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Is screen time associated with psychosocial symptoms in 5-year-olds?
Janette Niiranen, a researcher in the department of public health solutions at the Finnish Institute for Health and Welfare in Helsinki, and colleagues examined the frequency of electronic media use by 699 preschool children.
They analyzed longitudinal associations between media use at age 18 months and psychosocial symptoms at age 5 years. They also looked at whether media use at age 5 years was associated with the presence of psychosocial symptoms at that time.
The study relied on data collected between 2011 and 2017 as part of the Finnish CHILD-SLEEP longitudinal birth cohort study. Parents reported child media use via questionnaires at age 18 months and age 5 years. Researchers measured psychosocial symptoms at age 5 years using two parent-reported questionnaires: Five-to-Fifteen (FTF) and the Strengths and Difficulties Questionnaire (SDQ).
At age 5 years, a high amount of total screen time – at least 135 minutes per day, representing the 75th percentile of use – was associated with increased likelihood of attention and concentration difficulties, hyperactivity and impulsivity, emotional internalizing and externalizing symptoms, and conduct problems, the researchers reported. Odds ratios ranged from 1.57 to 2.18. In a model that adjusted for confounding factors, internalizing symptoms was the only symptom significantly associated with screen time (OR, 2.01).
In a longitudinal analysis, increased media use at 18 months was associated with peer problems at age 5 years (OR, 1.59).
Compared with program viewing, electronic game playing at age 5 years appeared to be associated with fewer psychosocial risks, the researchers noted. In an unadjusted model, a high amount of game playing was associated with hyperactivity, whereas program viewing was associated with a broad range of symptoms.
Use of electronic media beyond recommended amounts was common.
“The results of our study show that 95% of preschool aged children exceed the recommended daily e-media use of 1 hour,” the authors wrote.
No causal link
Amy Orben, DPhil, a researcher at Emmanuel College and the MRC Cognition and Brain Sciences Unit, University of Cambridge (England) highlighted limitations of the research.
The study is “purely observational” and does not “establish a causal link between time spent on electronic media and developmental outcomes in small children,” Dr. Orben said. Factors that may influence how much time a child spends on electronic media – such as whether both parents work and where a child lives – may also influence psychosocial symptoms.
“This means that an association can exist even if no causal link is present,” Dr. Orben said. Furthermore, the statistically significant associations found in the study “could well be noise,” she added.
As the study authors note, associations between screen time and children’s psychosocial well-being “may be bidirectional,” commented Karalyn Kinsella, MD, a pediatrician in private practice in Cheshire, Conn.
“There is no way to tell if the families who allow more screen time are doing that because the child already has some psychosocial issues like hyperactivity or dysregulation, and they are using media to calm them,” Dr. Kinsella said. “Or perhaps parents do not have the ability to interact as much with the child due to lack of time/work.” The lack of interaction, rather than electronic media use, may interfere with typical development.
“The end result is still pertinent, as we know children learn through play and social interaction,” Dr. Kinsella added. “I did find it interesting that electronic game playing when played with friends or family was less of a risk.”
Brainstorming alternatives
Libby Matile Milkovich, MD, a developmental pediatrician at Children’s Mercy Hospital, Kansas City, Mo., sees family electronic media use as an environmental factor that has significant variability for each patient.
“The need for electronic media to connect to others, to access entertainment, and to learn intensified with the pandemic,” Dr. Milkovich said. “In practice, after I identify concerning media habits, I try to help families create alternatives to their current habits as opposed to being prescriptive and saying to stop or limit media use. ... An alternative may not be limiting screen time but may be changing to more appropriate media content or sharing the media as a family activity.”
Seeing media use in the clinic can provide useful information and opportunities for discussion, Dr. Milkovich noted.
“When I see parents in the clinic room using media to calm a toddler or using their own media, these are great opportunities to open the door to brainstorming alternatives,” Dr. Milkovich said. “Commonly, family media use comes up when children have difficulty sleeping or disruptive behaviors related to media use, but I would challenge medical providers to think about problematic media use in all chief complaints where a behavioral component exists like toileting and feeding.”
The research was supported by the Academy of Finland, the Signe and Ane Gyllenberg Foundation, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, the Finnish Cultural Foundation, and the Tampere University Hospital and Doctors’ Association in Tampere. The study authors, Dr. Milkovich, Dr. Orben, and Dr. Kinsella had no relevant financial disclosures. Dr. Kinsella serves on the Pediatric News editorial advisory board.
Janette Niiranen, a researcher in the department of public health solutions at the Finnish Institute for Health and Welfare in Helsinki, and colleagues examined the frequency of electronic media use by 699 preschool children.
They analyzed longitudinal associations between media use at age 18 months and psychosocial symptoms at age 5 years. They also looked at whether media use at age 5 years was associated with the presence of psychosocial symptoms at that time.
The study relied on data collected between 2011 and 2017 as part of the Finnish CHILD-SLEEP longitudinal birth cohort study. Parents reported child media use via questionnaires at age 18 months and age 5 years. Researchers measured psychosocial symptoms at age 5 years using two parent-reported questionnaires: Five-to-Fifteen (FTF) and the Strengths and Difficulties Questionnaire (SDQ).
At age 5 years, a high amount of total screen time – at least 135 minutes per day, representing the 75th percentile of use – was associated with increased likelihood of attention and concentration difficulties, hyperactivity and impulsivity, emotional internalizing and externalizing symptoms, and conduct problems, the researchers reported. Odds ratios ranged from 1.57 to 2.18. In a model that adjusted for confounding factors, internalizing symptoms was the only symptom significantly associated with screen time (OR, 2.01).
In a longitudinal analysis, increased media use at 18 months was associated with peer problems at age 5 years (OR, 1.59).
Compared with program viewing, electronic game playing at age 5 years appeared to be associated with fewer psychosocial risks, the researchers noted. In an unadjusted model, a high amount of game playing was associated with hyperactivity, whereas program viewing was associated with a broad range of symptoms.
Use of electronic media beyond recommended amounts was common.
“The results of our study show that 95% of preschool aged children exceed the recommended daily e-media use of 1 hour,” the authors wrote.
No causal link
Amy Orben, DPhil, a researcher at Emmanuel College and the MRC Cognition and Brain Sciences Unit, University of Cambridge (England) highlighted limitations of the research.
The study is “purely observational” and does not “establish a causal link between time spent on electronic media and developmental outcomes in small children,” Dr. Orben said. Factors that may influence how much time a child spends on electronic media – such as whether both parents work and where a child lives – may also influence psychosocial symptoms.
“This means that an association can exist even if no causal link is present,” Dr. Orben said. Furthermore, the statistically significant associations found in the study “could well be noise,” she added.
As the study authors note, associations between screen time and children’s psychosocial well-being “may be bidirectional,” commented Karalyn Kinsella, MD, a pediatrician in private practice in Cheshire, Conn.
“There is no way to tell if the families who allow more screen time are doing that because the child already has some psychosocial issues like hyperactivity or dysregulation, and they are using media to calm them,” Dr. Kinsella said. “Or perhaps parents do not have the ability to interact as much with the child due to lack of time/work.” The lack of interaction, rather than electronic media use, may interfere with typical development.
“The end result is still pertinent, as we know children learn through play and social interaction,” Dr. Kinsella added. “I did find it interesting that electronic game playing when played with friends or family was less of a risk.”
Brainstorming alternatives
Libby Matile Milkovich, MD, a developmental pediatrician at Children’s Mercy Hospital, Kansas City, Mo., sees family electronic media use as an environmental factor that has significant variability for each patient.
“The need for electronic media to connect to others, to access entertainment, and to learn intensified with the pandemic,” Dr. Milkovich said. “In practice, after I identify concerning media habits, I try to help families create alternatives to their current habits as opposed to being prescriptive and saying to stop or limit media use. ... An alternative may not be limiting screen time but may be changing to more appropriate media content or sharing the media as a family activity.”
Seeing media use in the clinic can provide useful information and opportunities for discussion, Dr. Milkovich noted.
“When I see parents in the clinic room using media to calm a toddler or using their own media, these are great opportunities to open the door to brainstorming alternatives,” Dr. Milkovich said. “Commonly, family media use comes up when children have difficulty sleeping or disruptive behaviors related to media use, but I would challenge medical providers to think about problematic media use in all chief complaints where a behavioral component exists like toileting and feeding.”
The research was supported by the Academy of Finland, the Signe and Ane Gyllenberg Foundation, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, the Finnish Cultural Foundation, and the Tampere University Hospital and Doctors’ Association in Tampere. The study authors, Dr. Milkovich, Dr. Orben, and Dr. Kinsella had no relevant financial disclosures. Dr. Kinsella serves on the Pediatric News editorial advisory board.
Janette Niiranen, a researcher in the department of public health solutions at the Finnish Institute for Health and Welfare in Helsinki, and colleagues examined the frequency of electronic media use by 699 preschool children.
They analyzed longitudinal associations between media use at age 18 months and psychosocial symptoms at age 5 years. They also looked at whether media use at age 5 years was associated with the presence of psychosocial symptoms at that time.
The study relied on data collected between 2011 and 2017 as part of the Finnish CHILD-SLEEP longitudinal birth cohort study. Parents reported child media use via questionnaires at age 18 months and age 5 years. Researchers measured psychosocial symptoms at age 5 years using two parent-reported questionnaires: Five-to-Fifteen (FTF) and the Strengths and Difficulties Questionnaire (SDQ).
At age 5 years, a high amount of total screen time – at least 135 minutes per day, representing the 75th percentile of use – was associated with increased likelihood of attention and concentration difficulties, hyperactivity and impulsivity, emotional internalizing and externalizing symptoms, and conduct problems, the researchers reported. Odds ratios ranged from 1.57 to 2.18. In a model that adjusted for confounding factors, internalizing symptoms was the only symptom significantly associated with screen time (OR, 2.01).
In a longitudinal analysis, increased media use at 18 months was associated with peer problems at age 5 years (OR, 1.59).
Compared with program viewing, electronic game playing at age 5 years appeared to be associated with fewer psychosocial risks, the researchers noted. In an unadjusted model, a high amount of game playing was associated with hyperactivity, whereas program viewing was associated with a broad range of symptoms.
Use of electronic media beyond recommended amounts was common.
“The results of our study show that 95% of preschool aged children exceed the recommended daily e-media use of 1 hour,” the authors wrote.
No causal link
Amy Orben, DPhil, a researcher at Emmanuel College and the MRC Cognition and Brain Sciences Unit, University of Cambridge (England) highlighted limitations of the research.
The study is “purely observational” and does not “establish a causal link between time spent on electronic media and developmental outcomes in small children,” Dr. Orben said. Factors that may influence how much time a child spends on electronic media – such as whether both parents work and where a child lives – may also influence psychosocial symptoms.
“This means that an association can exist even if no causal link is present,” Dr. Orben said. Furthermore, the statistically significant associations found in the study “could well be noise,” she added.
As the study authors note, associations between screen time and children’s psychosocial well-being “may be bidirectional,” commented Karalyn Kinsella, MD, a pediatrician in private practice in Cheshire, Conn.
“There is no way to tell if the families who allow more screen time are doing that because the child already has some psychosocial issues like hyperactivity or dysregulation, and they are using media to calm them,” Dr. Kinsella said. “Or perhaps parents do not have the ability to interact as much with the child due to lack of time/work.” The lack of interaction, rather than electronic media use, may interfere with typical development.
“The end result is still pertinent, as we know children learn through play and social interaction,” Dr. Kinsella added. “I did find it interesting that electronic game playing when played with friends or family was less of a risk.”
Brainstorming alternatives
Libby Matile Milkovich, MD, a developmental pediatrician at Children’s Mercy Hospital, Kansas City, Mo., sees family electronic media use as an environmental factor that has significant variability for each patient.
“The need for electronic media to connect to others, to access entertainment, and to learn intensified with the pandemic,” Dr. Milkovich said. “In practice, after I identify concerning media habits, I try to help families create alternatives to their current habits as opposed to being prescriptive and saying to stop or limit media use. ... An alternative may not be limiting screen time but may be changing to more appropriate media content or sharing the media as a family activity.”
