Day: 02/01/2023

Nitrosamines: A Carcinogen Found in Popular Drugs

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What can be done to prevent this in the future?

Various medicine pills in their original packaging in Brussels on Aug. 9, 2019. (Yves Herman/Illustration/Reuters)

Various medicine pills in their original packaging in Brussels on Aug. 9, 2019.

In recent years, a lot of popular drugs, including diabetic, hypertension, and heartburn drugs, have been found to be contaminated with a carcinogen: nitrosamine.

In 2018, Swiss drugmaker Novartis first discovered that its blockbuster blood pressure medication valsartan contained harmful levels of a carcinogen known as nitrosamine. In the following two years, over 1,400 product lots were recalled by the U.S. Food and Drug Administration (FDA) due to their containing this chemical above acceptable intake limits.

As recently as Aug. 19, 2022, Merck’s blockbuster diabetes medication, Januvia, was found to be contaminated with nitrosamine. This led to a month-long investigation by Merck. However, Januvia was not recalled to avoid drug shortages.

Products that have been recalled include other commonly used drugs, such as metformin, losartan, Zantac, and quinapril.

According to the National Cancer Institute, some nitrosamines have caused cancer in laboratory animals. In humans, nitrosamines pose a risk of rectum and proximal colon, pancreatic, stomach, esophageal, mouth, and pharynx cancers.

Nitrosamines: A Carcinogen Found Last Century

While we have known about nitrosamines for nearly 80 years, British scientists John Barnes and Peter Magee reported that nitrosamines caused liver tumors in rodents in 1956. Since Barnes’ and Magee’s discovery, awareness and concern about nitrosamines have impacted the pharmaceutical and food industries.

Nitrosamines have been found in products such as cured meats, bacon, and beer. While concerning, nitrosamine levels in these products are often very low and undetectable. In pharmaceutical products, acceptable levels of nitrosamine range from 26.5–96 ng/day, depending on the chemical composition of the nitrosamine.

The generally acceptable risk for potential carcinogens in pharmaceuticals is one case of cancer per 100,000 subjects. For example, the estimated risk calculated for the drug valsartan ranges from 12–30 cases per 100,000 people.

Studies have examined susceptibility and biological compounds that nitrosamines interact with. For example, when nitrosamine interacts with certain amino acids, it causes genetic mutations which can lead to the development of cancer in both cell and animal models.

What Drugs Have Been Recalled Due to Nitrosamine Impurities?

Since 2018, several drugs have been recalled due to containing nitrosamines. Medications that have a recall history due to nitrosamine impurities include:

  • valsartan
  • losartan
  • irbesartan
  • nizatidine
  • Accuretic (quinapril HCl/hydrochlorothiazide)
  • Accupril (quinapril)
  • generic quinapril/hydrochlorothiazide tablets
  • Zantac (ranitidine)
  • Chantix (varenicline)
  • metformin
  • rifampin

How Does Nitrosamine Contamination in Drugs Happen?

Nitrosamines form when a secondary or tertiary amine reacts with nitrous acid. In sartan compounds, most sartans contain a tetrazole ring. This ring requires the use of sodium nitrite. Because the chemicals used to make this ring are amines or contain traces of amines, they result in the formation of nitrosamine compounds. Unlike in sartan medications, like in the case of Zantac, the origins of nitrosamine contamination are still unclear.

Other factors that contribute to nitrosamine impurities in pharmaceuticals include using nitrosating agents during production, the presence of reactive elements in starting materials, using acidic manufacturing processes, the presence of nitrosamine precursors in raw materials, and product contact with nitrogen oxides during storage.

In addition to these factors, metabolic processes within the body may also produce nitrosamines. Special attention should be given to the whole lifecycle of a drug—from manufacturing, storage, shipping, and metabolism—to reduce the risk of introducing nitrosamines into the body.

What Should We Do to Reduce Risk of Nitrosamine Exposure?

In formulating pharmaceutical products, the FDA recommends adding antioxidant compounds such as vitamin C and vitamin E as nitrosamine-formation inhibitors. One study demonstrated that these compounds showed over 80 percent effectiveness in inhibiting nitrosamine formation.

Another approach is increasing the pH of the environment in which the pharmaceutical is made. This prevents the formation of nitrous acid, which is needed to create nitrosamine.

