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How old is too old to work as a doctor?
Air traffic controllers face mandatory retirement at age 56, with exceptions up to 61. Commercial airline pilots must bow out at 65; same for foreign service employees. Physicians, however, have no age limit, regardless of specialty.
As the profession rapidly ages – some 30% of the physician workforce is currently a senior, according to the American Medical Association – the topic of whether or not there should be a standard measure or age for retirement is front and center. The AMA’s Council on Medical Education formed a workgroup to look into the issue in 2015 and 2018, and in 2021, delegates adopted a set of guidelines for screening and assessing physicians, but stopped short of a mandate.
Mark Katlic, MD, chair of surgery at Lifebridge Health System, Baltimore, has devoted a decade to studying this topic. “I’m a bit of an outlier looking into this,” he says. “The public is unaware and seemingly unconcerned about the issue. Even among the medical profession, there’s been a series of fits and starts to develop a cohesive approach.”
One of the reasons guidelines – mandatory or otherwise – have been tough to come by is that aging brings with it a huge degree of variability. “If you look at a group of 80-year-olds, there will be much more variability than within a group of 40-year-olds,” Dr. Katlic pointed out.
Indeed, some 80-year-olds can easily continue to teach college courses, keep up in 10K running races, or perform delicate surgeries. Yet others in their peer group might struggle to properly button a shirt, walk a flight of stairs, or remember yesterday’s meals. Functional age is not the same as chronological age.
Frank Stockdale, MD, PhD, an 86-year-old practicing oncologist at Stanford (Calif.) University Health, counts himself in the camp opposed to age-based assessments. “It’s age discrimination,” he says. “Physicians receive assessments throughout their careers as part of the accreditation process – there’s no need to change that as doctors reach a certain age.”
Dr. Stockdale suggests that in many cases, malpractice suits are filed against mid-career doctors, not those of advanced age. “If you’re using the argument that there is an accumulation of deficits with age, the fact is that those deficits begin well before your 70s,” he said. “It’s better to have a uniform screening policy and begin at a much younger age.”
At Stanford, in fact, there was a former assessment policy that included cognitive testing, but physicians were successful in seeing that portion of testing eliminated. “It is a physical examination, by a physician of choice, certifying that for the privileges requested there is no physical or mental reason the candidate cannot safely perform them,” Dr. Stockdale explained.
In some cases, medical staffs have filed lawsuits to fight age-related testing. In New Haven, Conn., for instance, the U.S. Equal Employment Opportunity Commission (EEOC) filed a suit in 2020 on behalf of the Yale New Haven Hospital staff, alleging a discriminatory “late career practitioner policy.”
A similar case in Minnesota reached a settlement in 2021, providing monetary relief to staff impacted by out-of-pocket costs for the assessment, in addition to requiring that the hospital in question report to the EEOC any complaints related to age discrimination.
James Ellison, MD, MPH, chair in Memory Care and Geriatrics with ChristianaCare in Wilmington, Del., points out that aging can bring benefits for practicing physicians. “Age is very individualized and there are good and bad consequences,” he said. “Experience can build knowledge and confidence and expertise, and it does improve diagnostic accuracy.”
On the flip side, however, age-related brain changes include loss of volume and lower levels of some neurotransmitters, resulting in cognitive changes. “Functional changes occur too,” Dr. Ellison said.
“Just as some aging athletes may lose a degree of speed, strength, and flexibility, and some aging scientists may lose a part of their former cognitive speed, flexibility, and mental strength, aging health care providers can lose some of the physical coordination, strength, and visual acuity necessary to perform demanding surgical operations. They can also lose some of the processing speed, working memory, and executive function that allows them to excel in cognitive professional tasks.”
An estimated 5.8 million Americans age 65 and older have Alzheimer’s dementia, according to the Alzheimer’s Association.
Picking an arbitrary age for mandatory retirement isn’t the right approach for physicians, said Dr. Katlic. Rather, he said, the answer is to establish late-practitioner screening programs. “Very few hospitals have them, however,” he pointed out. “We do [at Lifebridge Health], and so do a few dozen others, but that’s out of hundreds.”
Instead, what typically plays out is that hospital staff might begin to notice a decline in a colleague. Things like a disheveled appearance or lack of hygiene, or trouble with memory, such as getting lost en route back to his or her office. Even dangerous behaviors such as nodding off during a procedure are not unheard of.
There are many examples of physician decline that fly under the radar. “Unfortunately, it’s unusual for cognitively impaired health care providers to recognize and report their own difficulties,” said Dr. Ellison. “Although peers are expected to report cognitively impaired colleagues, they often fail to do so. In some other countries, age-based assessment is an accepted policy. In the U.S., this is not a uniform policy.”
Sometimes physicians can remain on the job in spite of decline thanks to certain “props,” according to Dr. Ellison. “Good procedures, efficient supports, and various workarounds compensate,” he said, “but often are not sufficient to maintain high-quality practice.”
Most often, these situations play out slowly, until the problem becomes glaringly obvious and potentially dangerous, and someone in a position of power must step in.
“Often, it’s hearsay from a nurse or another staff member, and then a hospital president or chief of staff must make a career-affecting decision for the doctor in question,” said Dr. Katlic.
Because there is little self- or colleague policing – and barring official or binding guidelines on the aging physician issue – both Dr. Katlic and Dr. Ellison are proponents of late-career screening.
How screening can help
As it stands, Dr. Katlic maintains that the profession isn’t doing enough to ensure public safety. “We have peer review and recertification processes, but when you get down to it, we don’t police ourselves well,” he said. “All physicians are assessed throughout their careers as part of the hospital accreditation process, which is fair and adequate.”
Dr. Katlic said that there are three main benchmarks that physicians should be able to meet at an agreed upon age: a physical exam, a neurocognitive screening, and an eye exam. “At some reasonable age, I personally believe these exams should take place,” he said. “We can allow doctors to pick their own practitioners for the eye and physical exams, but the neurocognitive exam should be completed by a PhD neuropsychologist.”
At Lifebridge, for instance, these screenings begin at age 75 and take place every 2 years, during the recredentialing process. It applies to all specialties, not just surgeons. “Surgery is a little different in that it requires fine motor skills in addition to the others we test, but you want any physician to be cognitively intact,” Dr. Katlic pointed out. “All doctors need the ability to make decisions quickly, often under noisy, distracting conditions.”
Dr. Ellison supports applying the screenings to all specialties. “Let’s not forget that all physicians must be alert to the many ways in which their patients reveal what needs attention, evaluation, and treatment,” he said. “Some health care tasks could be performed without visual input; for example, perhaps psychotherapy could be provided competently by a clinician who lacks visual acuity. Auditory input might not be necessary for reading x-rays – but the information a health care provider gets from their eyes and ears is important, not just for surgeons.”