Seeing media use in the clinic can provide useful information and opportunities for discussion, Dr. Milkovich noted.
“When I see parents in the clinic room using media to calm a toddler or using their own media, these are great opportunities to open the door to brainstorming alternatives,” Dr. Milkovich said. “Commonly, family media use comes up when children have difficulty sleeping or disruptive behaviors related to media use, but I would challenge medical providers to think about problematic media use in all chief complaints where a behavioral component exists like toileting and feeding.”
The research was supported by the Academy of Finland, the Signe and Ane Gyllenberg Foundation, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, the Finnish Cultural Foundation, and the Tampere University Hospital and Doctors’ Association in Tampere. The study authors, Dr. Milkovich, Dr. Orben, and Dr. Kinsella had no relevant financial disclosures. Dr. Kinsella serves on the Pediatric News editorial advisory board.
FROM BMJ OPEN
An international trip: Global experts weigh in on psychedelics
In 1967, when the United Nations Convention on Drugs classified psychedelics as schedule I substances, it effectively ended research into these agents as potential therapeutics for psychiatric disorders.
Psychedelics induce altered states of perception. They bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include psilocybin, which is derived from “magic mushrooms”; N,N-dimethyltryptamine (DMT), a component of ayahuasca and mescaline (peyote cactus); and the synthesized compound D-lysergic acid diethylamide (LSD). Other agents, such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, are sometimes considered psychedelics as well.
Before they were classified as schedule I agents, psychedelics had been shown to be particularly beneficial for patients with treatment-resistant conditions, including depression and posttraumatic stress disorder (PTSD), especially when administered in a supportive, therapeutic setting.
Now, after a hiatus of almost 50 years, there is renewed global interest in the scientific investigation of psychedelics. The attention was spurred in part by several exploratory studies of DMT in humans conducted in the 1990s by Rick Strassman, MD, and colleagues at the University of New Mexico, Albuquerque.
Around the same time, Franz X. Vollenweider, MD, and colleagues at the University of Zürich began researching psilocybin and its effects on human behavior. However, it was a 2006 study of psilocybin by a team of researchers at Johns Hopkins University, Baltimore, that is widely cited as a catalyst for the current renaissance in psychedelic research.
To provide a broad-based, international perspective on these agents, including their current legal status and indications, treatment regimens, safety, efficacy, and future considerations, this news organization interviewed nine expert researchers from around the globe.
Global legal status
In most, if not all, countries, it is still illegal to prescribe psychedelics in other than a research setting.
They can be used in research, but only with approval from the Food and Drug Administration under licensure from the Drug Enforcement Administration.
France lists all synthetic hallucinogens and hallucinogenic mushrooms as narcotic. As a result, possession, use, transportation, and collection are subject to criminal sanctions.
In France, NMDA antagonists such as ketamine and nitrous oxide are regarded as psychedelic molecules and can be used off label for various conditions or as part of research protocols authorized by the French public health code.
Although psychedelics are illegal under Mexican law, they are commonly used in indigenous communities as part of traditional rituals.
“The line between traditional consumption and psychedelic tourism is very thin,” José J. Mendoza Velásquez, MD, professor in the department of mental health, National Autonomous University of Mexico, Mexico City, said in an interview.
Psychedelics also are illegal in the United Kingdom, although government agencies have recently allowed research groups to investigate them. Psychedelics cannot be prescribed in Germany, Spain, or Italy. However, investigators in these countries can request permission from regulatory agencies to conduct research.
Brazil allows psychedelic substances to be researched, particularly ayahuasca, which has long traditional and religious roots in the country.
However, as in other countries, none of the classic psychedelics is regulated for therapeutic use in Brazil. It is widely expected that the Brazilian government will approve MDMA sometime in 2024 for use in the treatment of PTSD.
Potential indications
Psychedelics are currently under investigation as potential treatments for major depression, treatment-resistant depression, PTSD, pain management, and anorexia, among other conditions.
In France, Florian Ferreri, MD, PhD, at Hospital Saint-Antoine, Paris, is researching ketamine for treatment of patients with suicidal crisis/ideation and treatment-resistant depression.
In the United Kingdom, David Nutt, FMedSci, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and his team have conducted studies of the use of psychedelics in conjunction with psychological support for patients with treatment-resistant depression, and they are currently exploring their use in the treatment of anorexia and various pain syndromes.
In Germany, Gerhard Gründer, MD, professor of psychiatry at the Central Institute of Mental Health, in Mannheim, noted that a study of psilocybin for treatment-resistant depression will launch sometime in 2021. In Italy, current research is focusing on MDMA and ketamine in the laboratory environment and in animal models for treating depression and drug abuse.
Researcher Helen Dolengevich-Segal, MD, a psychiatrist at Hospital Universitario del Henares, Madrid, noted that although research on esketamine for the treatment of severe depressive disorder with suicidal thoughts is underway, there is very limited published research from that country into the use of classic psychedelics for various psychiatric disorders, given their current illegal status.
Mexico’s Dr. Velásquez noted that although he is prohibited from prescribing psychedelics, he does have patients who take the drugs to augment medical treatment. For instance, he said, his patients frequently use psilocybin to help with severe depression, pain, and insomnia.
Environment is key
Most researchers agree that for psychedelics to be safe and effective, patient education and administration in a controlled environment by experienced clinicians are key to successful treatment.
Roland R. Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins, said that ongoing U.S. psilocybin research – primarily in major depressive disorder and psychological distress associated with life-threatening illness, drug addiction, anorexia nervosa, obsessive-compulsive disorder, and headache – generally includes one or two treatment sessions, each of which lasts 6-8 hours.
Such sessions typically involve oral administration of a moderately high dose of a psychedelic under what he characterizes as “psychologically supported conditions.”
For Dr. Griffiths, there are serious potential risks associated with the use of psilocybin and other psychedelics outside such environments.
“When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others, including life-threatening risk,” he said.
Dr. Gründer agreed.
“At the moment, I cannot imagine that you would go to the pharmacy with a prescription for psilocybin and get yourself a pill and then take it in a quiet little room,” he said. Dr. Dolengevich-Segal and Dr. Velásquez echoed these sentiments, noting the optimal location for administration is one that is quiet and secure and where patients feel safe.
Luís Fernando Tófoli, MD, PhD, professor of medical psychology and psychiatry at the University of Campinas, and Eduardo Schenberg, PhD, founder and CEO of Instituto Phaneros in São Paulo, Brazil, said more research is needed to determine the optimal therapeutic environment for individual agents.
“Most studies have a low number of participants (around 20 or 30), especially in neuroimaging, with high unblinding rates,” Dr. Schenberg said. “Therefore, novel methodological approaches are also necessary, as these substances do not easily fit into the traditional pharmacology epistemic model.”
Risks, abuse potential
The abuse potential of psychedelics is an ongoing concern for the public, researchers, and regulators, but the consensus among nearly all of these experts is that when administered by medical professionals in controlled settings, these drugs are associated with extremely low risk.
It is recreational use that presents an abuse concern, said Dr. Ferreri, but with the low doses used in psychiatry, the risk is “very limited or even nonexistent.”
Dr. Nutt said the abuse potential of psychedelics is so low that they can be used to treat addiction.
“Functionally, psychedelics are antiaddictive,” Dr. Nutt said. “The fact is, if you take them repeatedly, you develop tolerance, and the effect disappears. You can’t overcome it. But everyone believes they’re addictive because they’re scheduled drugs.”
Dr. Velásquez is something of an outlier. He believes the abuse potential with psychedelics is poorly understood and that some patients may develop tolerance, which is a potential gateway to dependence.
“Such is the case with LSD,” he said, “where this substance also favors tolerance to other psychedelic drugs such as psilocybin.”
Dosing also seems to play a key role in mitigating potential abuse, said Luca Pani, MD, professor of pharmacology and psychiatry at the University of Modena, Italy. Dr. Pani explained that with low doses and microdoses of psychedelics, the potential for abuse is eliminated.
Dr. Nutt, Dr. Pani, and Dr. Ferreri also noted the importance of medical supervision. For instance, said Dr. Ferreri, when administering ketamine, his team closely monitors both mental and physical parameters – heart rate and blood pressure, in particular – because the drug can have hypertensive effects.
Dr. Schenberg noted that ibogaine, a naturally occurring psychedelic frequently used by traditional communities in Africa in rituals and for healing purposes, could cause potentially fatal arrhythmias, so it’s critical that the treatment is administered in a hospital setting that has a cardiac unit.
Dr. Pani said there is a need for more research, especially regarding the molecular mechanisms behind the behavioral effects of low-dose psychedelic therapy and the potential risks of multiple treatments with the drugs.
“Although extensive toxicology has been conducted on a single active dose of psilocybin, which has been proven to be safe, further research is required to understand better the possible health risks, especially in relation to cardiac and lung tissue,” he said.
Psychologically challenging
The experts note that given the relative lack of experience with psychedelic therapy, preparing patients for potential adverse effects is paramount. This is particularly relevant in the research setting and highlights the need for adequate patient screening and aftercare.
Dr. Gründer and Dr. Dolengevich-Segal emphasized the importance of having qualified personnel available in the event that patients experience adverse psychological events during treatment.
For Dr. Gründer, the potential for psilocybin to cause patients to lose control, experience psychotic symptoms, or become paranoid warrants considerable preparation by treating physicians.
Patients occasionally experience fear and anxiety during treatment, though it’s usually short-lived, said Dr. Griffiths. Nevertheless, these experiences may open the door to greater insight. “A number of people report that these psychologically challenging states are a valuable part of the overall experience,” he said.
The situation is similar in Spain, where Dr. Dolengevich-Segal noted that typical treatment regimens have a strong focus on the patient’s experience as a therapeutic tool. As in the United Kingdom and the United States, her team guides patients to what they call a “peak experience,” which allows them to gain a better understanding of the trauma underlying their mental health problems.
Dr. Nutt said that in the United Kingdom, they haven’t seen adverse reactions in patients receiving psychedelic therapy, although sedatives such as benzodiazepines could be used to manage them. He added that at his center, two therapists are present at every treatment session, and all personnel are “trained medics or psychologists.”
Patient education
Preparing and educating patients about the therapy are critical, said Dr. Gründer, especially given the intense response psychedelic treatment often invokes.
Echoing Dr. Gründer, Dr. Tófoli said explaining the nature of psychedelic treatment to potential patients helps ease anxiety.
Dr. Griffiths noted that in the United States, study participants are not only educated about the potential effects of psychedelic agents but also undergo several hours of psychological preparation in advance of their first treatment session and are provided with psychological support after treatment.
There is also a strong emphasis on patient preparation and education in the United Kingdom, where patients meet with therapists before and after treatment. During these posttreatment debriefings, clinicians use the patients’ experience with psychedelics to help them gain insight into the underlying cause of their depression.
Dr. Schenberg noted that at his institution in São Paulo, there are online courses to teach clinicians about psychedelic therapy for psychiatric disorders. Next year, he added, a new training program in MDMA-assisted psychotherapy will begin.
Working out treatment protocols
Treatment protocols for psychedelics vary by agent and indication from country to country. For instance, Dr. Pani noted that current psychedelic research in Italy predominantly focuses more on microdosing, which involves administering 1% of the pharmacologically active dose to a maximum of 100 mcg, in contrast to low dosing or full dosing.
Therapeutic regimens in Brazil, said Dr. Schenberg, also differ by agent but share common elements. For instance, psychedelics are always administered in a research setting, and sessions include concomitant psychotherapy.
In Germany, investigators are working to determine optimal treatment regimen for psilocybin for resistant depression in a randomized three-arm study planned for 2021.
For Mexico’s Dr. Velásquez, treatment regimens are complex and varied. Either way, he said, patients always require long-term follow-up.
With ketamine therapy, Dr. Ferreri said his team administers the drug in 45- to 60-minute intravenous infusion sessions in a hospital room without light or sound stimulation. Regardless of the drug’s immediate effect, he said, the protocol is repeated within a 6-month period.
The question of the duration of treatment effect is important. Dr. Griffiths said research suggests that the positive effects of psilocybin are long lasting and that most individuals report positive changes in mood, attitude, and behavior that endure for months or even years after the session.
“Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experiences of their lives,” said Dr. Griffiths.
Dr. Nutt agreed, noting that a single intense “trip” can improve mood for weeks, months, or even years. Nevertheless, he said, in his experience, approximately three-quarters of patients treated with psychedelics for major depression relapse within 3-9 months.
“Most get better,” he said, “but the majority of depression comes back over a period of months.”
Given the current illegal status of the drugs, he said it’s nearly impossible to provide patients with regular, subsequent treatment with psychedelics over time.
“My suspicion is that you might well have to dose four or five times over a couple of years to get people to escape from very severe depression,” said Dr. Nutt. “The longer they’ve been depressed, the harder it is for them to make a full recovery, because it’s more entrenched in the brain.”
All experts agree that exciting times are ahead for psychedelics as therapeutics for a wide range of psychiatric disorders.
“We can look forward to continued growth and expansion of this research,” said Dr. Griffiths, “including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.”
A version of this article first appeared on Medscape.com.
In 1967, when the United Nations Convention on Drugs classified psychedelics as schedule I substances, it effectively ended research into these agents as potential therapeutics for psychiatric disorders.
Psychedelics induce altered states of perception. They bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include psilocybin, which is derived from “magic mushrooms”; N,N-dimethyltryptamine (DMT), a component of ayahuasca and mescaline (peyote cactus); and the synthesized compound D-lysergic acid diethylamide (LSD). Other agents, such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, are sometimes considered psychedelics as well.
Before they were classified as schedule I agents, psychedelics had been shown to be particularly beneficial for patients with treatment-resistant conditions, including depression and posttraumatic stress disorder (PTSD), especially when administered in a supportive, therapeutic setting.
Now, after a hiatus of almost 50 years, there is renewed global interest in the scientific investigation of psychedelics. The attention was spurred in part by several exploratory studies of DMT in humans conducted in the 1990s by Rick Strassman, MD, and colleagues at the University of New Mexico, Albuquerque.
Around the same time, Franz X. Vollenweider, MD, and colleagues at the University of Zürich began researching psilocybin and its effects on human behavior. However, it was a 2006 study of psilocybin by a team of researchers at Johns Hopkins University, Baltimore, that is widely cited as a catalyst for the current renaissance in psychedelic research.
To provide a broad-based, international perspective on these agents, including their current legal status and indications, treatment regimens, safety, efficacy, and future considerations, this news organization interviewed nine expert researchers from around the globe.
Global legal status
In most, if not all, countries, it is still illegal to prescribe psychedelics in other than a research setting.
They can be used in research, but only with approval from the Food and Drug Administration under licensure from the Drug Enforcement Administration.
France lists all synthetic hallucinogens and hallucinogenic mushrooms as narcotic. As a result, possession, use, transportation, and collection are subject to criminal sanctions.
In France, NMDA antagonists such as ketamine and nitrous oxide are regarded as psychedelic molecules and can be used off label for various conditions or as part of research protocols authorized by the French public health code.
Although psychedelics are illegal under Mexican law, they are commonly used in indigenous communities as part of traditional rituals.
“The line between traditional consumption and psychedelic tourism is very thin,” José J. Mendoza Velásquez, MD, professor in the department of mental health, National Autonomous University of Mexico, Mexico City, said in an interview.
Psychedelics also are illegal in the United Kingdom, although government agencies have recently allowed research groups to investigate them. Psychedelics cannot be prescribed in Germany, Spain, or Italy. However, investigators in these countries can request permission from regulatory agencies to conduct research.
Brazil allows psychedelic substances to be researched, particularly ayahuasca, which has long traditional and religious roots in the country.
However, as in other countries, none of the classic psychedelics is regulated for therapeutic use in Brazil. It is widely expected that the Brazilian government will approve MDMA sometime in 2024 for use in the treatment of PTSD.
Potential indications
Psychedelics are currently under investigation as potential treatments for major depression, treatment-resistant depression, PTSD, pain management, and anorexia, among other conditions.
In France, Florian Ferreri, MD, PhD, at Hospital Saint-Antoine, Paris, is researching ketamine for treatment of patients with suicidal crisis/ideation and treatment-resistant depression.
In the United Kingdom, David Nutt, FMedSci, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and his team have conducted studies of the use of psychedelics in conjunction with psychological support for patients with treatment-resistant depression, and they are currently exploring their use in the treatment of anorexia and various pain syndromes.
In Germany, Gerhard Gründer, MD, professor of psychiatry at the Central Institute of Mental Health, in Mannheim, noted that a study of psilocybin for treatment-resistant depression will launch sometime in 2021. In Italy, current research is focusing on MDMA and ketamine in the laboratory environment and in animal models for treating depression and drug abuse.
Researcher Helen Dolengevich-Segal, MD, a psychiatrist at Hospital Universitario del Henares, Madrid, noted that although research on esketamine for the treatment of severe depressive disorder with suicidal thoughts is underway, there is very limited published research from that country into the use of classic psychedelics for various psychiatric disorders, given their current illegal status.
Mexico’s Dr. Velásquez noted that although he is prohibited from prescribing psychedelics, he does have patients who take the drugs to augment medical treatment. For instance, he said, his patients frequently use psilocybin to help with severe depression, pain, and insomnia.
Environment is key
Most researchers agree that for psychedelics to be safe and effective, patient education and administration in a controlled environment by experienced clinicians are key to successful treatment.
Roland R. Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins, said that ongoing U.S. psilocybin research – primarily in major depressive disorder and psychological distress associated with life-threatening illness, drug addiction, anorexia nervosa, obsessive-compulsive disorder, and headache – generally includes one or two treatment sessions, each of which lasts 6-8 hours.
Such sessions typically involve oral administration of a moderately high dose of a psychedelic under what he characterizes as “psychologically supported conditions.”
For Dr. Griffiths, there are serious potential risks associated with the use of psilocybin and other psychedelics outside such environments.
“When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others, including life-threatening risk,” he said.
Dr. Gründer agreed.
“At the moment, I cannot imagine that you would go to the pharmacy with a prescription for psilocybin and get yourself a pill and then take it in a quiet little room,” he said. Dr. Dolengevich-Segal and Dr. Velásquez echoed these sentiments, noting the optimal location for administration is one that is quiet and secure and where patients feel safe.
Luís Fernando Tófoli, MD, PhD, professor of medical psychology and psychiatry at the University of Campinas, and Eduardo Schenberg, PhD, founder and CEO of Instituto Phaneros in São Paulo, Brazil, said more research is needed to determine the optimal therapeutic environment for individual agents.
“Most studies have a low number of participants (around 20 or 30), especially in neuroimaging, with high unblinding rates,” Dr. Schenberg said. “Therefore, novel methodological approaches are also necessary, as these substances do not easily fit into the traditional pharmacology epistemic model.”
Risks, abuse potential
The abuse potential of psychedelics is an ongoing concern for the public, researchers, and regulators, but the consensus among nearly all of these experts is that when administered by medical professionals in controlled settings, these drugs are associated with extremely low risk.
It is recreational use that presents an abuse concern, said Dr. Ferreri, but with the low doses used in psychiatry, the risk is “very limited or even nonexistent.”
Dr. Nutt said the abuse potential of psychedelics is so low that they can be used to treat addiction.
“Functionally, psychedelics are antiaddictive,” Dr. Nutt said. “The fact is, if you take them repeatedly, you develop tolerance, and the effect disappears. You can’t overcome it. But everyone believes they’re addictive because they’re scheduled drugs.”
Dr. Velásquez is something of an outlier. He believes the abuse potential with psychedelics is poorly understood and that some patients may develop tolerance, which is a potential gateway to dependence.
“Such is the case with LSD,” he said, “where this substance also favors tolerance to other psychedelic drugs such as psilocybin.”
Dosing also seems to play a key role in mitigating potential abuse, said Luca Pani, MD, professor of pharmacology and psychiatry at the University of Modena, Italy. Dr. Pani explained that with low doses and microdoses of psychedelics, the potential for abuse is eliminated.
Dr. Nutt, Dr. Pani, and Dr. Ferreri also noted the importance of medical supervision. For instance, said Dr. Ferreri, when administering ketamine, his team closely monitors both mental and physical parameters – heart rate and blood pressure, in particular – because the drug can have hypertensive effects.
Dr. Schenberg noted that ibogaine, a naturally occurring psychedelic frequently used by traditional communities in Africa in rituals and for healing purposes, could cause potentially fatal arrhythmias, so it’s critical that the treatment is administered in a hospital setting that has a cardiac unit.
Dr. Pani said there is a need for more research, especially regarding the molecular mechanisms behind the behavioral effects of low-dose psychedelic therapy and the potential risks of multiple treatments with the drugs.
“Although extensive toxicology has been conducted on a single active dose of psilocybin, which has been proven to be safe, further research is required to understand better the possible health risks, especially in relation to cardiac and lung tissue,” he said.
Psychologically challenging
The experts note that given the relative lack of experience with psychedelic therapy, preparing patients for potential adverse effects is paramount. This is particularly relevant in the research setting and highlights the need for adequate patient screening and aftercare.
Dr. Gründer and Dr. Dolengevich-Segal emphasized the importance of having qualified personnel available in the event that patients experience adverse psychological events during treatment.
For Dr. Gründer, the potential for psilocybin to cause patients to lose control, experience psychotic symptoms, or become paranoid warrants considerable preparation by treating physicians.
Patients occasionally experience fear and anxiety during treatment, though it’s usually short-lived, said Dr. Griffiths. Nevertheless, these experiences may open the door to greater insight. “A number of people report that these psychologically challenging states are a valuable part of the overall experience,” he said.
The situation is similar in Spain, where Dr. Dolengevich-Segal noted that typical treatment regimens have a strong focus on the patient’s experience as a therapeutic tool. As in the United Kingdom and the United States, her team guides patients to what they call a “peak experience,” which allows them to gain a better understanding of the trauma underlying their mental health problems.
Dr. Nutt said that in the United Kingdom, they haven’t seen adverse reactions in patients receiving psychedelic therapy, although sedatives such as benzodiazepines could be used to manage them. He added that at his center, two therapists are present at every treatment session, and all personnel are “trained medics or psychologists.”
Patient education
Preparing and educating patients about the therapy are critical, said Dr. Gründer, especially given the intense response psychedelic treatment often invokes.
Echoing Dr. Gründer, Dr. Tófoli said explaining the nature of psychedelic treatment to potential patients helps ease anxiety.
Dr. Griffiths noted that in the United States, study participants are not only educated about the potential effects of psychedelic agents but also undergo several hours of psychological preparation in advance of their first treatment session and are provided with psychological support after treatment.
There is also a strong emphasis on patient preparation and education in the United Kingdom, where patients meet with therapists before and after treatment. During these posttreatment debriefings, clinicians use the patients’ experience with psychedelics to help them gain insight into the underlying cause of their depression.
Dr. Schenberg noted that at his institution in São Paulo, there are online courses to teach clinicians about psychedelic therapy for psychiatric disorders. Next year, he added, a new training program in MDMA-assisted psychotherapy will begin.
Working out treatment protocols
Treatment protocols for psychedelics vary by agent and indication from country to country. For instance, Dr. Pani noted that current psychedelic research in Italy predominantly focuses more on microdosing, which involves administering 1% of the pharmacologically active dose to a maximum of 100 mcg, in contrast to low dosing or full dosing.
Therapeutic regimens in Brazil, said Dr. Schenberg, also differ by agent but share common elements. For instance, psychedelics are always administered in a research setting, and sessions include concomitant psychotherapy.
In Germany, investigators are working to determine optimal treatment regimen for psilocybin for resistant depression in a randomized three-arm study planned for 2021.
For Mexico’s Dr. Velásquez, treatment regimens are complex and varied. Either way, he said, patients always require long-term follow-up.
With ketamine therapy, Dr. Ferreri said his team administers the drug in 45- to 60-minute intravenous infusion sessions in a hospital room without light or sound stimulation. Regardless of the drug’s immediate effect, he said, the protocol is repeated within a 6-month period.
The question of the duration of treatment effect is important. Dr. Griffiths said research suggests that the positive effects of psilocybin are long lasting and that most individuals report positive changes in mood, attitude, and behavior that endure for months or even years after the session.
“Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experiences of their lives,” said Dr. Griffiths.
Dr. Nutt agreed, noting that a single intense “trip” can improve mood for weeks, months, or even years. Nevertheless, he said, in his experience, approximately three-quarters of patients treated with psychedelics for major depression relapse within 3-9 months.
“Most get better,” he said, “but the majority of depression comes back over a period of months.”
Given the current illegal status of the drugs, he said it’s nearly impossible to provide patients with regular, subsequent treatment with psychedelics over time.
“My suspicion is that you might well have to dose four or five times over a couple of years to get people to escape from very severe depression,” said Dr. Nutt. “The longer they’ve been depressed, the harder it is for them to make a full recovery, because it’s more entrenched in the brain.”
All experts agree that exciting times are ahead for psychedelics as therapeutics for a wide range of psychiatric disorders.
“We can look forward to continued growth and expansion of this research,” said Dr. Griffiths, “including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.”
A version of this article first appeared on Medscape.com.
In 1967, when the United Nations Convention on Drugs classified psychedelics as schedule I substances, it effectively ended research into these agents as potential therapeutics for psychiatric disorders.
Psychedelics induce altered states of perception. They bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include psilocybin, which is derived from “magic mushrooms”; N,N-dimethyltryptamine (DMT), a component of ayahuasca and mescaline (peyote cactus); and the synthesized compound D-lysergic acid diethylamide (LSD). Other agents, such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, are sometimes considered psychedelics as well.
Before they were classified as schedule I agents, psychedelics had been shown to be particularly beneficial for patients with treatment-resistant conditions, including depression and posttraumatic stress disorder (PTSD), especially when administered in a supportive, therapeutic setting.
Now, after a hiatus of almost 50 years, there is renewed global interest in the scientific investigation of psychedelics. The attention was spurred in part by several exploratory studies of DMT in humans conducted in the 1990s by Rick Strassman, MD, and colleagues at the University of New Mexico, Albuquerque.
Around the same time, Franz X. Vollenweider, MD, and colleagues at the University of Zürich began researching psilocybin and its effects on human behavior. However, it was a 2006 study of psilocybin by a team of researchers at Johns Hopkins University, Baltimore, that is widely cited as a catalyst for the current renaissance in psychedelic research.
To provide a broad-based, international perspective on these agents, including their current legal status and indications, treatment regimens, safety, efficacy, and future considerations, this news organization interviewed nine expert researchers from around the globe.
Global legal status
In most, if not all, countries, it is still illegal to prescribe psychedelics in other than a research setting.
They can be used in research, but only with approval from the Food and Drug Administration under licensure from the Drug Enforcement Administration.
France lists all synthetic hallucinogens and hallucinogenic mushrooms as narcotic. As a result, possession, use, transportation, and collection are subject to criminal sanctions.
In France, NMDA antagonists such as ketamine and nitrous oxide are regarded as psychedelic molecules and can be used off label for various conditions or as part of research protocols authorized by the French public health code.
Although psychedelics are illegal under Mexican law, they are commonly used in indigenous communities as part of traditional rituals.
“The line between traditional consumption and psychedelic tourism is very thin,” José J. Mendoza Velásquez, MD, professor in the department of mental health, National Autonomous University of Mexico, Mexico City, said in an interview.
Psychedelics also are illegal in the United Kingdom, although government agencies have recently allowed research groups to investigate them. Psychedelics cannot be prescribed in Germany, Spain, or Italy. However, investigators in these countries can request permission from regulatory agencies to conduct research.
Brazil allows psychedelic substances to be researched, particularly ayahuasca, which has long traditional and religious roots in the country.
However, as in other countries, none of the classic psychedelics is regulated for therapeutic use in Brazil. It is widely expected that the Brazilian government will approve MDMA sometime in 2024 for use in the treatment of PTSD.
Potential indications
Psychedelics are currently under investigation as potential treatments for major depression, treatment-resistant depression, PTSD, pain management, and anorexia, among other conditions.
In France, Florian Ferreri, MD, PhD, at Hospital Saint-Antoine, Paris, is researching ketamine for treatment of patients with suicidal crisis/ideation and treatment-resistant depression.
In the United Kingdom, David Nutt, FMedSci, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and his team have conducted studies of the use of psychedelics in conjunction with psychological support for patients with treatment-resistant depression, and they are currently exploring their use in the treatment of anorexia and various pain syndromes.
In Germany, Gerhard Gründer, MD, professor of psychiatry at the Central Institute of Mental Health, in Mannheim, noted that a study of psilocybin for treatment-resistant depression will launch sometime in 2021. In Italy, current research is focusing on MDMA and ketamine in the laboratory environment and in animal models for treating depression and drug abuse.
Researcher Helen Dolengevich-Segal, MD, a psychiatrist at Hospital Universitario del Henares, Madrid, noted that although research on esketamine for the treatment of severe depressive disorder with suicidal thoughts is underway, there is very limited published research from that country into the use of classic psychedelics for various psychiatric disorders, given their current illegal status.
Mexico’s Dr. Velásquez noted that although he is prohibited from prescribing psychedelics, he does have patients who take the drugs to augment medical treatment. For instance, he said, his patients frequently use psilocybin to help with severe depression, pain, and insomnia.
Environment is key
Most researchers agree that for psychedelics to be safe and effective, patient education and administration in a controlled environment by experienced clinicians are key to successful treatment.
Roland R. Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins, said that ongoing U.S. psilocybin research – primarily in major depressive disorder and psychological distress associated with life-threatening illness, drug addiction, anorexia nervosa, obsessive-compulsive disorder, and headache – generally includes one or two treatment sessions, each of which lasts 6-8 hours.
Such sessions typically involve oral administration of a moderately high dose of a psychedelic under what he characterizes as “psychologically supported conditions.”
For Dr. Griffiths, there are serious potential risks associated with the use of psilocybin and other psychedelics outside such environments.
“When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others, including life-threatening risk,” he said.
Dr. Gründer agreed.
“At the moment, I cannot imagine that you would go to the pharmacy with a prescription for psilocybin and get yourself a pill and then take it in a quiet little room,” he said. Dr. Dolengevich-Segal and Dr. Velásquez echoed these sentiments, noting the optimal location for administration is one that is quiet and secure and where patients feel safe.
Luís Fernando Tófoli, MD, PhD, professor of medical psychology and psychiatry at the University of Campinas, and Eduardo Schenberg, PhD, founder and CEO of Instituto Phaneros in São Paulo, Brazil, said more research is needed to determine the optimal therapeutic environment for individual agents.
“Most studies have a low number of participants (around 20 or 30), especially in neuroimaging, with high unblinding rates,” Dr. Schenberg said. “Therefore, novel methodological approaches are also necessary, as these substances do not easily fit into the traditional pharmacology epistemic model.”
Risks, abuse potential
The abuse potential of psychedelics is an ongoing concern for the public, researchers, and regulators, but the consensus among nearly all of these experts is that when administered by medical professionals in controlled settings, these drugs are associated with extremely low risk.
It is recreational use that presents an abuse concern, said Dr. Ferreri, but with the low doses used in psychiatry, the risk is “very limited or even nonexistent.”
Dr. Nutt said the abuse potential of psychedelics is so low that they can be used to treat addiction.
“Functionally, psychedelics are antiaddictive,” Dr. Nutt said. “The fact is, if you take them repeatedly, you develop tolerance, and the effect disappears. You can’t overcome it. But everyone believes they’re addictive because they’re scheduled drugs.”
Dr. Velásquez is something of an outlier. He believes the abuse potential with psychedelics is poorly understood and that some patients may develop tolerance, which is a potential gateway to dependence.
“Such is the case with LSD,” he said, “where this substance also favors tolerance to other psychedelic drugs such as psilocybin.”
Dosing also seems to play a key role in mitigating potential abuse, said Luca Pani, MD, professor of pharmacology and psychiatry at the University of Modena, Italy. Dr. Pani explained that with low doses and microdoses of psychedelics, the potential for abuse is eliminated.
Dr. Nutt, Dr. Pani, and Dr. Ferreri also noted the importance of medical supervision. For instance, said Dr. Ferreri, when administering ketamine, his team closely monitors both mental and physical parameters – heart rate and blood pressure, in particular – because the drug can have hypertensive effects.
Dr. Schenberg noted that ibogaine, a naturally occurring psychedelic frequently used by traditional communities in Africa in rituals and for healing purposes, could cause potentially fatal arrhythmias, so it’s critical that the treatment is administered in a hospital setting that has a cardiac unit.
Dr. Pani said there is a need for more research, especially regarding the molecular mechanisms behind the behavioral effects of low-dose psychedelic therapy and the potential risks of multiple treatments with the drugs.
“Although extensive toxicology has been conducted on a single active dose of psilocybin, which has been proven to be safe, further research is required to understand better the possible health risks, especially in relation to cardiac and lung tissue,” he said.
Psychologically challenging
The experts note that given the relative lack of experience with psychedelic therapy, preparing patients for potential adverse effects is paramount. This is particularly relevant in the research setting and highlights the need for adequate patient screening and aftercare.
Dr. Gründer and Dr. Dolengevich-Segal emphasized the importance of having qualified personnel available in the event that patients experience adverse psychological events during treatment.
For Dr. Gründer, the potential for psilocybin to cause patients to lose control, experience psychotic symptoms, or become paranoid warrants considerable preparation by treating physicians.
Patients occasionally experience fear and anxiety during treatment, though it’s usually short-lived, said Dr. Griffiths. Nevertheless, these experiences may open the door to greater insight. “A number of people report that these psychologically challenging states are a valuable part of the overall experience,” he said.
The situation is similar in Spain, where Dr. Dolengevich-Segal noted that typical treatment regimens have a strong focus on the patient’s experience as a therapeutic tool. As in the United Kingdom and the United States, her team guides patients to what they call a “peak experience,” which allows them to gain a better understanding of the trauma underlying their mental health problems.
Dr. Nutt said that in the United Kingdom, they haven’t seen adverse reactions in patients receiving psychedelic therapy, although sedatives such as benzodiazepines could be used to manage them. He added that at his center, two therapists are present at every treatment session, and all personnel are “trained medics or psychologists.”
Patient education
Preparing and educating patients about the therapy are critical, said Dr. Gründer, especially given the intense response psychedelic treatment often invokes.
Echoing Dr. Gründer, Dr. Tófoli said explaining the nature of psychedelic treatment to potential patients helps ease anxiety.
Dr. Griffiths noted that in the United States, study participants are not only educated about the potential effects of psychedelic agents but also undergo several hours of psychological preparation in advance of their first treatment session and are provided with psychological support after treatment.
There is also a strong emphasis on patient preparation and education in the United Kingdom, where patients meet with therapists before and after treatment. During these posttreatment debriefings, clinicians use the patients’ experience with psychedelics to help them gain insight into the underlying cause of their depression.
Dr. Schenberg noted that at his institution in São Paulo, there are online courses to teach clinicians about psychedelic therapy for psychiatric disorders. Next year, he added, a new training program in MDMA-assisted psychotherapy will begin.
Working out treatment protocols
Treatment protocols for psychedelics vary by agent and indication from country to country. For instance, Dr. Pani noted that current psychedelic research in Italy predominantly focuses more on microdosing, which involves administering 1% of the pharmacologically active dose to a maximum of 100 mcg, in contrast to low dosing or full dosing.
Therapeutic regimens in Brazil, said Dr. Schenberg, also differ by agent but share common elements. For instance, psychedelics are always administered in a research setting, and sessions include concomitant psychotherapy.
In Germany, investigators are working to determine optimal treatment regimen for psilocybin for resistant depression in a randomized three-arm study planned for 2021.
For Mexico’s Dr. Velásquez, treatment regimens are complex and varied. Either way, he said, patients always require long-term follow-up.
With ketamine therapy, Dr. Ferreri said his team administers the drug in 45- to 60-minute intravenous infusion sessions in a hospital room without light or sound stimulation. Regardless of the drug’s immediate effect, he said, the protocol is repeated within a 6-month period.
