Tag: side effects

Categories : Cardiovascular DiseaseTags :

Statins do not Cause the Majority of Their Listed Side Effects

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Photo by Towfiqu Barbhuiya on Unsplash

Statins do not cause the majority of the conditions that have been listed in their package leaflets, including memory loss, depression, sleep disturbance, and erectile and sexual dysfunction, according to the most comprehensive review of possible side effects. The study was led by researchers at Oxford Population Health and published in The Lancet.

Cardiovascular disease results in around 20 million deaths worldwide and causes around a quarter of all deaths in the UK. Statins are highly effective drugs that lower LDL (‘bad’) cholesterol levels and have been repeatedly proven to reduce the risk of cardiovascular disease. However, there have been concerns about possible side effects.

The researchers gathered data from 23 large-scale randomised studies from the Cholesterol Treatment Trialists’ Collaboration: 123 940 participants in 19 large-scale clinical trials comparing the effects of statin therapies against a placebo, and 30 724 participants in four trials comparing more intensive versus less intensive statin therapy.

They found similar numbers of reports for those taking the statins and those taking the placebo for almost all the conditions listed in package leaflets as possible side effects. For example, each year, the number of reports of cognitive or memory impairment was 0.2% in those taking the statins, but also 0.2% in those taking the placebo. This means that while people may notice these problems whilst taking statins, there is no good evidence that they are caused by the statin.

Key findings:

  • There was no statistically significant excess risk from statin therapy for almost all the conditions listed in package leaflets as potential side effects.
  • Taking a statin did not cause any meaningful excess of memory loss or dementia, depression, sleep disturbance, erectile dysfunction, weight gain, nausea, fatigue or headache, and many other conditions.
  • There was a small increase in risk (about 0.1%) for liver blood test abnormalities. However, there was no increase in liver disease such as hepatitis or liver failure, indicating that the liver blood test changes do not typically lead to more serious liver problems.

Christina Reith, Associate Professor at Oxford Population Health and lead author of the study, said: ‘Statins are life-saving drugs used by hundreds of millions of people over the past 30 years. However, concerns about the safety of statins have deterred many people who are at risk of severe disability or death from a heart attack or stroke. Our study provides reassurance that, for most people, the risk of side effects is greatly outweighed by the benefits of statins.’

Previous work by the same researchers established that most muscle symptoms are not caused by statins; statin therapy caused muscle symptoms in only 1% of people during the first year of treatment with no excess thereafter. It has also shown that statins can cause a small increase in blood sugar levels, so people already at high risk may develop diabetes sooner.

Professor Bryan Williams, Chief Scientific and Medical Officer at the British Heart Foundation, said: ‘These findings are hugely important and provide authoritative, evidence-based reassurance for patients. Statins are lifesaving drugs, which have been proven to protect against heart attacks and strokes. Among the large number of patients assessed in this well-conducted analysis, only four side effects out of 66 were found to have any association with taking statins, and only in a very small proportion of patients.

‘This evidence is a much-needed counter to the misinformation around statins and should help prevent unnecessary deaths from cardiovascular disease. Recognising which side effects might genuinely be associated with statins is also important as it will help doctors make decisions about when to use alternative treatments.’

Professor Sir Rory Collins, Emeritus Professor of Medicine and Epidemiology at Oxford Population Health and senior author of the paper said: ‘Statin product labels list certain adverse health outcomes as potential treatment-related effects based mainly on information from non-randomised studies which may be subject to bias. We brought together all of the information from large randomised trials to assess the evidence reliably. Now that we know that statins do not cause the majority of side effects listed in package leaflets, statin information requires rapid revision to help patients and doctors make better-informed health decisions.’

All of the trials included in the analyses were large-scale (involving at least 1000 participants) and tracked patient outcomes for a median of nearly five years. The trials were double-blind, meaning that neither the trial participants nor those managing the participants or leading the study knew who was receiving which treatment, to avoid potential biases due to knowledge of treatment allocation. The list of possible side effects was compiled from those listed for the five most commonly prescribed statins.

