may offer early improvement, with the potential for remission—the ultimate goal of treatment.”

This approval is based on positive results from two Phase 3, global, double-blind, placebo-controlled trials – Study 501 and 502 – which both met their primary and key secondary endpoints, providing statistically significant and clinically meaningful improvement in depression symptoms compared to an oral antidepressant plus placebo, as measured by Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impression Scale-Severity index (CGI-S) total scores.1,2

A large separation in total MADRS score was seen between Caplyta® and placebo in Study 501 (-4.9 points, effect size 0.61) and Study 502 (-4.5 points, effect size 0.56), at six weeks. Separation from placebo was seen as early as one week in Study 501 and two weeks in Study 502. Significant reductions in the key secondary endpoint of mean change in total CGI-S scores from baseline were also demonstrated at six weeks in Study 501 (-0.7 points, effect size 0.67) and Study 502 (-0.5 points, effect size 0.51).1,2

In pivotal trials, the Caplyta® safety profile was consistent with the existing body of clinical data in its schizophrenia and bipolar depression I and II indications. No new safety concerns were identified. Weight gain and metabolic changes (lipid and glucose levels), as well as akathisia and restlessness, were similar to placebo. Reports of sexual side effects were not common. The most common side effects of Caplyta® include sleepiness, dizziness, nausea, dry mouth, feeling tired, and diarrhea.

“Major depressive disorder affects millions of Americans, impacting how a person feels, thinks, and acts,” said Michael Pollock, CEO of Depression and Bipolar Support Alliance (DBSA). “DBSA believes that all individuals have the right to direct their own treatment, and we understand that for many people, ongoing antidepressant therapy alone may not offer meaningful relief. The introduction of new treatment options, and continued innovation in mental health, has enabled us to reset expectations for living with depression and offers people hope that achieving lasting wellness and remission is possible.”

Long-term data, evidenced by the 503 open-label extension safety study, showed Caplyta® was safe and well tolerated, consistent with the safety profile of Studies 501 and 502. Patients experienced low risk of weight gain, cardiometabolic effects, and extrapyramidal symptoms.8 Caplyta® also demonstrated the potential to help patients achieve remission. During this 26-week safety study, 80% of patients responded to treatment and 65% of patients experienced remission (defined as MADRS Total score ≤ 10) at 6 months.3

Although its exact mechanism of action is unknown, Caplyta® is characterized by high serotonin 5-HT2A receptor occupancy and moderate amounts of dopamine D2 receptor occupancy at therapeutic doses. Caplyta® does not need dose titration, allowing patients to start treatment at the effective dose of 42 mg.8

“Caplyta® has the potential to become a new standard of care across multiple mental health disorders, including major depressive disorder,” said Bill Martin, Ph.D., Global Therapeutic Area Head, Neuroscience, Johnson & Johnson Innovative Medicine. “This approval is a testament to our nearly 70-year commitment of bringing innovative and differentiated therapies that redefine treatment expectations—and introduce the possibility of remission—to patients living with some of today’s most prevalent and debilitating mental health conditions.”

This additional FDA approval builds upon the established, robust clinical efficacy and proven real-world safety profile of Caplyta® for the treatment of adults living with schizophrenia and for the treatment of depressive episodes associated with bipolar I or II disorder.

A supplemental New Drug Application (sNDA) for Caplyta® with long-term data evaluating the safety and efficacy of the medication for the prevention of relapse in schizophrenia was recently submitted to the FDA. The medication is also being studied for other neuropsychiatric and neurological disorders. Caplyta® is not FDA-approved for these disorders.

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

FDA Approves Caplyta (lumateperone) as an Adjunctive Therapy for the Treatment of Major Depressive Disorder (MDD) in Adults

FDA Approves KETARx (ketamine) for Surgical Pain Management

PharmaTher Holdings Ltd. announced     the U.S. Food and Drug Administration (FDA) approval of  KETARx™, on August 8th, 2025, for its indicated uses in surgical pain management. This FDA approval signifies a momentous achievement for Pharma. 

Fabio Chianelli, Founder, Chairman and CEO of PharmaTher, commented:

“Today marks a new chapter for PharmaTher. With FDA approval for ketamine now in hand, we are closer to realizing our goal of becoming a global leader in ketamine-based pharmaceuticals. This historic FDA approval for PharmaTher is a testament to years of dedicated development, signalling a new era of growth. We remain steadfast in our mission to harness the pharmaceutical potential of ketamine for a range of mental health, neurological, and pain disorders.”