The question of the duration of treatment effect is important. Dr. Griffiths said research suggests that the positive effects of psilocybin are long lasting and that most individuals report positive changes in mood, attitude, and behavior that endure for months or even years after the session.
“Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experiences of their lives,” said Dr. Griffiths.
Dr. Nutt agreed, noting that a single intense “trip” can improve mood for weeks, months, or even years. Nevertheless, he said, in his experience, approximately three-quarters of patients treated with psychedelics for major depression relapse within 3-9 months.
“Most get better,” he said, “but the majority of depression comes back over a period of months.”
Given the current illegal status of the drugs, he said it’s nearly impossible to provide patients with regular, subsequent treatment with psychedelics over time.
“My suspicion is that you might well have to dose four or five times over a couple of years to get people to escape from very severe depression,” said Dr. Nutt. “The longer they’ve been depressed, the harder it is for them to make a full recovery, because it’s more entrenched in the brain.”
All experts agree that exciting times are ahead for psychedelics as therapeutics for a wide range of psychiatric disorders.
“We can look forward to continued growth and expansion of this research,” said Dr. Griffiths, “including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.”
A version of this article first appeared on Medscape.com.
Frailty screening should be routine in endometrial cancer surgery
Endometrial cancer patients should be screened for frailty before hysterectomies, and frail patients should be counseled thoroughly about their increased risk for poor outcomes, according to a review of 144,809 cases in the Nationwide Readmissions Database.
Overall, 1.8% of the women were frail according to the Johns Hopkins Adjusted Clinical Groups (ACG) frailty indicator, which characterizes patients as frail or not based on diagnostic codes in a range of areas, including abnormal weight loss, dementia, urinary or fecal incontinence, difficulty walking, inadequate social support, and other matters.
Frailty was associated with an almost fourfold increased risk of intensive care after surgery; a more than twofold risk of inpatient mortality, and a 59% increased risk of something other than routine discharge to home. Frail patients were 33% more likely to be readmitted within 30 days and 21% more likely to be readmitted within 90 days, and they had a higher risk of dying on readmission. Hospital costs and lengths of stay were higher for frail women, according to the report, which was published online in Gynecologic Oncology.
The findings were adjusted for patient, hospital, and clinical factors, and the readmission outcomes were unchanged when limited to patients who had minimally invasive surgery.
Frailty is a well-known risk factor for poor surgical outcomes, so it “comes as little surprise” that it was associated with worse outcomes in hysterectomies for endometrial cancer. Even so, “frailty is oftentimes not screened for in oncology clinics” leading to “a large number of potentially unrecognized frail patients who are recommended to undergo surgery,” said investigators led by Tiffany Sia, MD, an obstetrics and gynecology resident at Columbia University, New York.
“We believe that each potential patient’s frailty status should be assessed during the preoperative period ... frail patients should be counseled regarding these risks in the perioperative setting,” Dr. Sia said in an interview.
“Researchers and clinicians have adopted the scoring instrument that corresponds best with the data they have available,” but “lack of a widely recognized gold standard or easily utilized diagnostic tool makes frailty rather difficult to formally assess in a clinical setting,” she said.
The investigators found a “surprisingly high rate” of frail patients (82%) who underwent total abdominal hysterectomies compared to less invasive options, with 16.5% undergoing extended procedures. The reason is unknown because stage, tumor grade, and histology – factors that likely influenced decision making – were not captured in the analysis.
However, almost half of the frail subjects were 70 years or older, and increasing age is associated with more aggressive tumor characteristics and worse prognosis.
The team said future research should integrate screening instruments into routine clinic workflow, but there have been a number of roadblocks. Current screening instruments are “cumbersome to use and difficult to implement ... as they typically require measurement of a frailty phenotype such as a timed up-and-go test or grip strength and require numerous patient surveys,” they added.
Proposed screening tools include the Frailty Index, Memorial Sloan Kettering–Frailty Index, Hopkins’ frailty indicator, and the Vulnerable Elders Survey, but no preferred method has emerged, and each scale captures different subpopulations of frailty and differs in its prognostic ability.
There was no external funding, and Dr. Sia didn’t have any disclosures.
Endometrial cancer patients should be screened for frailty before hysterectomies, and frail patients should be counseled thoroughly about their increased risk for poor outcomes, according to a review of 144,809 cases in the Nationwide Readmissions Database.
Overall, 1.8% of the women were frail according to the Johns Hopkins Adjusted Clinical Groups (ACG) frailty indicator, which characterizes patients as frail or not based on diagnostic codes in a range of areas, including abnormal weight loss, dementia, urinary or fecal incontinence, difficulty walking, inadequate social support, and other matters.
Frailty was associated with an almost fourfold increased risk of intensive care after surgery; a more than twofold risk of inpatient mortality, and a 59% increased risk of something other than routine discharge to home. Frail patients were 33% more likely to be readmitted within 30 days and 21% more likely to be readmitted within 90 days, and they had a higher risk of dying on readmission. Hospital costs and lengths of stay were higher for frail women, according to the report, which was published online in Gynecologic Oncology.
The findings were adjusted for patient, hospital, and clinical factors, and the readmission outcomes were unchanged when limited to patients who had minimally invasive surgery.
Frailty is a well-known risk factor for poor surgical outcomes, so it “comes as little surprise” that it was associated with worse outcomes in hysterectomies for endometrial cancer. Even so, “frailty is oftentimes not screened for in oncology clinics” leading to “a large number of potentially unrecognized frail patients who are recommended to undergo surgery,” said investigators led by Tiffany Sia, MD, an obstetrics and gynecology resident at Columbia University, New York.
“We believe that each potential patient’s frailty status should be assessed during the preoperative period ... frail patients should be counseled regarding these risks in the perioperative setting,” Dr. Sia said in an interview.
“Researchers and clinicians have adopted the scoring instrument that corresponds best with the data they have available,” but “lack of a widely recognized gold standard or easily utilized diagnostic tool makes frailty rather difficult to formally assess in a clinical setting,” she said.
The investigators found a “surprisingly high rate” of frail patients (82%) who underwent total abdominal hysterectomies compared to less invasive options, with 16.5% undergoing extended procedures. The reason is unknown because stage, tumor grade, and histology – factors that likely influenced decision making – were not captured in the analysis.
However, almost half of the frail subjects were 70 years or older, and increasing age is associated with more aggressive tumor characteristics and worse prognosis.
The team said future research should integrate screening instruments into routine clinic workflow, but there have been a number of roadblocks. Current screening instruments are “cumbersome to use and difficult to implement ... as they typically require measurement of a frailty phenotype such as a timed up-and-go test or grip strength and require numerous patient surveys,” they added.
Proposed screening tools include the Frailty Index, Memorial Sloan Kettering–Frailty Index, Hopkins’ frailty indicator, and the Vulnerable Elders Survey, but no preferred method has emerged, and each scale captures different subpopulations of frailty and differs in its prognostic ability.
There was no external funding, and Dr. Sia didn’t have any disclosures.
Endometrial cancer patients should be screened for frailty before hysterectomies, and frail patients should be counseled thoroughly about their increased risk for poor outcomes, according to a review of 144,809 cases in the Nationwide Readmissions Database.
Overall, 1.8% of the women were frail according to the Johns Hopkins Adjusted Clinical Groups (ACG) frailty indicator, which characterizes patients as frail or not based on diagnostic codes in a range of areas, including abnormal weight loss, dementia, urinary or fecal incontinence, difficulty walking, inadequate social support, and other matters.
Frailty was associated with an almost fourfold increased risk of intensive care after surgery; a more than twofold risk of inpatient mortality, and a 59% increased risk of something other than routine discharge to home. Frail patients were 33% more likely to be readmitted within 30 days and 21% more likely to be readmitted within 90 days, and they had a higher risk of dying on readmission. Hospital costs and lengths of stay were higher for frail women, according to the report, which was published online in Gynecologic Oncology.
The findings were adjusted for patient, hospital, and clinical factors, and the readmission outcomes were unchanged when limited to patients who had minimally invasive surgery.
Frailty is a well-known risk factor for poor surgical outcomes, so it “comes as little surprise” that it was associated with worse outcomes in hysterectomies for endometrial cancer. Even so, “frailty is oftentimes not screened for in oncology clinics” leading to “a large number of potentially unrecognized frail patients who are recommended to undergo surgery,” said investigators led by Tiffany Sia, MD, an obstetrics and gynecology resident at Columbia University, New York.
“We believe that each potential patient’s frailty status should be assessed during the preoperative period ... frail patients should be counseled regarding these risks in the perioperative setting,” Dr. Sia said in an interview.
“Researchers and clinicians have adopted the scoring instrument that corresponds best with the data they have available,” but “lack of a widely recognized gold standard or easily utilized diagnostic tool makes frailty rather difficult to formally assess in a clinical setting,” she said.
The investigators found a “surprisingly high rate” of frail patients (82%) who underwent total abdominal hysterectomies compared to less invasive options, with 16.5% undergoing extended procedures. The reason is unknown because stage, tumor grade, and histology – factors that likely influenced decision making – were not captured in the analysis.
However, almost half of the frail subjects were 70 years or older, and increasing age is associated with more aggressive tumor characteristics and worse prognosis.
The team said future research should integrate screening instruments into routine clinic workflow, but there have been a number of roadblocks. Current screening instruments are “cumbersome to use and difficult to implement ... as they typically require measurement of a frailty phenotype such as a timed up-and-go test or grip strength and require numerous patient surveys,” they added.
Proposed screening tools include the Frailty Index, Memorial Sloan Kettering–Frailty Index, Hopkins’ frailty indicator, and the Vulnerable Elders Survey, but no preferred method has emerged, and each scale captures different subpopulations of frailty and differs in its prognostic ability.
There was no external funding, and Dr. Sia didn’t have any disclosures.
FROM GYNECOLOGIC ONCOLOGY
Longitudinal associations between income changes and incident CVD
Background: Low income is associated with CVD, although causality remains debated because low income is also associated with depression and negative health behaviors, which can be associated with CVD. For more robust causal inference, changes in income and their association with CVD must be observed.
Study design: Prospective observational cohort study.
Setting: Four U.S. urban centers – Jackson, Miss.; suburbs of Minneapolis; Washington County, Md.; and Forsyth County, N.C.
Synopsis: Among a large cohort of community-dwelling middle-aged adults, this study showed that negative income changes are associated with an increased incidence of CVD. Among 8,989 patients recruited from the four urban centers above, 10% experienced an income drop, 70% did not have a change in income, and 20% experienced an income increase over the first 6 years of the study. Patients were followed for a mean of 17 years, and those who experienced an income drop were found to have a 17% higher risk of incident CVD, whereas those who experienced an income increase had a 14% lower risk of CVD.
The study was limited by difficulties classifying income and its changes; the complicated nature of income, its relationship with other socioeconomic factors, and causation inferences; and the relatively short span over which income was monitored.
Bottom line: Income decrease is associated with an increased risk of incident CVD.
Citation: Wang S et al. Longitudinal associations between income changes and incident cardiovascular disease, the atherosclerosis risk in communities study. JAMA Cardiol. 2019 Oct 9;4(12):1203-12.
Dr. Rupp is a hospitalist and clinical instructor of medicine at the University of Utah, Salt Lake City.
Background: Low income is associated with CVD, although causality remains debated because low income is also associated with depression and negative health behaviors, which can be associated with CVD. For more robust causal inference, changes in income and their association with CVD must be observed.
Study design: Prospective observational cohort study.
Setting: Four U.S. urban centers – Jackson, Miss.; suburbs of Minneapolis; Washington County, Md.; and Forsyth County, N.C.
Synopsis: Among a large cohort of community-dwelling middle-aged adults, this study showed that negative income changes are associated with an increased incidence of CVD. Among 8,989 patients recruited from the four urban centers above, 10% experienced an income drop, 70% did not have a change in income, and 20% experienced an income increase over the first 6 years of the study. Patients were followed for a mean of 17 years, and those who experienced an income drop were found to have a 17% higher risk of incident CVD, whereas those who experienced an income increase had a 14% lower risk of CVD.
The study was limited by difficulties classifying income and its changes; the complicated nature of income, its relationship with other socioeconomic factors, and causation inferences; and the relatively short span over which income was monitored.