University of California San Diego has established what it calls its Physician Assessment and Clinical Education (PACE) program. One of the nation’s oldest and largest such programs, the hospital founded PACE in 1996. Most physicians taking part arrive as a requirement of disciplinary action from the state medical board, but a small percentage self-refers.
PACE involves two phases. The first is a 2-day set of tests and measures core competency knowledge. Phase 2 is more comprehensive and lasts 5 days. Here, within their specialty, physicians participate in the activities of the corresponding residency program. Faculty evaluates the physician, and a multidisciplinary team meets to review all the findings of the combined phases.
Depending on the results, doctors may face remediation steps that range from programs to address performance deficiencies to residency-level clinical experiences. According to a paper on the program published by the institution, “most physicians referred to the PACE program are found to have mild to moderate performance dyscompetence.”
In the case of the 2021 guidelines adopted by AMA delegates, there are nine principles for assessment. They should be evidence-based, ethical, relevant, accountable, fair and equitable, transparent, supportive, and nonburdensome, and should afford physicians due process protections.
Looking ahead
Even Dr. Katlic worries about the possibility of Congress intervening to establish federal-level, mandatory retirement age. “This just doesn’t make sense for our profession given the great variability we see,” he said. “My biggest hope is that more individual hospitals will institute these screenings.”
As the physician population ages – and the influx of new doctors shrinks – the slope becomes even more slippery. The AMA is predicting a physician shortage of nearly 40,000 by the year 2034. This strengthens arguments to keep existing physicians practicing for as long as possible and might make institutions less likely to screen.
It’s all a delicate balancing act and a continuing work in progress, said Dr. Ellison. “Ultimately, I believe we need to find a way to understand and address the possible implications for public safety, while at the same time protecting the privacy and dignity of our valued older physicians and other health care providers.”
A version of this article first appeared on Medscape.com.
Air traffic controllers face mandatory retirement at age 56, with exceptions up to 61. Commercial airline pilots must bow out at 65; same for foreign service employees. Physicians, however, have no age limit, regardless of specialty.
As the profession rapidly ages – some 30% of the physician workforce is currently a senior, according to the American Medical Association – the topic of whether or not there should be a standard measure or age for retirement is front and center. The AMA’s Council on Medical Education formed a workgroup to look into the issue in 2015 and 2018, and in 2021, delegates adopted a set of guidelines for screening and assessing physicians, but stopped short of a mandate.
Mark Katlic, MD, chair of surgery at Lifebridge Health System, Baltimore, has devoted a decade to studying this topic. “I’m a bit of an outlier looking into this,” he says. “The public is unaware and seemingly unconcerned about the issue. Even among the medical profession, there’s been a series of fits and starts to develop a cohesive approach.”
One of the reasons guidelines – mandatory or otherwise – have been tough to come by is that aging brings with it a huge degree of variability. “If you look at a group of 80-year-olds, there will be much more variability than within a group of 40-year-olds,” Dr. Katlic pointed out.
Indeed, some 80-year-olds can easily continue to teach college courses, keep up in 10K running races, or perform delicate surgeries. Yet others in their peer group might struggle to properly button a shirt, walk a flight of stairs, or remember yesterday’s meals. Functional age is not the same as chronological age.
Frank Stockdale, MD, PhD, an 86-year-old practicing oncologist at Stanford (Calif.) University Health, counts himself in the camp opposed to age-based assessments. “It’s age discrimination,” he says. “Physicians receive assessments throughout their careers as part of the accreditation process – there’s no need to change that as doctors reach a certain age.”
Dr. Stockdale suggests that in many cases, malpractice suits are filed against mid-career doctors, not those of advanced age. “If you’re using the argument that there is an accumulation of deficits with age, the fact is that those deficits begin well before your 70s,” he said. “It’s better to have a uniform screening policy and begin at a much younger age.”
At Stanford, in fact, there was a former assessment policy that included cognitive testing, but physicians were successful in seeing that portion of testing eliminated. “It is a physical examination, by a physician of choice, certifying that for the privileges requested there is no physical or mental reason the candidate cannot safely perform them,” Dr. Stockdale explained.
In some cases, medical staffs have filed lawsuits to fight age-related testing. In New Haven, Conn., for instance, the U.S. Equal Employment Opportunity Commission (EEOC) filed a suit in 2020 on behalf of the Yale New Haven Hospital staff, alleging a discriminatory “late career practitioner policy.”
A similar case in Minnesota reached a settlement in 2021, providing monetary relief to staff impacted by out-of-pocket costs for the assessment, in addition to requiring that the hospital in question report to the EEOC any complaints related to age discrimination.
James Ellison, MD, MPH, chair in Memory Care and Geriatrics with ChristianaCare in Wilmington, Del., points out that aging can bring benefits for practicing physicians. “Age is very individualized and there are good and bad consequences,” he said. “Experience can build knowledge and confidence and expertise, and it does improve diagnostic accuracy.”
On the flip side, however, age-related brain changes include loss of volume and lower levels of some neurotransmitters, resulting in cognitive changes. “Functional changes occur too,” Dr. Ellison said.
“Just as some aging athletes may lose a degree of speed, strength, and flexibility, and some aging scientists may lose a part of their former cognitive speed, flexibility, and mental strength, aging health care providers can lose some of the physical coordination, strength, and visual acuity necessary to perform demanding surgical operations. They can also lose some of the processing speed, working memory, and executive function that allows them to excel in cognitive professional tasks.”
An estimated 5.8 million Americans age 65 and older have Alzheimer’s dementia, according to the Alzheimer’s Association.
Picking an arbitrary age for mandatory retirement isn’t the right approach for physicians, said Dr. Katlic. Rather, he said, the answer is to establish late-practitioner screening programs. “Very few hospitals have them, however,” he pointed out. “We do [at Lifebridge Health], and so do a few dozen others, but that’s out of hundreds.”
Instead, what typically plays out is that hospital staff might begin to notice a decline in a colleague. Things like a disheveled appearance or lack of hygiene, or trouble with memory, such as getting lost en route back to his or her office. Even dangerous behaviors such as nodding off during a procedure are not unheard of.
There are many examples of physician decline that fly under the radar. “Unfortunately, it’s unusual for cognitively impaired health care providers to recognize and report their own difficulties,” said Dr. Ellison. “Although peers are expected to report cognitively impaired colleagues, they often fail to do so. In some other countries, age-based assessment is an accepted policy. In the U.S., this is not a uniform policy.”