Ketamine stands out among psychedelic and psychedelic-adjacent drugs as the only one included on the World Health Organization's Model List of Essential Medicines1. The global ketamine market is expected to experience substantial growth, currently valued at $750 million and projected to reach $3.42 billion by 2034, indicating a compound annual growth rate of 16.4%2. Furthermore, SPRAVATO® (esketamine), an FDA approved treatment for depression, is tracking a sales run rate of $1.6 billion, with guidance anticipating $3 billion to $3.5 billion by 2027-20283. This promising market outlook underscores the potential of KETARx™ and PharmaTher’s strategic position in the industry.

The FDA's approval of the Company’s ketamine product, KETARx™, provides a strong foundation for expanding the development of ketamine across diverse therapeutic areas within the Company's product pipeline. These areas include mental health conditions like depression, neurological disorders such as Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS), and the management of rare or chronic pain, including Complex Regional Pain Syndrome (CRPS).

Since February 2018, ketamine has been regularly listed on the FDA drug shortage list, highlighting a significant need for a consistent, high-quality supply. This issue is cautioned by a compounding risk alert issued by the FDA on October 10, 20234, which detailed potential risks associated with compounded ketamine products used for psychiatric disorders. Robert F. Kennedy Jr., Secretary of Health and Human Services, has also emphasized the importance of expanding research and ensuring legal access to psychedelic therapies for veterans5. The Veterans Health Administration, the largest integrated healthcare system in the U.S., currently approves and funds ketamine infusions for retired military personnel afflicted with depression, PTSD, and chronic pain6. Furthermore, FDA Commissioner Marty Makary's establishment of the Commissioner's National Priority Voucher program signifies the FDA's dedication to expediting access to safe and effective treatments, instilling confidence in potential future regulatory support and accessibility for ketamine.

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

FDA Approves KETARx (ketamine) for Surgical Pain Management

FDA Approves Rezenopy (naloxone hydrochloride) Nasal Spray for the Emergency Treatment of Opioid Overdose

The U.S. Food and Drug Administration has approved Rezenopy (naloxone hydrochloride) nasal spray 10 mg for emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression in adult and pediatric patients.

Drug overdose, including most commonly opioid overdose, is one of the leading causes of accidental death in the United States.

Rezenopy nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present.

Naloxone hydrochloride is an opioid antagonist that works to reverse the effects of opioids during an overdose, including respiratory depression, sedation and hypotension.

Rezenopy is a high-dose naloxone hydrochloride nasal spray formulation containing 10 mg of naloxone per spray available on prescription. There are a number of naloxone hydrochloride nasal spray products available that contain a lower dose of naloxone, including Kloxxado (8 mg/spray) and Rextovy (4 mg/spray) which are available on prescription, and Narcan (4 mg/spray) and ReVive (3 mg/spray) which are available over-the-counter.

Common adverse reactions reported with Rezenopy include upper abdominal pain, nasopharyngitis, and dysgeusia.

REF: https://en.wikipedia.org/wiki/Naloxone

FDA Approves Rezenopy (naloxone hydrochloride) Nasal Spray for the Emergency Treatment of Opioid Overdose

Defender Pharmaceuticals Receives Complete Response Letter from the U.S. Food and Drug Administration for its Intranasal Scopolamine (DPI-386) New Drug Application for the Prevention of Nausea and Vomiting Induced by Motion in Adults

Defender Pharmaceuticals, Inc. (the “Company” or “Defender”), a privately held life sciences company based in St. Louis, today announced the issuing of a Complete Response Letter (CRL) , by the U.S. Food and Drug Administration (FDA) to the Company’s New Drug Application (NDA) for intranasal scopolamine (DPI-386) for the prevention of nausea and vomiting induced by motion in adults.

“Following our review of the CRL, we plan on scheduling a formal meeting with the FDA to fully understand the issues raised in the CRL so we can develop and implement a comprehensive action plan,” said Barry I. Feinberg, M.D., President & CEO of Defender Pharmaceuticals. “We remain confident that our intranasal scopolamine is a safe and effective therapy for the prevention of motion sickness, and we will work closely with the FDA to ensure that we can bring this innovative new product to the market.”

About intranasal scopolamine (DPI-386) Development Program

Defender has worked with the United States Naval Medical Research Unit (NAMRU-D) and the National Aeronautics and Space Administration (NASA) on its intranasal scopolamine development program that is focused on specific military personnel and astronauts.

To date, more than 1,300 patients have participated in Defender clinical studies, including over 500 participants in the DPI-386-MS-33 study. Given the successful outcome of DPI-386-MS-33, Defender has submitted a New Drug Application (NDA) to the Food and Drug Administration (FDA) for DPI-386 Nasal Gel for the prevention of nausea and vomiting induced by motion in adults.