Individually, people can take charge and protect themselves from nitrosamine exposure. Suggested habits people can enact to reduce or eliminate their exposure to nitrosamines include avoiding cured meats, checking food labels for nitrates and nitrite additives, opting for organic products, testing your tap water for nitrates and nitrites, and eating a diet rich in vitamin C and E.

Currently, the FDA advises that individuals who are taking a medication that may have been recalled talk to their health care provider, as stopping medications without consulting one’s physician can be dangerous. Next, patients should call their pharmacist to see if their medication has been recalled. If so, people should consult their pharmacist and physician to find an alternative medication to manage their condition.

Despite the concern of nitrosamine contamination, drugs that contain nitrosamine have still been allowed on the market. In August 2022, the FDA temporarily allowed sales of Januvia by allowing impurity levels higher than the acceptable threshold.

The justification for this decision by the FDA was that patients dependent on Januvia could be in danger if they stopped taking the medication without consulting their physician.

Antioxidants From Mitochondria Protect Cells From Dying

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Summary: The STARD7 enzyme helps transport the antioxidant coenzyme Q from the mitochondria to the cell surface.

Source: Max Planck Institute

Antioxidants are often advertised as a cure-all in nutrition and offered as dietary supplements. However, our body also produces such radical scavengers itself, one of which is coenzyme Q.

Now researchers from the Max Planck Institute for Biology of Ageing in Cologne, Germany, have discovered how the substance, which is produced in our mitochondria, reaches the cell surface and protects our cells from dying.

Coenzyme Q is an antioxidant that is essential for our body. A deficiency of coenzyme Q leads to serious diseases such as Leigh syndrome – a hereditary disease in which certain brain regions become affected and, among other things, muscle weakness can occur.

A deficiency of coenzyme Q is also one of the first signs of ageing and can occur as early as the early 20s. But why can’t we simply take this substance in with our food?

“Coenzyme Q is a highly hydrophobic molecule that our bodies absorb very little from food,” explains Soni Deshwal, scientist at the Max Planck Institute for Biology of Aging and lead author of the study. But it is also a problem in our cells that coenzyme Q is not water soluble.

The antioxidant is formed in mitochondria and must pass through the watery cell interior called cytoplasm to the surface of the cells in order to neutralize oxidized lipid species.

This shows the stard7 enzyme
The enzyme STARD7 (green) helps mitochondria (red) to transport Coenzyme Q to protect cells from cell death.

“With our research, we have now been able to identify the proteins involved in coenzyme Q transport from the mitochondria to the cell surface”, explains Deshwal.

The researchers found that an enzyme called STARD7 helps transport the coenzyme. This protein is not only localized in the mitochondria, but also inside the cytoplasm.

Band-aids for the cell surface

“The mitochondria actively transport coenzyme Q to the cell surface to protect cells from cell death. It is as if the mitochondria deliver band-aids to the surface to protect the cell”, says Deshwal.

“This again shows that mitochondria are not only important as an energy supplier for our cells, but also play crucial regulatory roles.”

In the long term, the researchers hope that a precise understanding of this transport process will enable Coenzyme Q to be delivered into the cells of affected patients and thus provide a new therapeutic approach for diseases such as Leigh syndrome.

Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7

Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis.

Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood.

Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis.

Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane.

While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis.

A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth.

Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.

How Ketamine Acts as Antidepressant in Chronic Pain

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Summary: Chronic pain in mice activates Tiam1 in pyramidal neurons in the anterior cingulate cortex, increasing the number of dendritic spines and inducing synaptic plasticity. Ketamine’s antidepressant effect in chronic pain is mediated by the drug blocking Tiam1-dependent maladaptive synaptic plasticity in ACC neurons.

Source: University of Alabama at Birmingham

Chronic pain often leads to depression, which increases suffering and is clinically difficult to treat. Now, for the first time, researchers have uncovered the underlying mechanism that drives those depressive systems, according to a study published in The Journal of Clinical Investigation.

The mechanism acts to cause hypersensitivity in a part of the brain called the anterior cingulate cortex, or ACC, and knowledge of this mechanism identifies a potential therapeutic target for the treatment of chronic pain-induced depression, say Lingyong Li, Ph.D., and Kimberley Tolias, Ph.D., co-leaders of the research.

“Chronic pain is a major, unmet health issue that impacts the quality of life,” said Li, an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine. “Unfortunately, patients suffering from chronic pain have limited effective treatment options.”