The paper, ‘Assessment of adverse effects attributed to statin therapy in product labels: a meta-analysis of double-blind randomised controlled trials,’ is published in The Lancet.

Source: Oxford University

Categories : Cardiovascular DiseaseTags :

Calcium Leak is the Culprit Behind Statin Muscle Pains

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Photo by Kampus Production

Many people stop taking cholesterol-lowering statins because they experience muscle aches, weakness, and fatigue. A new study by Columbia researchers now suggests that at least for some people, the side effects arise when statins bind to a protein in muscle cells and cause a leak of calcium ions inside the cells.

“It is unlikely that this explanation applies to everyone who experiences muscular side effects with statins, but even if it explains a small subset, that’s a lot of people we could help if we can resolve the issue,” says Andrew Marks, chair of the Department of Physiology and Cellular Biophysics at the Vagelos College of Physicians and Surgeons.

About 10% of adults taking statins experience these muscular side effects.

“I’ve had patients who’ve been prescribed statins, and they refused to take them because of the side effects. It’s the most common reason patients quit statins, and it’s a very real problem that needs a solution,” says Marks.

Electron microscopy pinpoints statin-muscle interaction

Statins’ muscular side effects have puzzled researchers since the drugs hit the market in the late 80s. Statins are designed to lower cholesterol by binding to an enzyme involved in cholesterol synthesis. But statins also bind to other “off-target” molecules, and some previous studies have suggested that muscular side effects occur when statins bind to a specific protein in muscle.

With cryo-electron microscopy, a technique that can image molecules down to individual atoms, the researchers of the new study documented this binding and uncovered the precise details of the interaction.

Simvastatin molecules bind to two locations on a muscle protein, called the ryanodine receptor, which opens a channel in the receptor. The flow of calcium through the open channel could explain the muscular side effects of statins.

The images revealed two locations on the muscle protein, called the ryanodine receptor, where a statin called simvastatin binds, opening a channel in the receptor and allowing calcium to flow through.

The calcium leak could explain the muscular side effects of statins, Marks says, by weakening the muscle directly or by activating enzymes that degrade muscle tissue.

Building a better statin

The new images also suggest that statins could be redesigned so they do not bind the ryanodine receptor but retain their cholesterol-lowering ability.

Marks is now collaborating with chemists to create such a statin.

Plugging the calcium leak could be another option: Statin-induced calcium leaks in mice can be closed, the researchers showed, with an experimental drug developed in the Marks lab for other conditions involving calcium leaks.

These drugs are currently being tested in people with rare muscle diseases. If it shows efficacy in those patients, we can test it in statin-induced myopathies,” Marks says

Source: Columbia University Irving Medical Center

Categories : Neurodegenerative DiseasesTags :

Alzheimer’s Drug Lecanemab Well Tolerated in Real-world Use

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Side effects of lecanemab are manageable, study finds

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The Food and Drug Administration’s approval in 2023 of lecanemab – a novel Alzheimer’s therapy shown in clinical trials to modestly slow disease progression – was met with enthusiasm by many in the field as it represented the first medication of its kind able to influence the disease. But side effects of brain swelling and bleeding emerged during clinical trials that have left some patients and physicians hesitant about the treatment. [Especially considering its $26 500 per year cost – Ed.]

Medications can have somewhat different effects once they are released into the real world with broader demographics. Researchers at Washington University School of Medicine in St. Louis set out to study the adverse events associated with lecanemab treatment in their clinic patients and found that significant adverse events were rare and manageable.

Consistent with the results from carefully controlled clinical trials, researchers found that only 1% of patients experienced severe side effects that required hospitalisation. Patients in the earliest stage of Alzheimer’s with very mild symptoms experienced the lowest risk of complications, the researchers found, helping to inform patients and clinicians as they navigate discussions about the treatment’s risks.

The retrospective study, published in JAMA Neurology, focused on 234 patients with very mild or mild Alzheimer’s disease who received lecanemab infusions in the Memory Diagnostic Center at WashU Medicine, a clinic that specialises in treating patients with dementia.