Defender is also developing intranasal formulations designed to treat a wide variety of indications. We believe these new products have the potential to help safeguard health across civilian and military populations.

About Motion-Related Discomfort
Certain motions cause discomfort in individuals while engaged in various leisure or travel-related activities. Most forms of travel, whether on land, in the air, or on the water, can trigger symptoms such as nausea and vomiting (example: flying, boating/fishing, car, bus, and train). Symptoms induced by motion can also have a detrimental impact on the ability of various military personnel and astronauts to perform assigned duties, potentially impacting readiness and negatively impacting resources. Motion-related discomfort is a common and transient response to unfamiliar or unnatural motion or contradictory spatial sensory information, resulting in decrements to performance of tasks, pallor, cold sweating, nausea and vomiting. Prolonged exposure to certain motions may induce sopite-related symptoms such as loss of drive and concentration, drowsiness, sleepiness, apathy, depression, and a feeling of impending doom.

Ref : https://en.wikipedia.org/wiki/Scopolamine

Defender Pharmaceuticals Receives Complete Response Letter from the U.S. Food and Drug Administration for its Intranasal Scopolamine (DPI-386) New Drug Application for the Prevention of Nausea and Vomiting Induced by Motion in Adults

FDA Approves Auvelity (dextromethorphan and bupropion) for the Treatment of Major Depressive Disorder in Adults

 

        

dextromethorphan

 

Bupropion

In continuation of my updates on dextromethorphan and Bupropion, 

Axsome Therapeutics, Inc. , a biopharmaceutical company developing and delivering novel therapies for the management of central nervous system (CNS) disorders,  announced  the U.S. Food and Drug Administration (FDA)  approval of  Auvelity (dextromethorphan HBr -bupropion HCl) extended-release tablets for the treatment of major depressive disorder (MDD) in adults.¹ Auvelity is the first and only rapid-acting oral medicine approved for the treatment of MDD with labeling of statistically significant antidepressant efficacy compared to placebo starting at one week.  The rapid antidepressant effects of Auvelity were sustained at all subsequent timepoints. Auvelity is the first and only oral N-methyl D-aspartate (NMDA) receptor antagonist approved for the treatment of MDD.  Axsome anticipates Auvelity to be commercially available in the U.S. in the fourth quarter of 2022.

Maurizio Fava, MD, Psychiatrist-In-Chief, Department of Psychiatry, Massachusetts General Hospital, Executive Director, Clinical Trials Network & Institute, Associate Dean for Clinical & Translational Research, and Slater Family Professor of Psychiatry, Harvard Medical School said, “The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile. Auvelity, which was granted Breakthrough Therapy designation by the FDA, represents the first new oral non-monoamine-based mechanism of action approved to treat major depressive disorder in over sixty years. Nearly two thirds of patients treated with currently available antidepressants do not adequately respond, and those that do may not achieve clinically meaningful responses for up to six to eight weeks. Given the debilitating nature of depression, the efficacy of Auvelity observed at one week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition.”

Michael Pollock, Chief Executive Officer of the Depression and Bipolar Support Alliance (DBSA), a leading national patient advocacy organization focusing on depression and bipolar disorder said, “The mental health crisis in the United States is one of the most pressing health issues facing our country today. Over 20 million American adults experienced major depressive disorder each year prior to the COVID-19 pandemic. These numbers increased dramatically during the pandemic with approximately thirty percent of adults in the U.S. or more than 80 million Americans experiencing elevated symptoms of depression. The need for new treatment options, particularly those with new mechanisms of action, could not be clearer and more urgent for those living with, or impacted by, major depressive disorder.”

Dan V. Iosifescu, MD, Professor of Psychiatry at the New York University School of Medicine, and Director of the Clinical Research Division at the Nathan Kline Institute for Psychiatric Research said, “Major depressive disorder is disabling and potentially life-threatening, causes profound distress for patients and their families, and leads to substantial healthcare resource utilization. Auvelity’s oral NMDA receptor antagonist and sigma-1 receptor agonist activity, which targets glutamatergic neurotransmission, provides clinicians a long sought after new mechanistic approach which may benefit the millions of patients living with this serious condition. In clinical trials, Auvelity has demonstrated rapid and statistically significant improvement in depressive symptoms as early as Week 1, and increased rates of remission at Week 2 compared with placebo. This early benefit with Auvelity was maintained and increased with continued treatment, and was accompanied by a favorable safety and tolerability profile.”