Sometimes physicians can remain on the job in spite of decline thanks to certain “props,” according to Dr. Ellison. “Good procedures, efficient supports, and various workarounds compensate,” he said, “but often are not sufficient to maintain high-quality practice.”
Most often, these situations play out slowly, until the problem becomes glaringly obvious and potentially dangerous, and someone in a position of power must step in.
“Often, it’s hearsay from a nurse or another staff member, and then a hospital president or chief of staff must make a career-affecting decision for the doctor in question,” said Dr. Katlic.
Because there is little self- or colleague policing – and barring official or binding guidelines on the aging physician issue – both Dr. Katlic and Dr. Ellison are proponents of late-career screening.
How screening can help
As it stands, Dr. Katlic maintains that the profession isn’t doing enough to ensure public safety. “We have peer review and recertification processes, but when you get down to it, we don’t police ourselves well,” he said. “All physicians are assessed throughout their careers as part of the hospital accreditation process, which is fair and adequate.”
Dr. Katlic said that there are three main benchmarks that physicians should be able to meet at an agreed upon age: a physical exam, a neurocognitive screening, and an eye exam. “At some reasonable age, I personally believe these exams should take place,” he said. “We can allow doctors to pick their own practitioners for the eye and physical exams, but the neurocognitive exam should be completed by a PhD neuropsychologist.”
At Lifebridge, for instance, these screenings begin at age 75 and take place every 2 years, during the recredentialing process. It applies to all specialties, not just surgeons. “Surgery is a little different in that it requires fine motor skills in addition to the others we test, but you want any physician to be cognitively intact,” Dr. Katlic pointed out. “All doctors need the ability to make decisions quickly, often under noisy, distracting conditions.”
Dr. Ellison supports applying the screenings to all specialties. “Let’s not forget that all physicians must be alert to the many ways in which their patients reveal what needs attention, evaluation, and treatment,” he said. “Some health care tasks could be performed without visual input; for example, perhaps psychotherapy could be provided competently by a clinician who lacks visual acuity. Auditory input might not be necessary for reading x-rays – but the information a health care provider gets from their eyes and ears is important, not just for surgeons.”
University of California San Diego has established what it calls its Physician Assessment and Clinical Education (PACE) program. One of the nation’s oldest and largest such programs, the hospital founded PACE in 1996. Most physicians taking part arrive as a requirement of disciplinary action from the state medical board, but a small percentage self-refers.
PACE involves two phases. The first is a 2-day set of tests and measures core competency knowledge. Phase 2 is more comprehensive and lasts 5 days. Here, within their specialty, physicians participate in the activities of the corresponding residency program. Faculty evaluates the physician, and a multidisciplinary team meets to review all the findings of the combined phases.
Depending on the results, doctors may face remediation steps that range from programs to address performance deficiencies to residency-level clinical experiences. According to a paper on the program published by the institution, “most physicians referred to the PACE program are found to have mild to moderate performance dyscompetence.”
In the case of the 2021 guidelines adopted by AMA delegates, there are nine principles for assessment. They should be evidence-based, ethical, relevant, accountable, fair and equitable, transparent, supportive, and nonburdensome, and should afford physicians due process protections.
Looking ahead
Even Dr. Katlic worries about the possibility of Congress intervening to establish federal-level, mandatory retirement age. “This just doesn’t make sense for our profession given the great variability we see,” he said. “My biggest hope is that more individual hospitals will institute these screenings.”
As the physician population ages – and the influx of new doctors shrinks – the slope becomes even more slippery. The AMA is predicting a physician shortage of nearly 40,000 by the year 2034. This strengthens arguments to keep existing physicians practicing for as long as possible and might make institutions less likely to screen.
It’s all a delicate balancing act and a continuing work in progress, said Dr. Ellison. “Ultimately, I believe we need to find a way to understand and address the possible implications for public safety, while at the same time protecting the privacy and dignity of our valued older physicians and other health care providers.”
A version of this article first appeared on Medscape.com.
Air traffic controllers face mandatory retirement at age 56, with exceptions up to 61. Commercial airline pilots must bow out at 65; same for foreign service employees. Physicians, however, have no age limit, regardless of specialty.
As the profession rapidly ages – some 30% of the physician workforce is currently a senior, according to the American Medical Association – the topic of whether or not there should be a standard measure or age for retirement is front and center. The AMA’s Council on Medical Education formed a workgroup to look into the issue in 2015 and 2018, and in 2021, delegates adopted a set of guidelines for screening and assessing physicians, but stopped short of a mandate.
Mark Katlic, MD, chair of surgery at Lifebridge Health System, Baltimore, has devoted a decade to studying this topic. “I’m a bit of an outlier looking into this,” he says. “The public is unaware and seemingly unconcerned about the issue. Even among the medical profession, there’s been a series of fits and starts to develop a cohesive approach.”
One of the reasons guidelines – mandatory or otherwise – have been tough to come by is that aging brings with it a huge degree of variability. “If you look at a group of 80-year-olds, there will be much more variability than within a group of 40-year-olds,” Dr. Katlic pointed out.
Indeed, some 80-year-olds can easily continue to teach college courses, keep up in 10K running races, or perform delicate surgeries. Yet others in their peer group might struggle to properly button a shirt, walk a flight of stairs, or remember yesterday’s meals. Functional age is not the same as chronological age.
Frank Stockdale, MD, PhD, an 86-year-old practicing oncologist at Stanford (Calif.) University Health, counts himself in the camp opposed to age-based assessments. “It’s age discrimination,” he says. “Physicians receive assessments throughout their careers as part of the accreditation process – there’s no need to change that as doctors reach a certain age.”
Dr. Stockdale suggests that in many cases, malpractice suits are filed against mid-career doctors, not those of advanced age. “If you’re using the argument that there is an accumulation of deficits with age, the fact is that those deficits begin well before your 70s,” he said. “It’s better to have a uniform screening policy and begin at a much younger age.”
At Stanford, in fact, there was a former assessment policy that included cognitive testing, but physicians were successful in seeing that portion of testing eliminated. “It is a physical examination, by a physician of choice, certifying that for the privileges requested there is no physical or mental reason the candidate cannot safely perform them,” Dr. Stockdale explained.
In some cases, medical staffs have filed lawsuits to fight age-related testing. In New Haven, Conn., for instance, the U.S. Equal Employment Opportunity Commission (EEOC) filed a suit in 2020 on behalf of the Yale New Haven Hospital staff, alleging a discriminatory “late career practitioner policy.”