The research focused on a protein called Tiam1, which modulates the activity of other proteins that help build or unbuild the cytoskeletons of cells. Specifically, the research teams of Li and Tolias, a professor at Baylor College of Medicine, Houston, Texas, found that chronic pain in a mouse model leads to an activated Tiam1 in ACC pyramidal neurons, resulting in an increased number of spines on the neural dendrites. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons.

This higher spine density increased the number of connections, and the strength of those connections, between neurons, a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with depression in the mouse model. Reversing the number and strength of connections in the model, by using an antagonist of Tiam1, relieved the mice of depression and diminished hypersensitivity of the neurons.

The ACC was already known as a critical hub for comorbid depressive symptoms in the brain. To investigate the mechanism for those symptoms, the team led by Li and Tolias first showed that Tiam1 in the ACC was activated in two mouse models of chronic pain with depressive or anxiety-like behaviors, as compared to controls.

To show that Tiam1 in the ACC modulates chronic pain-induced depressive-like behaviors, the researchers used molecular scissors to delete Tiam1 from the forebrain excitatory neurons of the mice. These mice were viable, and fertile, and displayed no gross alterations, and they still showed hypersensitivity to chronic pain. Strikingly, however, these Tiam1 conditional knockout mice did not display depressive- or anxiety-like behaviors in five different tests that gauge depression or anxiety.

When researchers specifically deleted Tiam1 from ACC neurons, they found the same results as the broader forebrain deletion. Thus, Tiam1 expressed in ACC neurons appears to specifically mediate chronic pain-induced depressive-like behaviors.

Other studies have established that an underlying cause of stress-induced depression and anxiety disorders is alterations in synaptic connections in brain regions involved in mood regulation, including the prefrontal cortex, the hippocampus and the amygdala.

Li and Tolias found similar changes in dendritic neurons in the ACC for chronic pain-induced depressive-like behavior — they saw a significant increase in dendritic spine density and signs of increased cytoskeleton building.

This was accompanied by increased NMDA receptor proteins and increased amplitudes of NMDA currents in the ACC neurons, both associated with hyperactivity.

These maladaptive changes were not seen in the Tiam1-knockout mice.

This shows a man holding his back in pain
This higher spine density increased the number of connections, and the strength of those connections, between neurons, a change known as synaptic plasticity.

Researchers further showed that inhibiting Tiam1 signaling with a known inhibitor alleviated the chronic pain-induced depressive-like behaviors, without reducing the chronic pain hypersensitivity itself. The inhibition also normalized dendritic spine density, cytoskeleton building, NMDA receptor protein levels and NMDA current amplitudes.

Ketamine is a drug known to produce rapid and sustained antidepressant-like effects in chronic pain-induced depression, without decreasing sensory hypersensitivity. However, its mechanism is not fully understood. Li, Tolias and colleagues showed that ketamine’s sustained antidepressant-like effects in chronic pain are mediated, at least in part, by ketamine’s blocking the Tiam1-dependent, maladaptive synaptic plasticity in the mouse ACC neurons.

“Our work demonstrates the critical role Tiam1 plays in the pathophysiology of chronic pain-induced mood dysregulation and the sustained antidepressant-like effects of ketamine, revealing it as a potential therapeutic target for the treatment of comorbid mood disorders in chronic pain,” Li said.

Abstract

TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain

Chronic pain often leads to depression, increasing patient suffering and worsening prognosis. While hyperactivity of the anterior cingulate cortex (ACC) appears to be critically involved, the molecular mechanisms underlying comorbid depressive symptoms in chronic pain remain elusive. T cell lymphoma invasion and metastasis 1 (Tiam1) is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendrite, spine, and synapse development during brain development.

Here, we show that Tiam1 orchestrates synaptic structural and functional plasticity in ACC neurons via actin cytoskeleton reorganization and synaptic N-methyl-d-aspartate receptor (NMDAR) stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain–induced depressive-like behaviors.

Notably, administration of low-dose ketamine, an NMDAR antagonist emerging as a promising treatment for chronic pain and depression, induces sustained antidepressant-like effects in mouse models of chronic pain by blocking Tiam1-mediated maladaptive synaptic plasticity in ACC neurons.

Our results reveal Tiam1 as a critical factor in the pathophysiology of chronic pain–induced depressive-like behaviors and the sustained antidepressant-like effects of ketamine.

Magnesium: What You Need to Know About This Important Micronutrient

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Certain at-risk groups may need to take a supplement. (Ekaterina_Minaeva/Shutterstock)

Certain at-risk groups may need to take a supplement.