Auvelity was studied in a comprehensive clinical program which included more than 1,100 patients with depression. The efficacy of Auvelity in the treatment of MDD was demonstrated in the GEMINI placebo-controlled study, and confirmatory evidence which included the ASCEND study comparing Auvelity to bupropion sustained-release tablets. In the GEMENI study, Auvelity was statistically significantly superior to placebo in improvement of depressive symptoms as measured by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6, the study’s primary endpoint. To evaluate speed of onset of action, the change in MADRS total score from baseline to Week 1 and from baseline to Week 2 were pre-specified secondary efficacy endpoints. The difference between Auvelity and placebo in change from baseline in MADRS total score was statistically significant at Week 1 and at Week 2.¹ In the ASCEND study, Auvelity was statistically significantly superior to bupropion sustained-release tablets 105 mg twice daily on the primary outcome measure.⁵ The primary outcome measure of the ASCEND study was calculated by assessing the change from baseline in MADRS total scores from Week 1 to Week 6 and then taking the average of those scores.¹ In the placebo-controlled clinical study, the most common (incidence ≥5% for Auvelity and more than twice as frequently as placebo) adverse reactions were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis.¹

The FDA granted Breakthrough Therapy designation for Auvelity for the treatment of MDD in March 2019. This designation is granted to candidate drugs that show potential for benefit above that of available therapies based on preliminary clinical data, and it provides the sponsor with added focus from and greater interactions with FDA staff during the development of the candidate drug.⁶ The Auvelity New Drug Application (NDA) was evaluated by the FDA under Priority Review, which is granted by the FDA to applications for medicines that, if approved, would provide significant improvements in the effectiveness or safety of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.

 

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

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

 

Drug commonly used as antidepressant helps fight cancer in mice

A class of drug called monoamine oxidase inhibitors is commonly prescribed to treat depression; the medications work by boosting levels of serotonin, the brain's "happiness hormone."

A new study by UCLA researchers suggests that those drugs, commonly known as MAOIs, might have another health benefit: helping the immune system attack cancer. Their findings are reported in two papers, which are published in the journals Science Immunology and Nature Communications.

"MAOIs had not been linked to the immune system's response to cancer before," said Lili Yang, senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "What's especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn't as challenging as developing a completely new drug would be."

Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to evade that response, has led to new cancer immunotherapies—drugs that boost the immune system's activity to try to fight cancer.

In an effort to develop new cancer immunotherapies, Yang and her colleagues compared immune cells from melanoma tumors in mice to immune cells from cancer-free animals. Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine oxidase A, or MAOA. MAOA's corresponding protein, called MAO-A, controls levels of serotonin and is targeted by MAOI drugs.

"For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two," said Yang, who is also a UCLA associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. "So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells."

Next, the researchers studied mice that didn't produce MAO-A protein in immune cells. The scientists found that those mice were better at controlling the growth of melanoma and colon tumors. They also found that normal mice became more capable of fighting those cancers when treated with MAOIs.

Digging in to the effects of MAO-A on the immune system, the researchers discovered that T cells—the immune cells that target cancer cells for destruction—produce MAO-A when they recognize tumors, which diminishes their ability to fight cancer.

That discovery places MAO-A among a growing list of molecules known as immune checkpoints, which are molecules produced as part of a normal immune response to prevent T cells from overreacting or attacking healthy tissue in the body. Cancer has been known to exploit the activity of other previously identified immune checkpoints to evade attack by the immune system.

In the Science Immunology paper, the scientists report that MAOIs help block the function of MAO-A, which helps T cells overcome the immune checkpoint and more effectively fight the cancer.

But the drugs also have a second role in the immune system, Yang found. Rogue immune cells known as tumor-associated macrophages often help tumors evade the immune system by preventing anti-tumor cells including T cells from mounting an effective attack. High levels of those immunosuppressive tumor-associated macrophages in a tumor have been associated with poorer prognoses for people with some types of cancer.

But the researchers discovered that MAOIs block immunosuppressive tumor-associated macrophages, effectively breaking down one line of defense that tumors have against the human immune system. That finding is reported in the Nature Communications paper.

"It turns out that MAOIs seem to both directly help T cells do their job, and stop tumor-associated macrophages from putting the brakes on T cells," Yang said.

Combining MAOIs with existing immunotherapies

Yang said she suspects that MAOIs may work well in concert with a type of cancer immunotherapies called immune checkpoint blockade therapies, most of which work by targeting immune checkpoint molecules on the surface of immune cells. That's because MAOIs work on MAO-A proteins, which are inside cells and function differently from other known immune checkpoint molecules.