A similar case in Minnesota reached a settlement in 2021, providing monetary relief to staff impacted by out-of-pocket costs for the assessment, in addition to requiring that the hospital in question report to the EEOC any complaints related to age discrimination.
James Ellison, MD, MPH, chair in Memory Care and Geriatrics with ChristianaCare in Wilmington, Del., points out that aging can bring benefits for practicing physicians. “Age is very individualized and there are good and bad consequences,” he said. “Experience can build knowledge and confidence and expertise, and it does improve diagnostic accuracy.”
On the flip side, however, age-related brain changes include loss of volume and lower levels of some neurotransmitters, resulting in cognitive changes. “Functional changes occur too,” Dr. Ellison said.
“Just as some aging athletes may lose a degree of speed, strength, and flexibility, and some aging scientists may lose a part of their former cognitive speed, flexibility, and mental strength, aging health care providers can lose some of the physical coordination, strength, and visual acuity necessary to perform demanding surgical operations. They can also lose some of the processing speed, working memory, and executive function that allows them to excel in cognitive professional tasks.”
An estimated 5.8 million Americans age 65 and older have Alzheimer’s dementia, according to the Alzheimer’s Association.
Picking an arbitrary age for mandatory retirement isn’t the right approach for physicians, said Dr. Katlic. Rather, he said, the answer is to establish late-practitioner screening programs. “Very few hospitals have them, however,” he pointed out. “We do [at Lifebridge Health], and so do a few dozen others, but that’s out of hundreds.”
Instead, what typically plays out is that hospital staff might begin to notice a decline in a colleague. Things like a disheveled appearance or lack of hygiene, or trouble with memory, such as getting lost en route back to his or her office. Even dangerous behaviors such as nodding off during a procedure are not unheard of.
There are many examples of physician decline that fly under the radar. “Unfortunately, it’s unusual for cognitively impaired health care providers to recognize and report their own difficulties,” said Dr. Ellison. “Although peers are expected to report cognitively impaired colleagues, they often fail to do so. In some other countries, age-based assessment is an accepted policy. In the U.S., this is not a uniform policy.”
Sometimes physicians can remain on the job in spite of decline thanks to certain “props,” according to Dr. Ellison. “Good procedures, efficient supports, and various workarounds compensate,” he said, “but often are not sufficient to maintain high-quality practice.”
Most often, these situations play out slowly, until the problem becomes glaringly obvious and potentially dangerous, and someone in a position of power must step in.
“Often, it’s hearsay from a nurse or another staff member, and then a hospital president or chief of staff must make a career-affecting decision for the doctor in question,” said Dr. Katlic.
Because there is little self- or colleague policing – and barring official or binding guidelines on the aging physician issue – both Dr. Katlic and Dr. Ellison are proponents of late-career screening.
How screening can help
As it stands, Dr. Katlic maintains that the profession isn’t doing enough to ensure public safety. “We have peer review and recertification processes, but when you get down to it, we don’t police ourselves well,” he said. “All physicians are assessed throughout their careers as part of the hospital accreditation process, which is fair and adequate.”
Dr. Katlic said that there are three main benchmarks that physicians should be able to meet at an agreed upon age: a physical exam, a neurocognitive screening, and an eye exam. “At some reasonable age, I personally believe these exams should take place,” he said. “We can allow doctors to pick their own practitioners for the eye and physical exams, but the neurocognitive exam should be completed by a PhD neuropsychologist.”
At Lifebridge, for instance, these screenings begin at age 75 and take place every 2 years, during the recredentialing process. It applies to all specialties, not just surgeons. “Surgery is a little different in that it requires fine motor skills in addition to the others we test, but you want any physician to be cognitively intact,” Dr. Katlic pointed out. “All doctors need the ability to make decisions quickly, often under noisy, distracting conditions.”
Dr. Ellison supports applying the screenings to all specialties. “Let’s not forget that all physicians must be alert to the many ways in which their patients reveal what needs attention, evaluation, and treatment,” he said. “Some health care tasks could be performed without visual input; for example, perhaps psychotherapy could be provided competently by a clinician who lacks visual acuity. Auditory input might not be necessary for reading x-rays – but the information a health care provider gets from their eyes and ears is important, not just for surgeons.”
University of California San Diego has established what it calls its Physician Assessment and Clinical Education (PACE) program. One of the nation’s oldest and largest such programs, the hospital founded PACE in 1996. Most physicians taking part arrive as a requirement of disciplinary action from the state medical board, but a small percentage self-refers.
PACE involves two phases. The first is a 2-day set of tests and measures core competency knowledge. Phase 2 is more comprehensive and lasts 5 days. Here, within their specialty, physicians participate in the activities of the corresponding residency program. Faculty evaluates the physician, and a multidisciplinary team meets to review all the findings of the combined phases.
Depending on the results, doctors may face remediation steps that range from programs to address performance deficiencies to residency-level clinical experiences. According to a paper on the program published by the institution, “most physicians referred to the PACE program are found to have mild to moderate performance dyscompetence.”
In the case of the 2021 guidelines adopted by AMA delegates, there are nine principles for assessment. They should be evidence-based, ethical, relevant, accountable, fair and equitable, transparent, supportive, and nonburdensome, and should afford physicians due process protections.
Looking ahead
Even Dr. Katlic worries about the possibility of Congress intervening to establish federal-level, mandatory retirement age. “This just doesn’t make sense for our profession given the great variability we see,” he said. “My biggest hope is that more individual hospitals will institute these screenings.”
As the physician population ages – and the influx of new doctors shrinks – the slope becomes even more slippery. The AMA is predicting a physician shortage of nearly 40,000 by the year 2034. This strengthens arguments to keep existing physicians practicing for as long as possible and might make institutions less likely to screen.
It’s all a delicate balancing act and a continuing work in progress, said Dr. Ellison. “Ultimately, I believe we need to find a way to understand and address the possible implications for public safety, while at the same time protecting the privacy and dignity of our valued older physicians and other health care providers.”
A version of this article first appeared on Medscape.com.
Neurotransmitter-based diagnosis and treatment: A hypothesis (Part 1)
It is unfortunate that, in some clinical areas, medical conditions are still treated by name and not based on the underlying pathological process. It would be odd in 2022 to treat “dropsy” instead of heart or kidney disease (2 very different causes of edema). Similarly, if the FDA had been approving drugs 150 years ago, we would have medications on label for “dementia praecox,” not schizophrenia or Alzheimer disease. With the help of DSM-5, psychiatry still resides in the descriptive symptomatic world of disorders.