Bottom line: Income decrease is associated with an increased risk of incident CVD.
Citation: Wang S et al. Longitudinal associations between income changes and incident cardiovascular disease, the atherosclerosis risk in communities study. JAMA Cardiol. 2019 Oct 9;4(12):1203-12.
Dr. Rupp is a hospitalist and clinical instructor of medicine at the University of Utah, Salt Lake City.
Background: Low income is associated with CVD, although causality remains debated because low income is also associated with depression and negative health behaviors, which can be associated with CVD. For more robust causal inference, changes in income and their association with CVD must be observed.
Study design: Prospective observational cohort study.
Setting: Four U.S. urban centers – Jackson, Miss.; suburbs of Minneapolis; Washington County, Md.; and Forsyth County, N.C.
Synopsis: Among a large cohort of community-dwelling middle-aged adults, this study showed that negative income changes are associated with an increased incidence of CVD. Among 8,989 patients recruited from the four urban centers above, 10% experienced an income drop, 70% did not have a change in income, and 20% experienced an income increase over the first 6 years of the study. Patients were followed for a mean of 17 years, and those who experienced an income drop were found to have a 17% higher risk of incident CVD, whereas those who experienced an income increase had a 14% lower risk of CVD.
The study was limited by difficulties classifying income and its changes; the complicated nature of income, its relationship with other socioeconomic factors, and causation inferences; and the relatively short span over which income was monitored.
Bottom line: Income decrease is associated with an increased risk of incident CVD.
Citation: Wang S et al. Longitudinal associations between income changes and incident cardiovascular disease, the atherosclerosis risk in communities study. JAMA Cardiol. 2019 Oct 9;4(12):1203-12.
Dr. Rupp is a hospitalist and clinical instructor of medicine at the University of Utah, Salt Lake City.
AstraZeneca COVID vaccine: Clotting disorder mechanism revealed?
The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.
Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.
Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.
Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.
They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.
They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.
At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”
A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”
But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
VIPIT study
In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.
The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.
The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.
Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.
The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.
They said that their current findings have several important clinical implications.
“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.
They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.
Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.
They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
EMA data to date
Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.
Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.
He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.
The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.
These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.
For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”
Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
Concerns put in perspective
Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.
“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.
“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.
Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.
“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.
She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.
Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.
“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.
Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.
A version of this article first appeared on Medscape.com.
The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.
Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.
Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.
Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.
They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.
They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.
At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”
A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”
But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
VIPIT study
In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.
The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.
The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.
Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.
The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.
They said that their current findings have several important clinical implications.
“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.
They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.
Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.
They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
EMA data to date
Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.
Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.
He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.
The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.
These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.
For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”
Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
Concerns put in perspective
Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.
“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.
“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.
Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.
“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.
She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.
Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.
“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.
Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.
A version of this article first appeared on Medscape.com.
The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.
Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.
Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.
Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.
They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.
They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.
At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”
A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”
But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
VIPIT study
In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.
The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.
The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.
Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.
The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.
They said that their current findings have several important clinical implications.
“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.
They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.
Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.
They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
EMA data to date
Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.
Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.
He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.
The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.
These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.
For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”
Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
Concerns put in perspective
Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.
“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.
“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.
Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.
“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.
She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.
Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.
“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.
Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.
A version of this article first appeared on Medscape.com.
Risk-based mammography proposed for times of reduced capacity
Researchers evaluated almost 2 million mammograms that had been performed at more than 90 radiology centers and found that 12% of mammograms with “high” and “very high” cancer risk rates accounted for 55% of detected cancers.
In contrast, 44% of mammograms with very low cancer risk rates accounted for 13% of detected cancers. The study was published online March 25, 2021, in JAMA Network Open.
Cancer screening programs dramatically slowed or even came to a screeching halt during 2020, when restrictions and lockdowns were in place. The American Cancer Society even recommended that “no one should go to a health care facility for routine cancer screening,” as part of COVID-19 precautions.
However, concern was voiced that the pause in screening would allow patients with asymptomatic cancers or precursor lesions to develop into a more serious disease state.
The authors pointed out that several professional associations had posted guidance for scheduling individuals for breast imaging services during the COVID-19 pandemic, but these recommendations were based on expert opinion. The investigators’ goal was to help imaging facilities optimize the number of breast cancers that could be detected during periods of reduced capacity using clinical indication and individual characteristics.
The result was a risk-based strategy for triaging mammograms during periods of decreased capacity, which lead author Diana L. Miglioretti, PhD, explained was feasible to implement. Dr. Miglioretti is division chief of biostatistics in the department of public health sciences at University of California, Davis.
“Our risk model used information that is commonly collected by radiology facilities,” she said in an interview. “Vendors of electronic medical records could create tools that pull the information from the medical record, or could create fields in the scheduling system to efficiently collect this information when the mammogram is scheduled.”
Dr. Miglioretti emphasized that, once the information is collected in a standardized manner, “it would be straightforward to use a computer program to apply our algorithm to rank women based on their likelihood of having a breast cancer detected.”
“I think it is worth the investment to create these electronic tools now, given the potential for future shutdowns or periods of reduced capacity due to a variety of reasons, such as natural disasters and cyberattacks – or another pandemic,” she said.
Some facilities are still working through backlogs of mammograms that need to be rescheduled, which would be another way that this algorithm could be used. “They could use this approach to determine who should be scheduled first by using data available in the electronic medical record,” she added.
Five risk groups
Dr. Miglioretti and colleagues conducted a cohort study using data that was prospectively collected from mammography examinations performed from 2014 to 2019 at 92 radiology facilities in the Breast Cancer Surveillance Consortium. The cohort included 898,415 individuals who contributed to 1.8 million mammograms.
Information that included clinical indication for screening, breast symptoms, personal history of breast cancer, age, time since last mammogram/screening interval, family history of breast cancer, breast density, and history of high-risk breast lesion was collected from self-administered questionnaires at the time of mammography or extracted from electronic health records.
Following analysis, the data was categorized into five risk groups: very high (>50), high (22-50), moderate (10-22), low (5-10), and very low (<5) cancer detection rate per 1,000 mammograms. These thresholds were chosen based on the observed cancer detection rates and clinical expertise.
Of the group, about 1.7 million mammograms were from women without a personal history of breast cancer and 156,104 mammograms were from women with a breast cancer history. Most of the cohort were aged 50-69 years at the time of imaging, and 67.9% were White (11.2% Black, 11.3% Asian or Pacific Islander, 7% Hispanic, and 2.2% were another race/ethnicity or mixed race/ethnicity).
Their results showed that 12% of mammograms with very high (89.6-122.3 cancers detected per 1,000 mammograms) or high (36.1-47.5 cancers detected per 1,000 mammograms) cancer detection rates accounted for 55% of all detected cancers. These included mammograms that were done to evaluate an abnormal test or breast lump in individuals of all ages regardless of breast cancer history.
On the opposite end, 44.2% of mammograms with very low cancer detection rates accounted for 13.1% of detected cancers and that included annual screening tests in women aged 50-69 years (3.8 cancers detected per 1,000 mammograms) and all screening mammograms in individuals younger than 50 years regardless of screening interval (2.8 cancers detected per 1000 mammograms).
Treat with caution
In an accompanying editorial, Sarah M. Friedewald, MD, and Dipti Gupta, MD, both from Northwestern University, Chicago, pointed out that, while the authors examined a large dataset to identify a subgroup of patients who would most likely benefit from breast imaging in a setting where capacity is limited, “these data should be used with caution as the only barometer for whether a patient merits cancer screening during a period of rationing.”
They noted that, in the context of an acute crisis, when patient volume needs to be reduced very quickly, it is often impractical for clinicians to sift through patient records in order to capture the information necessary for triage. In addition, asking nonclinical schedulers to accurately pull data at this level, at the time when the patient calls to make an appointment, is unrealistic.
In the context of the pandemic, the editorialists wrote that, while this model uses risk for breast cancer to prioritize those to be seen in the clinic, the risk for complications from COVID-19 may also be an important factor to consider. For example, an older patient may be at a higher risk for breast cancer but may also face a higher risk for COVID-related complications. Conversely, a younger woman at a lower risk for serious COVID-related disease but who has breast cancer detected early will gain more life-years than an older patient.
There are also no algorithms to account for each patient’s perceived risk for breast cancer or COVID-19, and “the downstream effect of delaying cancer diagnosis may similarly lead to unintended consequences but may take longer to become apparent,” they wrote. “Focusing efforts on the operations of accommodating as many patients as possible, such as extending clinic hours, would be preferable.”
Finally, Dr. Friedewald and Dr. Gupta concluded that “the practicality of this process during the COVID-19 pandemic and extrapolation to other emergent settings are less obvious.”
The study was supported through a Patient-centered Outcomes Research Institute program award. Dr. Miglioretti reported receiving royalties from Elsevier outside the submitted work. Several coauthors report relationships with industry. Dr. Friedewald reported receiving grants from Hologic Research during the conduct of the study. Dr. Gupta disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Researchers evaluated almost 2 million mammograms that had been performed at more than 90 radiology centers and found that 12% of mammograms with “high” and “very high” cancer risk rates accounted for 55% of detected cancers.
In contrast, 44% of mammograms with very low cancer risk rates accounted for 13% of detected cancers. The study was published online March 25, 2021, in JAMA Network Open.
Cancer screening programs dramatically slowed or even came to a screeching halt during 2020, when restrictions and lockdowns were in place. The American Cancer Society even recommended that “no one should go to a health care facility for routine cancer screening,” as part of COVID-19 precautions.
However, concern was voiced that the pause in screening would allow patients with asymptomatic cancers or precursor lesions to develop into a more serious disease state.
The authors pointed out that several professional associations had posted guidance for scheduling individuals for breast imaging services during the COVID-19 pandemic, but these recommendations were based on expert opinion. The investigators’ goal was to help imaging facilities optimize the number of breast cancers that could be detected during periods of reduced capacity using clinical indication and individual characteristics.
The result was a risk-based strategy for triaging mammograms during periods of decreased capacity, which lead author Diana L. Miglioretti, PhD, explained was feasible to implement. Dr. Miglioretti is division chief of biostatistics in the department of public health sciences at University of California, Davis.
“Our risk model used information that is commonly collected by radiology facilities,” she said in an interview. “Vendors of electronic medical records could create tools that pull the information from the medical record, or could create fields in the scheduling system to efficiently collect this information when the mammogram is scheduled.”
Dr. Miglioretti emphasized that, once the information is collected in a standardized manner, “it would be straightforward to use a computer program to apply our algorithm to rank women based on their likelihood of having a breast cancer detected.”
“I think it is worth the investment to create these electronic tools now, given the potential for future shutdowns or periods of reduced capacity due to a variety of reasons, such as natural disasters and cyberattacks – or another pandemic,” she said.
Some facilities are still working through backlogs of mammograms that need to be rescheduled, which would be another way that this algorithm could be used. “They could use this approach to determine who should be scheduled first by using data available in the electronic medical record,” she added.
Five risk groups
Dr. Miglioretti and colleagues conducted a cohort study using data that was prospectively collected from mammography examinations performed from 2014 to 2019 at 92 radiology facilities in the Breast Cancer Surveillance Consortium. The cohort included 898,415 individuals who contributed to 1.8 million mammograms.
Information that included clinical indication for screening, breast symptoms, personal history of breast cancer, age, time since last mammogram/screening interval, family history of breast cancer, breast density, and history of high-risk breast lesion was collected from self-administered questionnaires at the time of mammography or extracted from electronic health records.
Following analysis, the data was categorized into five risk groups: very high (>50), high (22-50), moderate (10-22), low (5-10), and very low (<5) cancer detection rate per 1,000 mammograms. These thresholds were chosen based on the observed cancer detection rates and clinical expertise.
Of the group, about 1.7 million mammograms were from women without a personal history of breast cancer and 156,104 mammograms were from women with a breast cancer history. Most of the cohort were aged 50-69 years at the time of imaging, and 67.9% were White (11.2% Black, 11.3% Asian or Pacific Islander, 7% Hispanic, and 2.2% were another race/ethnicity or mixed race/ethnicity).