“This new class of medications for early symptomatic Alzheimer’s is the only approved treatment that influences disease progression,” said Barbara Joy Snider, MD, PhD, a professor of neurology and co-senior author on the study. “But fear surrounding the drug’s potential side effects can lead to treatment delays. Our study shows that WashU Medicine’s outpatient clinic has the infrastructure and expertise to safely administer and care for patients on lecanemab, including the few who may experience severe side effects, leading the way for more clinics to safely administer the drug to patients.”

Lecanemab is an antibody therapy that clears amyloid plaque proteins, extending independent living by 10 months, according to a recent study led by WashU Medicine researchers. Because amyloid accumulation is the first step in the disease, doctors recommend the drug for people in the early stage of Alzheimer’s, with very mild or mild symptoms. The researchers found that only 1.8% of patients with very mild Alzheimer’s symptoms developed any adverse symptoms from treatment compared with 27% of patients with mild Alzheimer’s.

“Patients with the very mildest symptoms of Alzheimer’s will likely have the greatest benefit and the least risk of adverse events from treatment,” said Snider, who led clinical trials for lecanemab at WashU Medicine. “Hesitation and avoidance can lead patients to delay treatment, which in turn increase the risk of side effects. We hope the results help reframe the conversations between physicians and patients about the medication’s risks.”

Hesitation around lecanemab stems from a side effect known as amyloid-related imaging abnormalities, or ARIA. The abnormalities, which typically only affect a very small area of the brain, appear on brain scans and indicate swelling or bleeding. In clinical trials of lecanemab, 12.6% of participants experienced ARIA and most cases were asymptomatic and resolved without intervention. A small percentage (2.8%) experienced symptoms such as headaches, confusion, nausea and dizziness. Occasional deaths have been linked to lecanemab in an estimated 0.2% of patients treated.

The Memory Diagnostic Center began treating patients with lecanemab in 2023 after the drug received full FDA approval. Patients receive the medication via infusions every two weeks in infusion centers. As part of each patient’s care, WashU Medicine doctors regularly gather sophisticated imaging to monitor the brain, which can detect bleeding and swelling with great sensitivity. Lecanemab is discontinued in patients with symptoms from ARIA or significant ARIA without symptoms, and the rare patients with severe ARIA are treated with steroids in the hospital.

In looking back on their patients’ outcomes, the authors found the extent of side effects aligned with those of the trials – most of the clinic’s cases of ARIA were asymptomatic and only discovered on sensitive brain scans used to monitor brain changes. Of the 11 patients who experienced symptoms from ARIA, the effects largely resolved within a few months and no patients died.

“Most patients on lecanemab tolerate the drug well,” said Suzanne Schindler, MD, PhD, an associate professor of neurology and a co-senior author of the study. “This report may help patients and providers better understand the risks of treatment, which are lower in patients with very mild symptoms of Alzheimer’s.”

Source: WashU Medicine

Categories : Cardiovascular DiseaseTags :

Possible Link Between Medication and Unexpected Blood Clots

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Thrombophilia. Credit: Scientific Animations CC4.0.

Why do medications that are supposed to help patients with chronic inflammatory diseases sometimes lead to blood clots? This is one of the questions that a team of researchers from Aarhus University has sought to answer in a study that has just been published in the journal Inflammopharmacology.

The study suggests that disturbances in the JAK-STAT signalling pathway, an important communication pathway in the body, may contribute to this side effect.

“In the study, we uncover the potential links between components of the JAK-STAK signalling pathway, blood markers in patients with blood clots, and the genetic factors that contribute to the risk of blood clots in patients. This helps improve our understanding of why we see an increased risk of blood clots when using JAK inhibitors,” explains Stine Rabech Haysen, former medical student at the Department of Biomedicine at Aarhus University, who is the first author of the publication. 

The potential of the study

In the study, researchers used publicly available data from a number of published studies about patients with blood clots and compared them with a healthy control group.

They found no direct genetic explanation, but they did find a statistically significant enrichment of genes that are subject to regulatory control of the JAK-STAT signalling pathway among genes whose expression is altered in patients with blood clots.