In the United States, thanks to Freud, psychiatric symptoms became separated from medical symptoms, which made it more difficult to associate psychiatric manifestations with the underlying pathophysiology. Though the physical manifestations that parallel emotional symptoms—such as the dry mouth of anxiety, the tremor and leg weakness of fear, the constipation and blurry vision of depression, the breathing difficulty of anger, the abdominal pain of stress, the blushing of shyness, the palpitations of flashbacks, and endless others—are well known, the present classification of psychiatric disorders is blind to it. Neurochemical causes of gastrointestinal spasm or muscle tension are better researched than underlying central neurochemistry, though the same neurotransmitters drive them.
Can the biochemistry of psychiatric symptoms be judged on the basis of peripheral symptoms? Can the mental manifestations be connected to biological causation, and vice versa? Would psychiatrists be better off selecting treatments by recognizing involved neurotransmitters instead of addressing descriptive “depression, anxiety, and psychosis”? Each of these clinical syndromes may be caused by entirely different underlying neuronal mechanisms. Such mechanisms could be suggested if medical symptoms (which are measurable and objective) would become part of the psychiatric diagnosis. Is treating the “cough” sufficient, or would recognition that tuberculosis caused the cough guide better treatment? Is it time to abandon descriptive conditions and replace them with a specific “mechanism-based” viewpoint?
Ample research has shown that serotonin, dopamine, norepinephrine, endorphins, glutamate, and gamma aminobutyric acid (GABA) are the neurotransmitters most responsible in the process of both psychiatric disorders and chronic pain. These neurotransmitters are involved in much more than emotions (including the feeling of pain). An abundance of medical symptom clusters point toward which neurotransmitter dysfunction may be leading in specific cases of distinct types of depression, psychosis, anxiety, or “chronic pain.” Even presently, there are medications available (both for FDA-approved indications and off-label) that can be used to regulate these neurotransmitters, allowing practitioners to target the possible biological underlining of psychiatric or pain pathology. Hopefully, in the not-so-distant future, there will be specific medications for serotonin, dopamine, and noradrenergic depression as well as for GABAergic anxiety, endorphin psychosis, noradrenergic insomnia, and similar conditions.
Numerous neurotransmitters may be connected to both depression and pain in all their forms. These include (but are not limited to) prostaglandins, bradykinins, substance P, potassium, magnesium, calcium, histamine, adenosine triphosphate, calcitonin gene-related peptide (CGRP), nitric oxide (NO), cholecystokinin 7 (CCK7), neurotrophic growth factor (NGF), neurotensin, acetylcholine (Ach), oxytocin, cannabinoids, and others. These have not been researched sufficiently to identify their clinical presentation of excessive or insufficient availability at the sites of neurotransmission. It is difficult to draw conclusions about what kind of clinical symptoms they may cause (outside of pain), and therefore, they are not addressed in this article.
Both high and low levels of certain neurotransmitters may be associated with psychiatric conditions and chronic pain. Too much is as bad as too little.1 This applies to both quantity of neurotransmitters as well as quality of the corresponding receptor activity. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation. Reading indirect signs of bodily functions is a basic clinical skill that should not be forgotten, even in the time of advanced technology.
A different way of viewing psychiatric disorders
In this article, we present 4 hypothetical clinical cases to emphasize a possible way of analyzing symptoms to identify underlying pathology and guide more effective treatment. In no way do these descriptions reflect the entire set of symptoms caused by neurotransmitters; we created them based on what is presently known or suspected, and extensive research is required to confirm or disprove what we describe here.
Continue to: There are no well-recognized...
There are no well-recognized, well-established, reliable, or validated syndromes described in our work. Our goal is to suggest an alternative way of looking at psychiatric disorders by viewing syndromal presentation through the lens of specific neurotransmitters. The collection of symptoms associated with various neurotransmitters as presented in this hypothesis is not complete. We have assembled what is described in the literature as a suggestion for specific future research. We simplified these clinical presentations by omitting scenarios in which a specific neurotransmitter increases in one area but not another. For example, all the symptoms of dopamine excess we describe would not have to occur concurrently in the same patient, but they may develop in certain patients depending on which dopaminergic pathway is exhibiting excess activity. Such distinctions may be established only by exhaustive research not yet conducted.
Our proposal may seem radical, but it truly is not. For example, if we know that dopamine excess may cause seizures, psychosis, and blood pressure elevation, why not consider dopamine excess as an underlying cause in a patient with depression who exhibits these symptoms simultaneously? And why not call it “dopamine excess syndrome”? We already have “serotonin syndrome” for a patient experiencing a serotonin storm. However, using the same logic, it should be called “serotonin excess syndrome.” And if we know of “serotonin excess syndrome,” why not consider “serotonin deficiency syndrome”?
In Part 1 of this article, we discuss serotonin and dopamine. Table 1 outlines medical and psychiatric symptoms that likely reflect serotonin excess2-18 and deficiency,14,19-29 and Table 2 lists symptoms that likely reflect dopamine excess14,30-41 and deficiency.4,14,20,38,40-43 In Part 2 we will touch on endorphins and norepinephrine, and in Part 3 we will conclude by looking at GABA and glutamate.
Serotonin excess (Table 12-18)
On a recent office visit, Ms. H reports that most of the time she does not feel much of anything, but she still experiences panic attacks8,9,13,15 and is easily agitated.6,8 Her mother died recently, and Ms. H is concerned that she did not grieve.15-18 She failed her last semester in college and was indifferent to her failure.18 She sleeps poorly,8 is failing her creative classes, and wonders why she has lost her artistic inclination.16-18 Ms. H has difficulty with amotivation, planning, social interactions, and speech.16,17 All of those symptoms worsened after she was prescribed fluoxetine approximately 1 year ago for her “blues.” Ms. H is obese and continues to gain weight,2 though she frequently has diarrhea,3,4,7,8 loud peristalsis, and abdominal cramps.4,7,8 She sweats easily6-8 and her heart frequently races.8,9 Additionally, Ms. H’s primary care physician told her that she has “borderline diabetes.”2 She is prone to frequent bruising11 and is easy to shake, even when she is experiencing minimal anxiety.6-9 Ms. H had consulted with a neurologist because of unusual electrical “zapping” in her brain and muscle twitches.5,8,9,13 She had experienced a seizure as a child, but this was possibly related to hypernatremia,2 and she has not taken any anticonvulsant medication for several years.8 She exhibits hyperactive deep tendon reflexes and tremors5,7,9 and blinks frequently.6,9 She experiences hot flashes,3,6-8,14 does not tolerate heat, and prefers cooler weather.8,9 Her pains and aches,12,14 to which she has been prone all of her life, have recently become much worse, and she was diagnosed with fibromyalgia in part because she frequently feels stiff all over.10 She complains of strange tingling and prickling sensations in her hands and feet, especially when anxious.7,9,10 Her headaches also worsened and may be precipitated by bright light, as her pupils are usually dilated.5,7,9 Her hypertension is fairly controlled with medication.6,8-10 Ms. H says she experienced a psychotic episode when she was in her mid-teens,6,8 but reassures you that “she is not that bad now,” although she remains hypervigilant.13 Also while in her teens, Ms. H was treated with paroxetine and experienced restlessness, agitation, delirium, tachycardia, fluctuating blood pressure, diaphoresis, diarrhea, and neuromuscular excitation, which prompted discontinuation of the antidepressant.5-7,9,10
Impression. Ms. H exhibits symptoms associated with serotonin hyperactivity. Discontinuing and avoiding selective serotonin reuptake inhibitors (SSRIs) would be prudent; prescribing an anticonvulsant would be reasonable. Using a GABAergic medication to suppress serotonin (eg, baclofen) is likely to help. Avoiding dopaminergic medications is a must. Antidepressive antipsychotics would be logical to use. The use of serotonin-suppressing medications may be considered. One may argue for the use of beta-blockers in such a patient.