There’s been a lot of chatter on social media over the past few months about the importance of magnesium supplements. Many suggest that symptoms such as trouble sleeping, tense muscles, and low energy are all signs you’re deficient and should be taking a magnesium supplement.

As it turns out, many of us probably are somewhat deficient in magnesium. According to research, most aren’t consuming the recommended amount of magnesium of 300 to 420 mg daily to support our body’s needs. According to a paper published in Open Heart, it’s also estimated that in developed countries, between 10–30 percent of the population has a slight magnesium deficiency.

Magnesium is one of the many micronutrients the body requires to remain healthy.

It’s essential for helping more than 300 enzymes carry out numerous chemical processes in the body, including those that produce proteins, support strong bones, control blood sugar and blood pressure, and maintain healthy muscles and nerves. Magnesium also acts as an electrical conductor that helps the heart beat and contract muscles.

Considering how important magnesium is for the body, if you aren’t getting enough, it can eventually lead to a range of health problems. But even though most of us are probably somewhat deficient in magnesium, that doesn’t mean you need to reach for supplements to make sure you’re getting enough. In fact, with the right planning, most of us can get all the magnesium we need from the foods we eat.

Signs of a Deficiency

According to the Open Heart paper, most people with a magnesium deficiency are undiagnosed because magnesium levels in the blood don’t accurately reflect how much magnesium is actually stored in our cells—not to mention that signs your magnesium levels are low only become obvious by the time you have a deficiency. Symptoms include weakness, loss of appetite, fatigue, nausea, and vomiting. But the symptoms you have and their severity will depend on just how low your magnesium levels are. Left unchecked, a magnesium deficiency is associated with an increased risk of certain chronic illnesses, including cardiovascular disease, osteoporosis, type 2 diabetes, migraine, and Alzheimer’s disease.

While anyone can develop a magnesium deficiency, certain groups are more at risk than others—including children and adolescents, older people, and postmenopausal women.

Conditions such as celiac disease and inflammatory bowel syndrome, which make it difficult for the body to absorb nutrients, may make you more prone to magnesium deficiency—even with a healthy diet. People with type 2 diabetes and alcoholics are also more likely to have low magnesium levels.

Healthy,Food,Nutrition,Dieting,Concept.,Assortment,Of,High,Magnesium,Sources.
Magnesium has many important functions in the body.

Furthermore, the vast majority of people in developed countries are at risk of a magnesium deficiency due to chronic illnesses, certain prescription drugs (such as diuretics and antibiotics, which deplete magnesium levels), declining magnesium contents in crops, and diets high in processed foods.

You Can Get Enough in Your Diet

Given the many problems that low magnesium levels can cause, it’s important to make sure you’re getting enough in your diet.

The recommended amount of magnesium a person should aim to consume daily will depend on their age and health. But in general, men aged 19–51 should get between 400–420 mg daily, while women should aim for 310–320 mg.

Although fruit and vegetables now contain less magnesium than they did 50 years ago—and processing removes around 80 percent of this mineral from foods, it’s still possible to get all the magnesium you need in your diet if you plan carefully. Foods such as nuts, seeds, whole grains, beans, green leafy vegetables (such as kale or broccoli), milk, yogurt, and fortified foods all contain plenty of magnesium. One ounce of almonds alone contains 20 percent of the daily magnesium requirements of adults.

While most of us will be able to get all the magnesium we need from the foods we eat, certain groups (such as older adults) and those with certain health conditions may need to take a magnesium supplement. But it’s important to speak with your doctor before starting supplements.

While magnesium supplements are safe in their suggested dosages, it’s important to only take the recommended amount. Taking too much can cause certain side effects, including diarrhea, low mood, and low blood pressure. It’s also vital that those with kidney disease do not take them unless they have been prescribed.

Magnesium can also alter the effectiveness of several medications, including some common antibiotics, diuretics, and heart medications, alongside over-the-counter antacids and laxatives. This is why it’s important to consult a doctor before starting magnesium supplements.

Magnesium supplements aren’t a quick fix. While they may be necessary at times, they won’t address the root causes of your deficiency, such as certain health conditions that may be contributing to low levels. This is why it’s important to focus on maintaining a healthy lifestyle, which includes exercise, good sleep, and eating a balanced diet. Not to mention that vitamins and minerals are better absorbed by the body when they come from whole foods.