Their results showed that 12% of mammograms with very high (89.6-122.3 cancers detected per 1,000 mammograms) or high (36.1-47.5 cancers detected per 1,000 mammograms) cancer detection rates accounted for 55% of all detected cancers. These included mammograms that were done to evaluate an abnormal test or breast lump in individuals of all ages regardless of breast cancer history.
On the opposite end, 44.2% of mammograms with very low cancer detection rates accounted for 13.1% of detected cancers and that included annual screening tests in women aged 50-69 years (3.8 cancers detected per 1,000 mammograms) and all screening mammograms in individuals younger than 50 years regardless of screening interval (2.8 cancers detected per 1000 mammograms).
Treat with caution
In an accompanying editorial, Sarah M. Friedewald, MD, and Dipti Gupta, MD, both from Northwestern University, Chicago, pointed out that, while the authors examined a large dataset to identify a subgroup of patients who would most likely benefit from breast imaging in a setting where capacity is limited, “these data should be used with caution as the only barometer for whether a patient merits cancer screening during a period of rationing.”
They noted that, in the context of an acute crisis, when patient volume needs to be reduced very quickly, it is often impractical for clinicians to sift through patient records in order to capture the information necessary for triage. In addition, asking nonclinical schedulers to accurately pull data at this level, at the time when the patient calls to make an appointment, is unrealistic.
In the context of the pandemic, the editorialists wrote that, while this model uses risk for breast cancer to prioritize those to be seen in the clinic, the risk for complications from COVID-19 may also be an important factor to consider. For example, an older patient may be at a higher risk for breast cancer but may also face a higher risk for COVID-related complications. Conversely, a younger woman at a lower risk for serious COVID-related disease but who has breast cancer detected early will gain more life-years than an older patient.
There are also no algorithms to account for each patient’s perceived risk for breast cancer or COVID-19, and “the downstream effect of delaying cancer diagnosis may similarly lead to unintended consequences but may take longer to become apparent,” they wrote. “Focusing efforts on the operations of accommodating as many patients as possible, such as extending clinic hours, would be preferable.”
Finally, Dr. Friedewald and Dr. Gupta concluded that “the practicality of this process during the COVID-19 pandemic and extrapolation to other emergent settings are less obvious.”
The study was supported through a Patient-centered Outcomes Research Institute program award. Dr. Miglioretti reported receiving royalties from Elsevier outside the submitted work. Several coauthors report relationships with industry. Dr. Friedewald reported receiving grants from Hologic Research during the conduct of the study. Dr. Gupta disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Researchers evaluated almost 2 million mammograms that had been performed at more than 90 radiology centers and found that 12% of mammograms with “high” and “very high” cancer risk rates accounted for 55% of detected cancers.
In contrast, 44% of mammograms with very low cancer risk rates accounted for 13% of detected cancers. The study was published online March 25, 2021, in JAMA Network Open.
Cancer screening programs dramatically slowed or even came to a screeching halt during 2020, when restrictions and lockdowns were in place. The American Cancer Society even recommended that “no one should go to a health care facility for routine cancer screening,” as part of COVID-19 precautions.
However, concern was voiced that the pause in screening would allow patients with asymptomatic cancers or precursor lesions to develop into a more serious disease state.
The authors pointed out that several professional associations had posted guidance for scheduling individuals for breast imaging services during the COVID-19 pandemic, but these recommendations were based on expert opinion. The investigators’ goal was to help imaging facilities optimize the number of breast cancers that could be detected during periods of reduced capacity using clinical indication and individual characteristics.
The result was a risk-based strategy for triaging mammograms during periods of decreased capacity, which lead author Diana L. Miglioretti, PhD, explained was feasible to implement. Dr. Miglioretti is division chief of biostatistics in the department of public health sciences at University of California, Davis.
“Our risk model used information that is commonly collected by radiology facilities,” she said in an interview. “Vendors of electronic medical records could create tools that pull the information from the medical record, or could create fields in the scheduling system to efficiently collect this information when the mammogram is scheduled.”
Dr. Miglioretti emphasized that, once the information is collected in a standardized manner, “it would be straightforward to use a computer program to apply our algorithm to rank women based on their likelihood of having a breast cancer detected.”
“I think it is worth the investment to create these electronic tools now, given the potential for future shutdowns or periods of reduced capacity due to a variety of reasons, such as natural disasters and cyberattacks – or another pandemic,” she said.
Some facilities are still working through backlogs of mammograms that need to be rescheduled, which would be another way that this algorithm could be used. “They could use this approach to determine who should be scheduled first by using data available in the electronic medical record,” she added.
Five risk groups
Dr. Miglioretti and colleagues conducted a cohort study using data that was prospectively collected from mammography examinations performed from 2014 to 2019 at 92 radiology facilities in the Breast Cancer Surveillance Consortium. The cohort included 898,415 individuals who contributed to 1.8 million mammograms.
Information that included clinical indication for screening, breast symptoms, personal history of breast cancer, age, time since last mammogram/screening interval, family history of breast cancer, breast density, and history of high-risk breast lesion was collected from self-administered questionnaires at the time of mammography or extracted from electronic health records.
Following analysis, the data was categorized into five risk groups: very high (>50), high (22-50), moderate (10-22), low (5-10), and very low (<5) cancer detection rate per 1,000 mammograms. These thresholds were chosen based on the observed cancer detection rates and clinical expertise.
Of the group, about 1.7 million mammograms were from women without a personal history of breast cancer and 156,104 mammograms were from women with a breast cancer history. Most of the cohort were aged 50-69 years at the time of imaging, and 67.9% were White (11.2% Black, 11.3% Asian or Pacific Islander, 7% Hispanic, and 2.2% were another race/ethnicity or mixed race/ethnicity).
Their results showed that 12% of mammograms with very high (89.6-122.3 cancers detected per 1,000 mammograms) or high (36.1-47.5 cancers detected per 1,000 mammograms) cancer detection rates accounted for 55% of all detected cancers. These included mammograms that were done to evaluate an abnormal test or breast lump in individuals of all ages regardless of breast cancer history.
On the opposite end, 44.2% of mammograms with very low cancer detection rates accounted for 13.1% of detected cancers and that included annual screening tests in women aged 50-69 years (3.8 cancers detected per 1,000 mammograms) and all screening mammograms in individuals younger than 50 years regardless of screening interval (2.8 cancers detected per 1000 mammograms).
Treat with caution
In an accompanying editorial, Sarah M. Friedewald, MD, and Dipti Gupta, MD, both from Northwestern University, Chicago, pointed out that, while the authors examined a large dataset to identify a subgroup of patients who would most likely benefit from breast imaging in a setting where capacity is limited, “these data should be used with caution as the only barometer for whether a patient merits cancer screening during a period of rationing.”
They noted that, in the context of an acute crisis, when patient volume needs to be reduced very quickly, it is often impractical for clinicians to sift through patient records in order to capture the information necessary for triage. In addition, asking nonclinical schedulers to accurately pull data at this level, at the time when the patient calls to make an appointment, is unrealistic.
In the context of the pandemic, the editorialists wrote that, while this model uses risk for breast cancer to prioritize those to be seen in the clinic, the risk for complications from COVID-19 may also be an important factor to consider. For example, an older patient may be at a higher risk for breast cancer but may also face a higher risk for COVID-related complications. Conversely, a younger woman at a lower risk for serious COVID-related disease but who has breast cancer detected early will gain more life-years than an older patient.
There are also no algorithms to account for each patient’s perceived risk for breast cancer or COVID-19, and “the downstream effect of delaying cancer diagnosis may similarly lead to unintended consequences but may take longer to become apparent,” they wrote. “Focusing efforts on the operations of accommodating as many patients as possible, such as extending clinic hours, would be preferable.”
Finally, Dr. Friedewald and Dr. Gupta concluded that “the practicality of this process during the COVID-19 pandemic and extrapolation to other emergent settings are less obvious.”
The study was supported through a Patient-centered Outcomes Research Institute program award. Dr. Miglioretti reported receiving royalties from Elsevier outside the submitted work. Several coauthors report relationships with industry. Dr. Friedewald reported receiving grants from Hologic Research during the conduct of the study. Dr. Gupta disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Clinical Edge Commentary: MDS April 2021
The OS was similar between the two arms, although the analysis was underpowered. Nausea, diarrhea, and vomiting were the most frequently occurring treatment-emergent adverse events for oral azacitidine vs placebo (76% vs 23%, 68% vs 23%, 63% vs 9%). While oral azacitidine is not approved for MDS and trial was stopped early, it can provide meaningful reduction in RBC transfusions in low grade MDS, and further evaluation is needed in MDS.
Paroxysmal nocturnal hemoglobinuria (PNH) clones have been observed in bone marrow failure syndromes including MDS and aplastic anemia (AA). Fattizzo et al analyzed PNH clone size with clinical outcomes in MDS and AA in a cohort of 3085 patients tested for PNH at King’s College Hospital in London. 20.3% of MDS patients had presence of PNH clone; PNH cases occurred more in hypoplastic MDS, and lower risk IPSS MDS patients. The presence of PNH clone was a predictor of response to immunosuppressive therapy and to allogeneic stem cell transplant (84% vs 45%, p=0.01, 71% vs 57%, p=0.09), but not to azacitidine. MDS patients with PNH clone had lower rate of progression by IPSS and AML transformation, and higher OS accounting for MDS with excess blasts. Each 10% increase in clone size resulted in a 1% decrease in cumulative incidence of death. PNH testing is often done especially in cases with hypoplastic MDS; the underlying mechanism and role for monitoring PNH clones in MDS needs further investigation.
Outcomes in MDS patients after azacitidine therapy are generally poor. Clavio et al analyzed outcomes of 402 MDS patients post-azacitidine in the Italian MDS Registry. At azacitidine discontinuation, 20% of patients still derived response to azacitidine, 35% had primary resistance, and 44% had adaptive resistance, which was defined as loss of response or progression after achievement of a response. As expected, OS was longer for patients who stopped treatment due to planned allogeneic stem cell transplant (median OS not reached), compared to patients with primary resistance (median OS 4 months), or adaptive resistance (median OS 5 months), or patients intolerant or noncompliant to azacitidine (median OS 4 months, p=0.004). The North American MDS Consortium scoring system was evaluated in the study cohort; patients with high risk had worse OS than low risk (3 and 7 months, p<0.001). This retrospective analysis confirms the poor outlook of MDS patients after treatment of azacitidine, and effective therapy in this patient population is an unmet need.
The OS was similar between the two arms, although the analysis was underpowered. Nausea, diarrhea, and vomiting were the most frequently occurring treatment-emergent adverse events for oral azacitidine vs placebo (76% vs 23%, 68% vs 23%, 63% vs 9%). While oral azacitidine is not approved for MDS and trial was stopped early, it can provide meaningful reduction in RBC transfusions in low grade MDS, and further evaluation is needed in MDS.
Paroxysmal nocturnal hemoglobinuria (PNH) clones have been observed in bone marrow failure syndromes including MDS and aplastic anemia (AA). Fattizzo et al analyzed PNH clone size with clinical outcomes in MDS and AA in a cohort of 3085 patients tested for PNH at King’s College Hospital in London. 20.3% of MDS patients had presence of PNH clone; PNH cases occurred more in hypoplastic MDS, and lower risk IPSS MDS patients. The presence of PNH clone was a predictor of response to immunosuppressive therapy and to allogeneic stem cell transplant (84% vs 45%, p=0.01, 71% vs 57%, p=0.09), but not to azacitidine. MDS patients with PNH clone had lower rate of progression by IPSS and AML transformation, and higher OS accounting for MDS with excess blasts. Each 10% increase in clone size resulted in a 1% decrease in cumulative incidence of death. PNH testing is often done especially in cases with hypoplastic MDS; the underlying mechanism and role for monitoring PNH clones in MDS needs further investigation.