Continue to: Serotonin deficiency
Serotonin deficiency (Table 114,19-29)
Mr. A is chronically depressed, hopeless,19 and easily angered.21 He does not believe anyone can help him.19 You are concerned for his safety because he had attempted to end his life by shooting himself in the chest.19,21,22,25 Even when he’s not particularly depressed, Mr. A does not enjoy much of anything.21,26,27 He becomes particularly agitated when he drinks alcohol,25 which unfortunately is common for him.29 He engages in binge eating to feel better; he knows this is not healthy but he cannot control his behavior.20,29 Mr. A is poorly compliant with his medications, even with a blood thinner, which he was prescribed due to an episode of deep vein thrombosis. He complains of chronic daily headaches and episodic migraines.23,24 He rarely blinks,23,28 his skin is dry and cool, his hair is brittle,23 his mouth is dry,14,23,27 and he constantly licks his chapped lips.14,26,27 Mr. A frequently has general body pain26,31 but is dismissive of his body aches and completely stops reporting pain when his depression gets particularly severe. When depressed, he is slow in movement and thinking.14,21,26,27 He is more concerned with anxiety than depression.21 Mr. A is plagued by constipation, abdominal pain, muscle tension, and episodes of shaking.14,26,27 He also frequently complains about chronic tinnitus.28
Impression. Mr. A shows symptoms associated with serotonin hypoactivity. SSRIs and any other antidepressants with serotonin activity would be an obvious choice for treatment. A mood-stabilizing antipsychotic with serotonin activity would be welcome in treatment. Thyroid hormone supplementation may be of value, especially if thyroid stimulating hormone level is high. Light therapy, a diet with food that contains tryptophan, psychotherapy, and exercise are desirable. Avoiding benzodiazepines would be a good idea.
Dopamine excess (Table 214,30-41)
Ms. L presents with complaints of “fibromyalgia” and “daily headaches,”14 and also dissociation (finding herself in places when she does not know how she got there) and “out-of-body experiences.”32 She is odd, and states that people do not understand her and that she is “different.”38 Her friend, who is present at the appointment, elaborates on Ms. L’s bizarreness and oddness in behavior, out-of-context emotions, suspiciousness, paranoia, and possible hallucinations.35,36,38 Ms. L discloses frequent diffuse body pains, headaches, nausea, excessive salivation, and tongue burning, as well as muscle twitching.14 Sex worsens her headaches and body pain. She reports seizures that are not registered on EEG. In the office, she is suspicious, exhibits odd posturing, tends to misinterpret your words, and makes you feel uncomfortable. Anxiety38 and multiple obsessive-compulsive symptoms, especially excessive cleaning and grooming, complicate Ms. L’s life.31,32,34 On examination, she is hypertensive, and she has scars caused by self-cutting and skin picking on her arms.30-32 An electrocardiogram shows an elevated heart rate, widened QRS complex, and ectopic heartbeats.14 Ms. L has experienced trichotillomania since adolescence32-34 and her fingernails are bitten to the skin.34 She has difficulty with impulse control, and thrill-seeking is a prominent part of her life, mainly via gambling, compulsive sex, and compulsive buying.35,36 She also says she experiences indigestion and delayed gastric emptying.37
Impression. Ms. L exhibits multiple symptoms associated with dopamine excess. Dopamine antagonists should be considered and may help not only with her psychiatric symptoms but also with her pain symptoms. Bupropion (as a dopamine agonist), caffeine, and stimulants should be avoided.
Excessive dopamine is, in extreme cases, associated with somatic psychosis, somatic symptom disorder, factitious disorder, pain disorder, and hypochondria.39 It may come with odd and bizarre/peculiar symptoms out of proportion with objectively identified pathology. These symptoms are common in chronic pain and headache patients, and need to be addressed by appropriate use of dopamine antagonizing medications.39
Continue to: Dopamine deficiency
Dopamine deficiency (Table 24,14,20,38,40-43)
Mr. W experiences widespread pain, including chronic back pain, headaches, and abdominal pain. He also has substantial anhedonia, lack of interest, procrastination, and hypersomnia.41,42 He is apathetic and has difficulty getting up in the morning.41,42 Unusual tiredness and weakness drive him to overuse caffeine; he states that 5 Mountain Dews and 4 cups of regular coffee a day make his headaches bearable.38,41-43 Sex also improves his headaches. Since childhood, he has taken stimulants for attention-deficit/hyperactivity disorder. He reports that occasional use of cocaine helps ease his pain and depression. Mr. W’s wife is concerned with her husband’s low sexual drive and alcohol consumption, and discloses that he has periodic trouble with gambling. Mr. W was forced into psychotherapy but never was able to work productively with his therapist.38,41-43 He loves eating and cannot control his weight.40 This contrasts with episodic anorexia he experienced when he was younger.20 His face is usually emotionless.43 Mr. W is prone to constipation.14 His restless leg syndrome and periodic limb movement disorder are so bad that his wife refuses to share a bed with him.14 He is clumsy and has a problem with repetitive motor tasks.43 A paucity of speech, limited eye contact, poor grooming, and difficulty forming therapeutic alliances have long been part of Mr. W’s history.38,42,43 On physical examination, he has a dry mouth; he is stiff, tremulous, and hypotensive.14
Impression. Mr. W shows multiple symptoms associated with dopamine deficiency. Bupropion may be reasonable to consider. Dopamine augmentation via the use of stimulants is warranted in such patients, especially if stimulants had not been tried before (lisdexamfetamine would be a good choice to minimize addictive potential). For a patient with dopamine deficiency, levodopa may improve more than just restless legs. Amantadine may improve dopaminergic signaling through the accelerated dopamine release and decrease in presynaptic uptake, so this medication may be carefully tried.44 Pain treatment would not be successful for Mr. W without simultaneous treatment for his substance use.