“Although we cannot draw definitive conclusions about the mechanistic link between the use of JAK inhibitors and the risk of blood clots, our study demonstrates the potential of using data mining to identify and shed light on possible mechanisms of drug side effects,” says one of the study’s senior authors, associate professor at the Department of Biomedicine Per Qvist.

What does this mean for patients?

Although JAK inhibitors rarely lead to blood clots, it’s important to understand the mechanism behind them so that the risk can be reduced.

“For the average person, our study means that we’re getting closer to understanding why some drugs can have dangerous side effects like blood clots. And going forward, our method could help identify and prevent serious side effects, potentially making drug treatment safer,” explains the other senior author of the study, associate professor at the Department of Biomedicine Tue Wenzel Kragstrup.

The researchers will now test the method on other types of medication to see if it can be used to detect side effects more widely.

Source: Aarhus University

Categories : Mental Health Metabolic DisordersTags :

What’s the Mechanism behind Behavioural Side Effects of GLP1RAs?

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Photo by I Yunmai on Unsplash

Glucagon-like peptide 1 receptor agonists (GLP1RA) – medications for type 2 diabetes and obesity that have recently been making headlines due to a rise in popularity as weight loss agents – have been linked with behavioural side effects. A large population-based analysis in Diabetes, Obesity and Metabolism assessed whether certain genetic variants might help explain these effects.

GLP1RA mimic the GLP-1 hormone in the body that helps control insulin and blood glucose levels and promotes feelings of satiety. GLP-1 binds to GLP1R on cells in the brain and pancreas.

Observational and epidemiological studies have shown that there may be neutral or protective effects of GLP1RAs on mental health symptoms. However, a study based on individuals taking GLP1RA suggests there is increased prescription of anti-depressants when used for treatment of diabetes. Early evidence in animal models suggest GLP1RA may decrease depressive and anxious symptoms, potentially presenting new treatment pathways; however, comparing these studies to human clinical evidence will not be possible for some time.

For the analysis, investigators examined common genetic variants in the GLP1R gene in 408 774 white British, 50 314 white European, 7 667 South Asian, 10 437 multiple ancestry, and 7641 African-Caribbean individuals.

Variants in the GLP1R gene had consistent associations with cardiometabolic traits (body mass index, blood pressure, and type 2 diabetes) across ancestries. GLP1R variants were also linked with risk-taking behavior, mood instability, chronic pain, and anxiety in most ancestries, but the results were less consistent. The genetic variants influencing cardiometabolic traits were separate from those influencing behavioral changes and separate from those influencing expression levels of the GLP1R gene.

The findings suggest that any observed behavioral changes with GLP1RA are likely not acting directly through GLP1R.

“Whilst it is not possible to directly compare genetic findings to the effects of a drug, our results suggest that behavioural changes are unlikely to be a direct result of the GLPRAs. Exactly how these indirect effects are occurring is currently unclear,” said corresponding author Rona J. Strawbridge, PhD, of the University of Glasgow, in the UK.

Source: Wiley

Categories : CancerTags :

Rare Disease Sheds Light on a Side Effect of Immunotherapy

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Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash

A multinational collaboration co-led by the Garvan Institute of Medical Research has uncovered a potential explanation for why some cancer patients receiving a type of immunotherapy called checkpoint inhibitors experience increased susceptibility to common infections.

The findings, published in the journal Immunity, provide new insights into immune responses and reveal a potential approach to preventing the common cancer therapy side effect.

“Immune checkpoint inhibitor therapies have revolutionised cancer treatment by allowing T cells to attack tumours and cancer cells more effectively. But this hasn’t been without side effects – one of which is that approximately 20% of cancer patients undergoing checkpoint inhibitor treatment experience an increased incidence of infections, a phenomenon that was previously poorly understood,” says Professor Stuart Tangye, co-senior author of the study and Head of the Immunology and Immunodeficiency Lab at Garvan.

“Our findings indicate that while checkpoint inhibitors boost anti-cancer immunity, they can also handicap B cells, which are the cells of the immune system that produce antibodies to protect against common infections. This understanding is a critical first step in understanding and reducing the side effects of this cancer treatment on immunity.”