Ultra-Processed Foods May Be Linked to Increased Risk of Cancer

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Summary: High consumption of ultra-processed foods, including soda, chips, and some white bread products, was associated with an increased risk of developing and dying from certain kinds of cancer, including brain cancer.

Source: Imperial College London

Higher consumption of ultra-processed foods may be linked to an increased risk of developing and dying from cancer, an Imperial College London-led observational study suggests.

Researchers from Imperial’s School of Public Health have produced the most comprehensive assessment to date of the association between ultra-processed foods and the risk of developing cancers.

Ultra-processed foods are food items which have been heavily processed during their production, such as fizzy drinks, mass-produced packaged breads, many ready meals and most breakfast cereals.

Ultra-processed foods are often relatively cheap, convenient, and heavily marketed, often as healthy options. But these foods are also generally higher in salt, fat, sugar, and contain artificial additives. It is now well documented that they are linked with a range of poor health outcomes including obesity, type 2 diabetes and cardiovascular disease.

The first UK study of its kind used UK Biobank records to collect information on the diets of 200,000 middle-aged adult participants. Researchers monitored participants’ health over a 10-year period, looking at the risk of developing any cancer overall as well as the specific risk of developing 34 types of cancer. They also looked at the risk of people dying from cancer.

The study found that higher consumption of ultra-processed foods was associated with a greater risk of developing cancer overall, and specifically with ovarian and brain cancers. It was also associated with an increased risk of dying from cancer, most notably with ovarian and breast cancers.

For every 10 percent increase in ultra-processed food in a person’s diet, there was an increased incidence of 2 percent for cancer overall, and a 19 percent increase for ovarian cancer specifically.

Each 10 percent increase in ultra-processed food consumption was also associated with increased mortality for cancer overall by 6 percent, alongside a 16 percent increase for breast cancer and a 30 percent increase for ovarian cancer.

These links remained after adjusting for a range of socio-economic, behavioral and dietary factors, such as smoking status, physical activity and body mass index (BMI).

The Imperial team carried out the study, which is published in eClinicalMedicine, in collaboration with researchers from the International Agency for Research on Cancer (IARC), University of São Paulo, and NOVA University Lisbon.

Previous research from the team reported the levels of consumption of ultra-processed foods in the UK, which are the highest in Europe for both adults and children. The team also found that higher consumption of ultra-processed foods was associated with a greater risk of developing obesity and type 2 diabetes in UK adults, and a greater weight gain in UK children extending from childhood to young adulthood.

Dr. Eszter Vamos, lead senior author for the study, from Imperial College London’s School of Public Health, said, “This study adds to the growing evidence that ultra-processed foods are likely to negatively impact our health including our risk for cancer. Given the high levels of consumption in UK adults and children, this has important implications for future health outcomes.

“Although our study cannot prove causation, other available evidence shows that reducing ultra-processed foods in our diet could provide important health benefits. Further research is needed to confirm these findings and understand the best public health strategies to reduce the widespread presence and harms of ultra-processed foods in our diet.”

Dr. Kiara Chang, first author for the study, from Imperial College London’s School of Public Health, said, “The average person in the UK consumes more than half of their daily energy intake from ultra-processed foods.

“This is exceptionally high and concerning as ultra-processed foods are produced with industrially derived ingredients and often use food additives to adjust color, flavor, consistency, texture, or extend shelf life.

This shows chips
The study found that higher consumption of ultra-processed foods was associated with a greater risk of developing cancer overall, and specifically with ovarian and brain cancers.

“Our bodies may not react the same way to these ultra-processed ingredients and additives as they do to fresh and nutritious minimally processed foods. However, ultra-processed foods are everywhere and highly marketed with cheap price and attractive packaging to promote consumption. This shows our food environment needs urgent reform to protect the population from ultra-processed foods.”

The World Health Organization and the United Nations’ Food and Agriculture Organization has previously recommended restricting ultra-processed foods as part of a healthy sustainable diet.

There are ongoing efforts to reduce ultra-processed food consumption around the world, with countries such as Brazil, France and Canada updating their national dietary guidelines with recommendations to limit such foods. Brazil has also banned the marketing of ultra-processed foods in schools. There are currently no similar measures to tackle ultra-processed foods in the UK.

Dr. Chang added, “We need clear front of pack warning labels for ultra-processed foods to aid consumer choices, and our sugar tax should be extended to cover ultra-processed fizzy drinks, fruit-based and milk-based drinks, as well as other ultra-processed products.