Bottom Line
Both high and low levels of serotonin and dopamine may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.
Related Resources
- Abell SR, El-Mallakh RS. Serotonin-mediated anxiety: How to recognize and treat it. Current Psychiatry. 2021;20(11):37-40. doi:10.12788/cp.0168
Drug Brand Names
Amantadine • Gocovri
Baclofen • Ozobax
Bupropion • Wellbutrin
Fluoxetine • Prozac
Lisdexamfetamine • Vyvanse
Paroxetine • Paxil
1. Stahl SM. Dazzled by the dominions of dopamine: clinical roles of D3, D2, and D1 receptors. CNS Spectr. 2017;22(4):305-311.
2. Young RL, Lumsden AL, Martin AM, et al. Augmented capacity for peripheral serotonin release in human obesity. Int J Obes (Lond). 2018;42(11):1880-1889.
3. Ahlman H. Serotonin and carcinoid tumors. J Cardiovasc Pharmacol. 1985;7(Suppl 7):S79-S85.
4. Terry N, Margolis KG. Serotonergic mechanisms regulating the GI tract: experimental evidence and therapeutic relevance. Handb Exp Pharmacol. 2017;239:319-342.
5. Prakash S, Belani P, Trivedi A. Headache as a presenting feature in patients with serotonin syndrome: a case series. Cephalalgia. 2014;34(2):148-153.
6. van Ewijk CE, Jacobs GE, Girbes ARJ. Unsuspected serotonin toxicity in the ICU. Ann Intensive Care. 2016;6(1):85.
7. Pedavally S, Fugate JE, Rabinstein AA. Serotonin syndrome in the intensive care unit: clinical presentations and precipitating medications. Neurocrit Care. 2014;21(1):108-113.
8. Nguyen H, Pan A, Smollin C, et al. An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California Poison Control System. J Clin Pharm Ther. 2019;44(2):327-334.
9. Ansari H, Kouti L. Drug interaction and serotonin toxicity with opioid use: another reason to avoid opioids in headache and migraine treatment. Curr Pain Headache Rep. 2016;20(8):50.
10. Ott M, Mannchen JK, Jamshidi F, et al. Management of severe arterial hypertension associated with serotonin syndrome: a case report analysis based on systematic review techniques. Ther Adv Psychopharmacol. 2019;9:2045125318818814. doi:10.1177/2045125318818814
11. Cerrito F, Lazzaro MP, Gaudio E, et al. 5HT2-receptors and serotonin release: their role in human platelet aggregation. Life Sci. 1993;53(3):209-215.
12. Ohayon MM. Pain sensitivity, depression, and sleep deprivation: links with serotoninergic dysfunction. J Psychiatr Res. 2009;43(16):1243-1245.
13. Maron E, Shlik J. Serotonin function in panic disorder: important, but why? Neuropsychopharmacology. 2006;31(1):1-11.
14. Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Spanish version. Elsevier; 2011:120,199,201-204,730-740.
15. Garland EJ, Baerg EA. Amotivational syndrome associated with selective serotonin reuptake inhibitors in children and adolescents. J Child Adolesc Psychopharmacol. 2001;11(2):181-186.
16. George MS, Trimble MR. A fluvoxamine-induced frontal lobe syndrome in a patient with comorbid Gilles de la Tourette’s syndrome and obsessive compulsive disorder. J Clin Psychiatry. 1992;53(10):379-380.
17. Hoehn-Saric R, Harris GJ, Pearlson GD, et al. A fluoxetine-induced frontal lobe syndrome in an obsessive compulsive patient. J Clin Psychiatry. 1991;52(3):131-133.
18. Hoehn-Saric R, Lipsey JR, McLeod DR. Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol. 1990;10(5):343-345.
19. Samuelsson M, Jokinen J, Nordström AL, et al. CSF 5-HIAA, suicide intent and hopelessness in the prediction of early suicide in male high-risk suicide attempters. Acta Psychiatr Scand. 2006;113(1):44-47.
20. Brewerton TD. Clinical Handbook of Eating Disorders: An Integrated Approach. CRC Press; 2004:257-281.
21. Mann JJ, Oquendo M, Underwood MD, et al. The neurobiology of suicide risk: a review for the clinician. J Clin Psychiatry. 1999;60 Suppl 2:7-116.
22. Mann JJ, Malone KM. Cerebrospinal fluid amines and higher-lethality suicide attempts in depressed inpatients. Biol Psychiatry. 1997;41(2):162-171.
23. Joseph R, Welch KM, D’Andrea G. Serotonergic hypofunction in migraine: a synthesis of evidence based on platelet dense body dysfunction. Cephalalgia. 1989;9(4):293-299.
24. Pakalnis A, Splaingard M, Splaingard D, et al. Serotonin effects on sleep and emotional disorders in adolescent migraine. Headache. 2009;49(10):1486-1492.
25. Virkkunen M, Goldman D, Nielsen DA, et al. Low brain serotonin turnover rate (low CSF 5-HIAA) and impulsive violence. J Psychiatry Neurosci. 1995;20(4):271-275.
26. Liu Y, Zhao J, Fan X, et al. Dysfunction in serotonergic and noradrenergic systems and somatic symptoms in psychiatric disorders. Front Psychiatry. 2019;10:286.
27. Ginsburg GS, Riddle MA, Davies M. Somatic symptoms in children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2006;45(10):1179-1187.
28. O’Malley PG, Jackson JL, Santoro J, et al. Antidepressant therapy for unexplained symptoms and symptom syndromes. J Fam Pract. 1999;48(12):980-990.
29. Fortuna JL. Sweet preference, sugar addiction and the familial history of alcohol dependence: shared neural pathways and genes. J Psychoactive Drugs. 2010;42(2):147-151.
30. Stanley B, Sher L, Wilson S, et al. Non-suicidal self-injurious behavior, endogenous opioids and monoamine neurotransmitters. J Affect Disord. 2010;124(1-2):134-140.
31. Graybiel AM, Saka E. A genetic basis for obsessive grooming. Neuron. 2002;33(1):1-2.
32. Tse W, Hälbig TD. Skin picking in Parkinson’s disease: a behavioral side-effect of dopaminergic treatment? Psychiatry Clin Neurosci. 2010;64(2):214.