Insights to improve immunotherapy

The researchers focused on the molecule PD-1, which acts as a ‘handbrake’ on the immune system, preventing overactivation of T cells. Checkpoint inhibitor therapies work by releasing this molecular ‘handbrake’ to enhance the immune system’s ability to fight cancer.

The study, which was conducted in collaboration with Rockefeller University in the USA and Kyoto University Graduate School of Medicine in Japan, examined the immune cells of patients with rare cases of genetic deficiency of PD-1, or its binding partner PD-L1, as well as animal models lacking PD-1 signalling. The researchers found that impaired or absent PD-1 activity can significantly reduce the diversity and quality of antibodies produced by memory B cells – the long-lived immune cells that ‘remember’ past infections.

“We found that people born with a deficiency in PD-1 or PD-L1 have reduced diversity in their antibodies and fewer memory B cells, which made it harder to generate high-quality antibodies against common pathogens such as viruses and bacteria,” says Dr Masato Ogishi, first author of the study, from Rockefeller University.

Professor Tangye adds: “This dampening of the generation and quality of memory B cells could explain the increased rates of infection reported in patients with cancer receiving checkpoint inhibitor therapy.”

Co-author Dr Kenji Chamoto, from Kyoto University, says, “PD-1 inhibition has a ‘yin and yang’ nature: it activates anti-tumour immunity but at the same time impedes B-cell immunity. And this duality seems to stem from a conserved mechanism of immune homeostasis.”

New recommendation for clinicians

The researchers say the findings highlight the need for clinicians to monitor B cell function in patients receiving checkpoint inhibitors and point to preventative interventions for those at higher risk of infections.

Co-senior author Dr Stéphanie Boisson-Dupuis, from Rockefeller University, says, “Although PD-1 inhibitors have greatly improved cancer care, our findings indicate that clinicians need to be aware of the potential trade-off between enhanced anti-tumour immunity and impaired antibody-mediated immunity.”

“One potential preventative solution is immunoglobulin replacement therapy (IgRT), an existing treatment used to replace missing antibodies in patients with immunodeficiencies, which could be considered as a preventative measure for cancer patients at higher risk of infections,” she says.

From rare cases to insights to benefit all

 “Studying cases of rare genetic conditions such as PD-1 or PD-L1 deficiency enables us to gain profound insights into how the human immune system normally works, and how our own manipulation of it can affect it. Thanks to these patients, we’ve found an avenue for fine-tuning cancer immunotherapies to maximise benefit while minimising harm,” says Professor Tangye.

Looking ahead, the researchers will explore ways to refine checkpoint inhibitor treatments to maintain their powerful anti-cancer effects while preserving the immune system’s ability to fight infections.

“This research highlights the potential for cancer, genomics and immunology research to inform one another, enabling discoveries that can benefit the broader population,” says Professor Tangye.

Professor Stuart Tangye is a Conjoint Professor at St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney.

Source: Garvan Institute of Medical Research

Categories : Healthcare Politics and RegulationsTags :

SAHPRA Encourages the Safe Use of Medicines and Reporting of Suspected Side Effects This #MedSafetyWeek

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The South African Health Products Regulatory Authority (SAHPRA) encourages members of the public to always report any suspected side effects they may experience from taking medicines, vaccines and/or using medical devices, to help make medicines safer for everyone.  While humanity benefits greatly from medicines in the treatment of illness and management of certain conditions, medicines may at times cause side effects. However, the risk of side effects and severe harm can be drastically reduced by taking medicines correctly and following the advice of a healthcare practitioner.

SAHPRA, together with over 90 other medicines and health products regulators as well as healthcare organisations globally, is participating in the annual #MedSafetyWeek awareness initiative, which takes place between 4 and 10 November 2024, under the theme “the importance of using medicines in the right way to prevent side effects, and to report side effects when they do occur”.

The awareness initiative is spearheaded by the Uppsala Monitoring Centre under the auspices of the World Health Organisation (WHO) Programme for International Drug Monitoring, a programme whose member organisations work nationally and collaborate internationally to monitor and identify adverse effects of medicines and vaccines, to reduce risks to patients, and to establish worldwide pharmacovigilance standards and systems.