Outcomes in MDS patients after azacitidine therapy are generally poor. Clavio et al analyzed outcomes of 402 MDS patients post-azacitidine in the Italian MDS Registry. At azacitidine discontinuation, 20% of patients still derived response to azacitidine, 35% had primary resistance, and 44% had adaptive resistance, which was defined as loss of response or progression after achievement of a response. As expected, OS was longer for patients who stopped treatment due to planned allogeneic stem cell transplant (median OS not reached), compared to patients with primary resistance (median OS 4 months), or adaptive resistance (median OS 5 months), or patients intolerant or noncompliant to azacitidine (median OS 4 months, p=0.004). The North American MDS Consortium scoring system was evaluated in the study cohort; patients with high risk had worse OS than low risk (3 and 7 months, p<0.001). This retrospective analysis confirms the poor outlook of MDS patients after treatment of azacitidine, and effective therapy in this patient population is an unmet need.
The OS was similar between the two arms, although the analysis was underpowered. Nausea, diarrhea, and vomiting were the most frequently occurring treatment-emergent adverse events for oral azacitidine vs placebo (76% vs 23%, 68% vs 23%, 63% vs 9%). While oral azacitidine is not approved for MDS and trial was stopped early, it can provide meaningful reduction in RBC transfusions in low grade MDS, and further evaluation is needed in MDS.
Paroxysmal nocturnal hemoglobinuria (PNH) clones have been observed in bone marrow failure syndromes including MDS and aplastic anemia (AA). Fattizzo et al analyzed PNH clone size with clinical outcomes in MDS and AA in a cohort of 3085 patients tested for PNH at King’s College Hospital in London. 20.3% of MDS patients had presence of PNH clone; PNH cases occurred more in hypoplastic MDS, and lower risk IPSS MDS patients. The presence of PNH clone was a predictor of response to immunosuppressive therapy and to allogeneic stem cell transplant (84% vs 45%, p=0.01, 71% vs 57%, p=0.09), but not to azacitidine. MDS patients with PNH clone had lower rate of progression by IPSS and AML transformation, and higher OS accounting for MDS with excess blasts. Each 10% increase in clone size resulted in a 1% decrease in cumulative incidence of death. PNH testing is often done especially in cases with hypoplastic MDS; the underlying mechanism and role for monitoring PNH clones in MDS needs further investigation.
Outcomes in MDS patients after azacitidine therapy are generally poor. Clavio et al analyzed outcomes of 402 MDS patients post-azacitidine in the Italian MDS Registry. At azacitidine discontinuation, 20% of patients still derived response to azacitidine, 35% had primary resistance, and 44% had adaptive resistance, which was defined as loss of response or progression after achievement of a response. As expected, OS was longer for patients who stopped treatment due to planned allogeneic stem cell transplant (median OS not reached), compared to patients with primary resistance (median OS 4 months), or adaptive resistance (median OS 5 months), or patients intolerant or noncompliant to azacitidine (median OS 4 months, p=0.004). The North American MDS Consortium scoring system was evaluated in the study cohort; patients with high risk had worse OS than low risk (3 and 7 months, p<0.001). This retrospective analysis confirms the poor outlook of MDS patients after treatment of azacitidine, and effective therapy in this patient population is an unmet need.
High-risk MDS: Stanozolol improves PFS after effective induction therapy with decitabine
Key clinical point: Adding stanozolol to decitabine after effective decitabine treatment may improve progression-free survival (PFS) and reduce the severity of neutropenia in patients with high-risk myelodysplastic syndrome (MDS).
Major finding: PFS was significantly longer in the stanozolol group vs. stanozolol+decitabine group (15.0 vs. 9.0 months; hazard ratio [HR], 0.35; P = .0005). The proportion of patients with grade 3-4 neutropenia was lower in stanozolol group (76.2% vs. 95.1%; P = .039).
Study details: Findings are from a retrospective analysis of 62 patients with newly diagnosed high-risk MDS who achieved at least partial remission after 4 cycles of decitabine. For maintenance treatment, 21 patients received stanozolol and decitabine and 41 patients received decitabine alone.
Disclosures: This study was partly supported by the National Natural Science Foundation of China, the Natural Science Foundation of Tianjin China, Key Technology Research and Development Program of Tianjin China, Beijing Natural Science Foundation, and Chinese Academy of Medical Sciences innovation for medical sciences. The authors declared no conflicts of interest.
Source: Liu Y et al. Int J Hematol. 2021 Mar 1. doi: 10.1007/s12185-021-03115-9.
Key clinical point: Adding stanozolol to decitabine after effective decitabine treatment may improve progression-free survival (PFS) and reduce the severity of neutropenia in patients with high-risk myelodysplastic syndrome (MDS).
Major finding: PFS was significantly longer in the stanozolol group vs. stanozolol+decitabine group (15.0 vs. 9.0 months; hazard ratio [HR], 0.35; P = .0005). The proportion of patients with grade 3-4 neutropenia was lower in stanozolol group (76.2% vs. 95.1%; P = .039).
Study details: Findings are from a retrospective analysis of 62 patients with newly diagnosed high-risk MDS who achieved at least partial remission after 4 cycles of decitabine. For maintenance treatment, 21 patients received stanozolol and decitabine and 41 patients received decitabine alone.
Disclosures: This study was partly supported by the National Natural Science Foundation of China, the Natural Science Foundation of Tianjin China, Key Technology Research and Development Program of Tianjin China, Beijing Natural Science Foundation, and Chinese Academy of Medical Sciences innovation for medical sciences. The authors declared no conflicts of interest.
Source: Liu Y et al. Int J Hematol. 2021 Mar 1. doi: 10.1007/s12185-021-03115-9.
Key clinical point: Adding stanozolol to decitabine after effective decitabine treatment may improve progression-free survival (PFS) and reduce the severity of neutropenia in patients with high-risk myelodysplastic syndrome (MDS).
Major finding: PFS was significantly longer in the stanozolol group vs. stanozolol+decitabine group (15.0 vs. 9.0 months; hazard ratio [HR], 0.35; P = .0005). The proportion of patients with grade 3-4 neutropenia was lower in stanozolol group (76.2% vs. 95.1%; P = .039).
Study details: Findings are from a retrospective analysis of 62 patients with newly diagnosed high-risk MDS who achieved at least partial remission after 4 cycles of decitabine. For maintenance treatment, 21 patients received stanozolol and decitabine and 41 patients received decitabine alone.
Disclosures: This study was partly supported by the National Natural Science Foundation of China, the Natural Science Foundation of Tianjin China, Key Technology Research and Development Program of Tianjin China, Beijing Natural Science Foundation, and Chinese Academy of Medical Sciences innovation for medical sciences. The authors declared no conflicts of interest.
Source: Liu Y et al. Int J Hematol. 2021 Mar 1. doi: 10.1007/s12185-021-03115-9.
FDA approves new ready-to-inject glucagon product
The Food and Drug Administration has approved dasiglucagon (Zegalogue 0.6 mg/0.6 mL, Zealand Pharma) autoinjector and prefilled syringe for the treatment of severe hypoglycemia in people with diabetes aged 6 years and older.
The product has a shelf-life of 36 months at refrigerated temperatures and is stable for up to 12 months at room temperature.
“This approval will help enable appropriate children and adults with diabetes to be able to address sudden and severe hypoglycemia, which can quickly progress from a mild event to an emergency,” Jeremy Pettus, MD, assistant professor of medicine at the University of California, San Diego, said in a company statement.
The approval marks the latest step in the development of newer glucagon formulations that are easier to use in hypoglycemic emergencies than the traditional formulation that requires several steps for reconstitution.
The first intranasal glucagon (Baqsimi, Eli Lilly) was approved in the United States in July 2019 for people with diabetes age 4 years and older.
In September 2019, the FDA approved another prefilled glucagon rescue pen (Gvoke HypoPen, Xeris Pharmaceuticals) for the treatment of severe hypoglycemia in adult and pediatric patients age 2 years and older with diabetes.
Dasiglucagon is currently in phase 3 trials as a subcutaneous infusion for treating congenital hyperinsulinemia, and in phase 2 trials as part of a bihormonal artificial pancreas pump system.
The FDA approval was based on results from three randomized, double-blind, placebo-controlled, phase 3 studies of dasiglucagon in children age 6-17 years and adults with type 1 diabetes.
The primary endpoint was time to achieving an increase in blood glucose of 20 mg/dL or greater from time of administration without additional intervention within 45 minutes. That endpoint was achieved in all three studies, with a median time to blood glucose recovery of 10 minutes overall, with 99% of adults recovering within 15 minutes.
The most common adverse events reported in 2% or more of study participants were nausea, vomiting, headache, and injection-site pain in both children and adults. Diarrhea was also reported in adults.
Full launch is expected in late June 2021.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved dasiglucagon (Zegalogue 0.6 mg/0.6 mL, Zealand Pharma) autoinjector and prefilled syringe for the treatment of severe hypoglycemia in people with diabetes aged 6 years and older.
The product has a shelf-life of 36 months at refrigerated temperatures and is stable for up to 12 months at room temperature.
“This approval will help enable appropriate children and adults with diabetes to be able to address sudden and severe hypoglycemia, which can quickly progress from a mild event to an emergency,” Jeremy Pettus, MD, assistant professor of medicine at the University of California, San Diego, said in a company statement.
The approval marks the latest step in the development of newer glucagon formulations that are easier to use in hypoglycemic emergencies than the traditional formulation that requires several steps for reconstitution.
The first intranasal glucagon (Baqsimi, Eli Lilly) was approved in the United States in July 2019 for people with diabetes age 4 years and older.
In September 2019, the FDA approved another prefilled glucagon rescue pen (Gvoke HypoPen, Xeris Pharmaceuticals) for the treatment of severe hypoglycemia in adult and pediatric patients age 2 years and older with diabetes.
Dasiglucagon is currently in phase 3 trials as a subcutaneous infusion for treating congenital hyperinsulinemia, and in phase 2 trials as part of a bihormonal artificial pancreas pump system.
The FDA approval was based on results from three randomized, double-blind, placebo-controlled, phase 3 studies of dasiglucagon in children age 6-17 years and adults with type 1 diabetes.
The primary endpoint was time to achieving an increase in blood glucose of 20 mg/dL or greater from time of administration without additional intervention within 45 minutes. That endpoint was achieved in all three studies, with a median time to blood glucose recovery of 10 minutes overall, with 99% of adults recovering within 15 minutes.
The most common adverse events reported in 2% or more of study participants were nausea, vomiting, headache, and injection-site pain in both children and adults. Diarrhea was also reported in adults.
Full launch is expected in late June 2021.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved dasiglucagon (Zegalogue 0.6 mg/0.6 mL, Zealand Pharma) autoinjector and prefilled syringe for the treatment of severe hypoglycemia in people with diabetes aged 6 years and older.
The product has a shelf-life of 36 months at refrigerated temperatures and is stable for up to 12 months at room temperature.
“This approval will help enable appropriate children and adults with diabetes to be able to address sudden and severe hypoglycemia, which can quickly progress from a mild event to an emergency,” Jeremy Pettus, MD, assistant professor of medicine at the University of California, San Diego, said in a company statement.
The approval marks the latest step in the development of newer glucagon formulations that are easier to use in hypoglycemic emergencies than the traditional formulation that requires several steps for reconstitution.
The first intranasal glucagon (Baqsimi, Eli Lilly) was approved in the United States in July 2019 for people with diabetes age 4 years and older.
In September 2019, the FDA approved another prefilled glucagon rescue pen (Gvoke HypoPen, Xeris Pharmaceuticals) for the treatment of severe hypoglycemia in adult and pediatric patients age 2 years and older with diabetes.
Dasiglucagon is currently in phase 3 trials as a subcutaneous infusion for treating congenital hyperinsulinemia, and in phase 2 trials as part of a bihormonal artificial pancreas pump system.
The FDA approval was based on results from three randomized, double-blind, placebo-controlled, phase 3 studies of dasiglucagon in children age 6-17 years and adults with type 1 diabetes.
The primary endpoint was time to achieving an increase in blood glucose of 20 mg/dL or greater from time of administration without additional intervention within 45 minutes. That endpoint was achieved in all three studies, with a median time to blood glucose recovery of 10 minutes overall, with 99% of adults recovering within 15 minutes.
The most common adverse events reported in 2% or more of study participants were nausea, vomiting, headache, and injection-site pain in both children and adults. Diarrhea was also reported in adults.
Full launch is expected in late June 2021.
A version of this article first appeared on Medscape.com.