“Lower income households are particularly vulnerable to these cheap and unhealthy ultra-processed foods. Minimally processed and freshly prepared meals should be subsidized to ensure everyone has access to healthy, nutritious and affordable options.”

The researchers note that their study is observational, so does not show a causal link between ultra-processed foods and cancer due to the observational nature of the research. More work is needed in this area to establish a causal link.

Beta-Blocker Use Associated With Lower Rates of Violence

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Summary: Beta-blockers, a class of drugs commonly used to treat hypertension and cardiovascular disorders, appear to reduce aggressive and violent behaviors, and can reduce suicidal behaviors.

Source: PLOS

Reductions in violence are seen in individuals using Beta adrenergic-blocking agents (β-blockers) compared with periods that they are not taking the medication, in a study published January 31st in the open access journal PLOS Medicine. 

If the findings are confirmed by other studies, β-blockers could be considered as a way to manage aggression and hostility in individuals with psychiatric conditions.

β-blockers are used to treat hypertension, angina and acute cardiovascular events, heart failure and arrhythmias as well as, migraine, symptoms of hyperthyroidism and glaucoma.

They are often used for anxiety and have been suggested for clinical depression and aggression, but evidence is conflicting. They have been linked to an increased risk of suicidal behavior though evidence is inconclusive.

Seena Fazel of the University of Oxford, UK, and colleagues at the Karolinska Institute in Sweden investigated psychiatric and behavioral outcomes: hospitalizations for psychiatric disorders; suicidal behavior and deaths from suicide; and charges of violent crime.

They compared 1.4 million β-blocker users in Sweden to themselves during medicated and non-medicated periods over an eight-year period from 2006-2013.

Periods on β-blocker treatment were associated with a 13% lower risk of being charged with a violent crime by the police, which remained consistent across the analyses. Additionally, an 8% lower risk of hospitalization due to a psychiatric disorder was reported as well as an 8% increased association of being treated for suicidal behavior.

However, these associations varied depending on psychiatric diagnosis, past psychiatric problems, as well as the severity and type of the cardiac condition the β-blockers were being used to treat.

Previous research has linked severe cardiac events to an increased risk of depression and suicide, and these results might suggest that the psychological distress and other disabilities associated with serious cardiac problems, rather than the β-blocker treatment, increases the risk of serious psychiatric events. In secondary analyses, associations with hospitalization were lower for major depressive but not for anxiety disorders.

This shows a man's fist
If these confirm the results of this study, β-blockers could be considered to manage aggression and violence in some individuals.

In order to understand the role of β-blockers in the management of aggression and violence, further studies including randomized controlled trials are needed. If these confirm the results of this study, β-blockers could be considered to manage aggression and violence in some individuals.

Fazel adds, “In a real-world study of 1.4 million persons, β-blockers were associated with reduced violent criminal charges in individuals with psychiatric disorders. Repurposing their use to manage aggression and violence could improve patient outcomes.”

Background

β-blockers are widely used for treating cardiac conditions and are suggested for the treatment of anxiety and aggression, although research is conflicting and limited by methodological problems. In addition, β-blockers have been associated with precipitating other psychiatric disorders and suicidal behaviour, but findings are mixed. We aimed to examine associations between β-blockers and psychiatric and behavioural outcomes in a large population-based cohort in Sweden.

Methods and findings

We conducted a population-based longitudinal cohort study using Swedish nationwide high-quality healthcare, mortality, and crime registers. We included 1,400,766 individuals aged 15 years or older who had collected β-blocker prescriptions and followed them for 8 years between 2006 and 2013. We linked register data on dispensed β-blocker prescriptions with main outcomes, hospitalisations for psychiatric disorders (not including self-injurious behaviour or suicide attempts), suicidal behaviour (including deaths from suicide), and charges of violent crime.

We applied within-individual Cox proportional hazards regression to compare periods on treatment with periods off treatment within each individual in order to reduce possible confounding by indication, as this model inherently adjusts for all stable confounders (e.g., genetics and health history).

We also adjusted for age as a time-varying covariate. In further analyses, we adjusted by stated indications, prevalent users, cardiac severity, psychiatric and crime history, individual β-blockers, β-blocker selectivity and solubility, and use of other medications. In the cohort, 86.8% (n = 1,215,247) were 50 years and over, and 52.2% (n = 731,322) were women.