During this #MedSafetyWeek and beyond, SAHPRA is calling upon patients, caregivers and healthcare professionals to utilise its reporting tools to report all suspected side effects and adverse reactions.

SAHPRA Chief Executive Officer, Dr Boitumelo Semete-Makokotlela, indicates that handling and storing as well as taking medicines as directed by a healthcare professional is key in reducing the incidence of adverse reactions. “Research shows that about half of all side effects are preventable. Patient safety is our top priority and during #MedSafetyWeek, we wish to remind patients to take their medicines as instructed and healthcare professionals to review therapies as well as each patient’s unique health conditions before prescribing or dispensing medicines,” says Dr Semete-Makokotlela.

SAHPRA calls upon the South African public and healthcare professionals to use either the MedSafety App or the eReporting portal both accessible on the SAHPRA website to report suspected side effects from health products. All reports are assessed and examined by SAHPRA to determine the correct steps to protect medicine users in South Africa from harm. The purpose is to gain better knowledge about known side effects and to discover new ones. This can result in warnings and changes to how a medicine is used. SAHPRA’s MedSafety App and eReporting portal can be used for reporting suspected adverse drug reactions from medicines, vaccines, herbal products, biological medicines and any quality issues relating to health products.

Source: SAHPRA

Categories : CancerTags :

Chemo Drug may Cause Significant Hearing Loss in Longtime Cancer Survivors   

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Photo by Brett Sayles

An interdisciplinary study led by researchers at the University of South Florida and Indiana University has uncovered significant findings on the long-term effects of one of the most common forms of chemotherapy on cancer survivors.

Published in JAMA Oncology, the study tracked a cohort of testicular cancer survivors who received cisplatin-based chemotherapy. The team followed the patients for an average of 14 years, revealing that 78% experience significant difficulties in everyday listening situations, negatively impacting their quality of life. This collaborative research is the first to measure real-world listening challenges and hearing loss progression in cancer survivors over a long period of time.

“It’s important that we understand the real-world effects of patients’ sensory problems and if we can understand that, then we can develop better therapeutic strategies and preventive measures to improve the long-term quality of life for cancer survivors,” said Robert Frisina, distinguished university professor and chair of the USF Department of Medical Engineering.

Cisplatin is commonly used in chemotherapy treatments for a variety of cancers, including bladder, lung, neck and testicular. It is administered intravenously and affects various parts of the body. However, the ears are particularly vulnerable as they have little ability to filter out the drug, causing it to become trapped. This leads to inflammation and the destruction of sensory cells that are critical for coding sound, causing permanent hearing loss that can progressively get worse well after cisplatin treatments are completed.

Lead author Victoria Sanchez, associate professor in the USF Health Department of Otolaryngology Head & Neck Surgery, said that despite the known risks, there’s a nationwide lack of routine hearing assessments for patients undergoing chemotherapy. “Most patients still do not get their hearing tested prior to, during or after chemotherapy. Our study highlights the need for regular auditory evaluations to manage and mitigate long-term hearing damage.”

The research team found higher doses of cisplatin led to more severe and progressing hearing loss, especially in patients with risk factors, such as high blood pressure and poor cardiovascular health. They also experienced increased difficulty hearing in common environments, such as a loud restaurant.

“It will be critically important to follow these patients for life. Their current median age is only 48 years, and eventually they will enter the years at which age-related hearing loss also begins to develop,” said Dr. Lois B. Travis, Lawrence H. Einhorn Professor of Cancer Research at Indiana University School of Medicine and a researcher at the IU Melvin and Bren Simon Comprehensive Cancer Center. This research is part of The Platinum Study, an ongoing research effort led by Dr. Travis and funded by the National Cancer Institute to study cisplatin-treated testicular cancer survivors.

The hope is that this study will inspire further investigation into alternative chemotherapeutic protocols and preventive measures, such as FDA-approved drugs to prevent or reduce hearing loss.