Studies in mice showed that any of three existing MAOIs—phenelzine, clorgyline or mocolobemide—either on their own or in combination with a form of immune checkpoint blockade therapy known as PD-1 blockers, could stop or slow the growth of colon cancer and melanoma.

Although they haven't tested the drugs in humans, the researchers analyzed clinical data from people with melanoma, colon, lung, cervical and pancreatic cancer; they found that people with higher levels of MAOA gene expression in their tumors had, on average, shorter survival times. That suggests that targeting MAOA with MAOIs could potentially help treat a broad range of cancers.

Yang and her collaborators are already planning additional studies to test the effectiveness of MAOIs in boosting human immune cells' response to various cancers.

Yang said MAOIs could potentially act on both the brain and immune cells in patients with cancer, who are up to four times as likely as the general population to experience depression.

"We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits," she said.

The experimental combination therapy in the study was used in preclinical tests only and has not been studied in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang, Xi Wang and Yu-Chen Wang as co-inventors.

Drug commonly used as antidepressant helps fight cancer in mice

Common drug could mitigate risk of 'a broken heart' during bereavement

In continuation of my update on aspirin

The increased risk of heart attack or "a broken heart" in early bereavement could be reduced by using common medication in a novel way, according to a world-first study led by the University of Sydney and funded by Heart Research Australia.

Lead Investigator Professor Geoffrey Tofler said while most people gradually adjust to the loss of a loved one, there is an increase in heart attack and death among bereaved people, particularly those grieving a spouse or child.

"The increased risk of heart attack can last up to six months. It is highest in the first days following bereavement and remains at four times the risk between seven days to one month after the loss."

The study, published in the American Heart Journal, is the first randomized controlled clinical trial to show it is possible to reduce several cardiac risk factors during this time, without adversely affecting the grieving process.

"Bereavement following the death of a loved one is one of the most stressful experiences to which almost every human is exposed," said Professor Tofler, Professor of Preventative Cardiology at the University of Sydney's Faculty of Medicine and Health, and Senior Staff Cardiologist at Royal North Shore Hospital.

"Our study is the first clinical trial to examine how the cardiac risk factors could be mitigated during early bereavement."

About the study

The research team from the University of Sydney, Royal North Shore Hospital and the Kolling Institute enrolled 85 spouses or parents in the study within two weeks of losing their family member.

Forty-two participants received low daily doses of a beta blocker and aspirin for six weeks, while 43 were given placebos. Heart rate and blood pressure were carefully monitored, and blood tests assessed blood clotting changes.

The main finding was that the active medication, used in a low dose once a day, successfully reduced spikes in blood pressure and heart rate, as well as demonstrating some positive change in blood clotting tendency."

Professor Geoffrey Tofler, lead investigator

The investigators also carefully monitored the grief reaction of participants.

"We were reassured that the medication had no adverse effect on the psychological responses, and indeed lessened symptoms of anxiety and depression," said Professor Tofler.

"Encouragingly, and to our surprise, reduced levels of anxiety and blood pressure persisted even after stopping the six weeks of daily beta blocker and aspirin."

Co-investigator Associate Professor Tom Buckley said the study builds on the team's novel work in this area with their earlier studies among the first to identify the physiological correlates of bereavement.

"While beta blockers and aspirin have been commonly used long term to reduce cardiovascular risk, they have not previously been used in this way as a short-term preventative therapy during bereavement," said

Associate Professor Buckley of the University of Sydney Susan Wakil School of Nursing and Midwifery.

Implications and next steps

The authors acknowledge that larger long-term studies are needed to identify who would benefit most however the findings provide encouragement for health care professionals to consider this preventative strategy among individuals that they consider to be at high risk associated with early bereavement.

"Our finding on the potentially protective benefit of this treatment is also a good reminder for clinicians to consider the well-being of the bereaved," said Associate Professor Buckley.

"Future studies are needed to assess if these medications could be used for other short periods of severe emotional stress such as after natural disasters or mass bereavement where currently there are no guidelines to inform clinicians."

Co-investigator Dr. Holly Prigerson, Co-Director of the Center for Research on End-of-Life Care at Weill Cornell Medicine in New York, said:

This is an important study because it shows ways to improve the physical and mental health of at-risk bereaved people. It is a preventive intervention that is potentially practice-changing, using inexpensive, commonly available medicines."

People experiencing cardiac symptoms should discuss their condition with a health care professional before taking medication as incorrect use could be harmful.

More about beta-blockers

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

https://www.sciencedirect.com/science/article/abs/pii/S0002870319303047?via%3Dihub