During the study period, 6.9% (n = 96,801) of the β-blocker users were hospitalised for a psychiatric disorder, 0.7% (n = 9,960) presented with suicidal behaviour, and 0.7% (n = 9,405) were charged with a violent crime.

There was heterogeneity in the direction of results; within-individual analyses showed that periods of β-blocker treatment were associated with reduced hazards of psychiatric hospitalisations (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.91 to 0.93, p < 0.001), charges of violent crime (HR: 0.87, 95% CI: 0.81 to 0.93, p < 0.001), and increased hazards of suicidal behaviour (HR: 1.08, 95% CI: 1.02 to 1.15, p = 0.012). After stratifying by diagnosis, reduced associations with psychiatric hospitalisations during β-blocker treatment were mainly driven by lower hospitalisation rates due to depressive (HR: 0.92, 95% CI: 0.89 to 0.96, p < 0.001) and psychotic disorders (HR: 0.89, 95% CI: 0.85 to 0.93, p < 0.001).

Reduced associations with violent charges remained in most sensitivity analyses, while associations with psychiatric hospitalisations and suicidal behaviour were inconsistent. Limitations include that the within-individual model does not account for confounders that could change during treatment, unless measured and adjusted for in the model.

Conclusions

In this population-wide study, we found no consistent links between β-blockers and psychiatric outcomes. However, β-blockers were associated with reductions in violence, which remained in sensitivity analyses. The use of β-blockers to manage aggression and violence could be investigated further.

Do Sleep Medications Increase Your Chances of Dementia?

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Summary: People who frequently take sleeping medications are 79% more likely to develop dementia than those who never use sleeping pills to aid their rest.

Source: UCSF

A new study shows that sleep medications increase the risk of dementia in whites. But the type and quantity of the medication may be factors in explaining the higher risk.  
 
It follows previous work that shows Blacks have a higher likelihood than whites of developing Alzheimer’s, the most common type of dementia, and that they have different risk factors and disease manifestation.  
 
The final corrected draft of the study publishes in the Journal of Alzheimer’s Disease on Jan. 31, 2023.  
 
In the study, approximately 3,000 older adults without dementia, who lived outside of nursing homes, were enrolled in the Health, Aging and Body Composition study and followed over an average duration of nine years. Their average age was 74; 42% were Black and 58% were white.  
 
During the study, 20% developed dementia. White participants who “often” or “almost always” took sleep medications had a 79% higher chance of developing dementia compared to those who “never” or “rarely” used them. Among Black participants – whose consumption of sleep aids was markedly lower – frequent users had a similar likelihood of developing dementia than those who abstained or rarely used the medications.  
 
Higher-Income Blacks May Be Less Likely to Get Dementia 
 
“Differences may be attributed to socio-economic status” said first author Yue Leng, PhD, of the UCSF Department of Psychiatry and Behavioral Sciences and Weill Institute for Neurosciences.

“Black participants who have access to sleep medications might be a select group with high socio-economic status and, thus, greater cognitive reserve, making them less susceptible to dementia. 
 
“It’s also possible that some sleep medications were associated with a higher risk of dementia than others.” 
 
The researchers found that whites, at 7.7%, were three times as likely as Blacks, at 2.7%, to take sleep medications often, five to 15 times a month, or almost always, 16 times a month to daily. Whites were almost twice as likely to use benzodiazepines, like Halcion, Dalmane and Restoril, prescribed for chronic insomnia.  
 
Whites were also 10 times as likely to take trazodone, an antidepressant known by the trade names of Desyrel and Oleptro, that may also be prescribed as a sleep aid. And they were more than seven times as likely to take “Z-drugs,” such as Ambien, a so-called sedative-hypnotic. 

This shows a brain
While future study may offer clarity on the cognitive risks or rewards of sleep medications and the role that race may play, patients with poor sleep should hesitate before considering medications, according to Leng.

While future study may offer clarity on the cognitive risks or rewards of sleep medications and the role that race may play, patients with poor sleep should hesitate before considering medications, according to Leng.   
 
“The first step is to determine what kind of sleep issues patients are dealing with. A sleep test may be required if sleep apnea is a possibility,” she said. “If insomnia is diagnosed, cognitive behavioral therapy for insomnia (CBT-i) is the first-line treatment. If medication is to be used, melatonin might be a safer option, but we need more evidence to understand its long-term impact on health.”