“This research gives oncologists the information they need to explore alternative treatment plans that could reduce the long-term side effects, such as altering the dosages and timing of the cisplatin in the treatment, when that could be an appropriate option,” Frisina said.

Innovative solutions, such as Pedmark, a new FDA-approved injection that mitigates cisplatin-induced hearing loss in children, represent promising steps forward, according to Frisina.

“We want to protect our hearing or treat a hearing loss if hearing damage occurs,” Sanchez said. “Hearing allows us to connect to the world we love. Staying connected through conversations with family and friends, enjoyment of music and entertainment, staying safe and finding pleasure in our vibrant surroundings. Promoting optimal hearing for overall wellness is essential for healthy living.”

According to the American Cancer Society, in addition to cisplatin, other platinum chemotherapy drugs, such as carboplatin, cause damage to the cochlea in the inner ear and lead to hearing loss. The risk of damage is greater with higher doses of chemotherapy.

Source: University of San Francisco

Categories : Diet and Nutrition Mental HealthTags :

Can a Ketogenic Diet Treat Serious Mental Illnesses?

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Photo by Inzmam Khan: https://www.pexels.com/photo/man-in-black-shirt-and-gray-denim-pants-sitting-on-gray-padded-bench-1134204/

Antipsychotic medications for serious mental illness like schizophrenia or bipolar disorder often causes metabolic side effects such as insulin resistance and obesity, leading some patients to discontinue the treatment.

Now, a pilot study led by Stanford Medicine researchers has found that a ketogenic diet not only restores metabolic health in these patients as they continue their medications, but it further improves their psychiatric conditions. The results, published in Psychiatry Research, suggest that a dietary intervention can be a powerful aid in treating mental illness.

“It’s very promising and very encouraging that you can take back control of your illness in some way, aside from the usual standard of care,” said Shebani Sethi, MD, associate professor of psychiatry and behavioral sciences and the first author of the new paper.

The senior author of the paper is Laura Saslow, PhD, associate professor of health behavior and biological sciences at the University of Michigan.

Making the connection

Sethi, who is board certified in obesity and psychiatry, remembers when she first noticed the connection. As a medical student working in an obesity clinic, she saw a patient with treatment-resistant schizophrenia whose auditory hallucinations quieted on a ketogenic diet.

That prompted her to dig into the medical literature. There were only a few, decades-old case reports on using the ketogenic diet to treat schizophrenia, but there was a long track record of success in using ketogenic diets to treat epileptic seizures.

“The ketogenic diet has been proven to be effective for treatment-resistant epileptic seizures by reducing the excitability of neurons in the brain,” Sethi said. “We thought it would be worth exploring this treatment in psychiatric conditions.”

A few years later, Sethi coined the term metabolic psychiatry, a new field that approaches mental health from an energy conversion perspective.

Meat and vegetables

In the four-month pilot trial, Sethi’s team followed 21 adult participants who were diagnosed with schizophrenia or bipolar disorder, taking antipsychotic medications, and had a metabolic abnormality – such as weight gain, insulin resistance, hypertriglyceridaemia, dyslipidaemia or impaired glucose tolerance. The participants were instructed to follow a ketogenic diet, with approximately 10% of the calories from carbohydrates, 30% from protein and 60% from fat. They were not told to count calories.

“The focus of eating is on whole non-processed foods including protein and non-starchy vegetables, and not restricting fats,” said Sethi, who shared keto-friendly meal ideas with the participants. They were also given keto cookbooks and access to a health coach.

The research team tracked how well the participants followed the diet through weekly measures of blood ketone levels, which are produced when the body breaks down fat instead of glucose for energy. By the end of the trial, 14 patients had been fully adherent, six were semi-adherent and only one was non-adherent.

Physical and mental improvement

The participants underwent a variety of psychiatric and metabolic assessments throughout the trial.

Before the trial, 29% of the participants met the criteria for metabolic syndrome, defined as having at least three of five conditions: abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure and elevated fasting glucose levels. After four months on a ketogenic diet, none of the participants had metabolic syndrome.

On average, the participants lost 10% of their body weight; reduced their waist circumference by 11% percent; and had lower blood pressure, body mass index, triglycerides, blood sugar levels and insulin resistance.

“We’re seeing huge changes,” Sethi said. “Even if you’re on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, the insulin resistance. I think that’s very encouraging for patients.”

The psychiatric benefits were also striking. On average, the participants improved 31% on a psychiatrist rating of mental illness known as the clinical global impressions scale, with three-quarters of the group showing clinically meaningful improvement. Overall, the participants also reported better sleep and greater life satisfaction.

“The participants reported improvements in their energy, sleep, mood and quality of life,” Sethi said. “They feel healthier and more hopeful.”

The researchers were impressed that most of the participants stuck with the diet. “We saw more benefit with the adherent group compared with the semi-adherent group, indicating a potential dose-response relationship,” Sethi said.

Alternative fuel for the brain

There is increasing evidence that psychiatric diseases such as schizophrenia and bipolar disorder stem from metabolic deficits in the brain, which affect the excitability of neurons, Sethi said. The researchers hypothesise that just as a ketogenic diet improves the rest of the body’s metabolism, it also improves the brain’s metabolism.

“Anything that improves metabolic health in general is probably going to improve brain health anyway,” Sethi said. “But the ketogenic diet can provide ketones as an alternative fuel to glucose for a brain with energy dysfunction.”

Likely there are multiple mechanisms at work, she added, and the main purpose of the small pilot trial is to help researchers detect signals that will guide the design of larger, more robust studies.

As a physician, Sethi cares for many patients with both serious mental illness and obesity or metabolic syndrome, but few studies have focused on this undertreated population. She is founder and director of the metabolic psychiatry clinic at Stanford Medicine.

“Many of my patients suffer from both illnesses, so my desire was to see if metabolic interventions could help them,” she said. “They are seeking more help. They are looking to just feel better.”

Source: Stanford Medicine

Categories : Cancer Cardiovascular DiseaseTags :

Clues to Ponatinib’s Deadly Side Effects could Make it a Safer Cancer Drug

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Pexels Photo by Freestocksorg

For some leukaemia patients, the only potential chemotherapy option is ponatinib, a drug that also carries a high risk of heart failure. This means that some patients who recover from their cancer will end up dying of heart disease brought on by the cure.

In a new study, researchers from the University of Illinois Chicago and other universities have identified mechanisms that cause ponatinib to harm the heart. They also identified a promising treatment that could reverse this process.

The paper, with senior author Sang Ging Ong, assistant professor of pharmacology and medicine at UIC, is published in Circulation Research. The study is part of a growing field called cardio-oncology that investigates drugs that shrink tumours but can also cause heart problems.

While there are three options of drugs for treating chronic myeloid leukaemia, many patients are resistant to the other two, leaving ponatinib as their only choice.

“These patients have no other options for treatment,” Ong said, despite the concerns about the drug’s side effects.

In fact, ponatinib was pulled from the market for a few months after its introduction in 2012 because of concerns about heart problems.

The researchers were interested in understanding the interaction between ponatinib and the heart cells responsible for contraction.

They discovered that ponatinib damages these cells by activating a process known as the integrated stress response.

The mechanism for this is related to the functioning of a kinase (an enzyme involved in energy transfer) called GCN2.

The researchers found that ponatinib, despite being a kinase inhibitor, actually activates GCN2, which in turn switches on the integrated stress response.

While this response isn’t always a bad thing, normally protecting cells, it can also lead to their death under prolonged stress.

To see if this response was harming the cells, the researchers studied what would happen if they used a small molecule to block the integrated stress response in both cells and in mice during ponatinib treatment.

They found that the treatment helped protect heart cells from the damaging side effects of the drug yet did not diminish ponatinib’s tumour-fighting efficacy.

“It protects the heart but at the same time, it still allows us to kill cancer cells,” Ong said.

More research is needed to know if this protective measure would work well in humans, Ong said.

The mechanisms they identified are important in other cardiac diseases, as well, which could lead to future research on how to protect cells against different conditions.

Source: University of Illinois Chicago