33. Ayaydın H. Probable emergence of symptoms of trichotillomania by atomoxetine: a case report. Psychiatry and Clinical Psychopharmacology. 2019;29(2)220-222.
34. Paholpak P, Mendez MF. Trichotillomania as a manifestation of dementia. Case Rep Psychiatry. 2016;2016:9782702. doi:10.1155/2016/9782702
35. Clark CA, Dagher A. The role of dopamine in risk taking: a specific look at Parkinson’s disease and gambling. Front Behav Neurosci. 2014;8:196.
36. Norbury A, Husain M. Sensation-seeking: dopaminergic modulation and risk for psychopathology. Behav Brain Res. 2015;288:79-93.
37. Chen TS, Chang FY. Elevated serum dopamine increases while coffee consumption decreases the occurrence of reddish streaks in the intact stomach. J Gastroenterol Hepatol. 2013;28(12):1810-1814.
38. Wong-Riley MT. Neuroscience Secrets. 1st edition. Spanish version. Hanley & Belfus; 1999:420-429.
39. Arbuck DM. Antipsychotics, dopamine, and pain. Current Psychiatry. 2020;19(1):25-29,31.
40. Bello NT, Hajnal A. Dopamine and binge eating behaviors. Pharmacol Biochem Behav. 2010;97(1):25-33.
41. Velligan DI, Weiden PJ, Sajatovic M, et al; Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70 Suppl 4:1-46.
42. Milev P, Ho BC, Arndt S, et al. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry. 2005;162(3):495-506.
43. Gepshtein S, Li X, Snider J, et al. Dopamine function and the efficiency of human movement. J Cogn Neurosci. 2014;26(3):645-657.
44. Scarff JR. The ABCDs of treating tardive dyskinesia. Current Psychiatry. 2020;19(4):21,55.
It is unfortunate that, in some clinical areas, medical conditions are still treated by name and not based on the underlying pathological process. It would be odd in 2022 to treat “dropsy” instead of heart or kidney disease (2 very different causes of edema). Similarly, if the FDA had been approving drugs 150 years ago, we would have medications on label for “dementia praecox,” not schizophrenia or Alzheimer disease. With the help of DSM-5, psychiatry still resides in the descriptive symptomatic world of disorders.
In the United States, thanks to Freud, psychiatric symptoms became separated from medical symptoms, which made it more difficult to associate psychiatric manifestations with the underlying pathophysiology. Though the physical manifestations that parallel emotional symptoms—such as the dry mouth of anxiety, the tremor and leg weakness of fear, the constipation and blurry vision of depression, the breathing difficulty of anger, the abdominal pain of stress, the blushing of shyness, the palpitations of flashbacks, and endless others—are well known, the present classification of psychiatric disorders is blind to it. Neurochemical causes of gastrointestinal spasm or muscle tension are better researched than underlying central neurochemistry, though the same neurotransmitters drive them.
Can the biochemistry of psychiatric symptoms be judged on the basis of peripheral symptoms? Can the mental manifestations be connected to biological causation, and vice versa? Would psychiatrists be better off selecting treatments by recognizing involved neurotransmitters instead of addressing descriptive “depression, anxiety, and psychosis”? Each of these clinical syndromes may be caused by entirely different underlying neuronal mechanisms. Such mechanisms could be suggested if medical symptoms (which are measurable and objective) would become part of the psychiatric diagnosis. Is treating the “cough” sufficient, or would recognition that tuberculosis caused the cough guide better treatment? Is it time to abandon descriptive conditions and replace them with a specific “mechanism-based” viewpoint?
Ample research has shown that serotonin, dopamine, norepinephrine, endorphins, glutamate, and gamma aminobutyric acid (GABA) are the neurotransmitters most responsible in the process of both psychiatric disorders and chronic pain. These neurotransmitters are involved in much more than emotions (including the feeling of pain). An abundance of medical symptom clusters point toward which neurotransmitter dysfunction may be leading in specific cases of distinct types of depression, psychosis, anxiety, or “chronic pain.” Even presently, there are medications available (both for FDA-approved indications and off-label) that can be used to regulate these neurotransmitters, allowing practitioners to target the possible biological underlining of psychiatric or pain pathology. Hopefully, in the not-so-distant future, there will be specific medications for serotonin, dopamine, and noradrenergic depression as well as for GABAergic anxiety, endorphin psychosis, noradrenergic insomnia, and similar conditions.
Numerous neurotransmitters may be connected to both depression and pain in all their forms. These include (but are not limited to) prostaglandins, bradykinins, substance P, potassium, magnesium, calcium, histamine, adenosine triphosphate, calcitonin gene-related peptide (CGRP), nitric oxide (NO), cholecystokinin 7 (CCK7), neurotrophic growth factor (NGF), neurotensin, acetylcholine (Ach), oxytocin, cannabinoids, and others. These have not been researched sufficiently to identify their clinical presentation of excessive or insufficient availability at the sites of neurotransmission. It is difficult to draw conclusions about what kind of clinical symptoms they may cause (outside of pain), and therefore, they are not addressed in this article.
Both high and low levels of certain neurotransmitters may be associated with psychiatric conditions and chronic pain. Too much is as bad as too little.1 This applies to both quantity of neurotransmitters as well as quality of the corresponding receptor activity. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation. Reading indirect signs of bodily functions is a basic clinical skill that should not be forgotten, even in the time of advanced technology.
A different way of viewing psychiatric disorders
In this article, we present 4 hypothetical clinical cases to emphasize a possible way of analyzing symptoms to identify underlying pathology and guide more effective treatment. In no way do these descriptions reflect the entire set of symptoms caused by neurotransmitters; we created them based on what is presently known or suspected, and extensive research is required to confirm or disprove what we describe here.
Continue to: There are no well-recognized...
There are no well-recognized, well-established, reliable, or validated syndromes described in our work. Our goal is to suggest an alternative way of looking at psychiatric disorders by viewing syndromal presentation through the lens of specific neurotransmitters. The collection of symptoms associated with various neurotransmitters as presented in this hypothesis is not complete. We have assembled what is described in the literature as a suggestion for specific future research. We simplified these clinical presentations by omitting scenarios in which a specific neurotransmitter increases in one area but not another. For example, all the symptoms of dopamine excess we describe would not have to occur concurrently in the same patient, but they may develop in certain patients depending on which dopaminergic pathway is exhibiting excess activity. Such distinctions may be established only by exhaustive research not yet conducted.
Our proposal may seem radical, but it truly is not. For example, if we know that dopamine excess may cause seizures, psychosis, and blood pressure elevation, why not consider dopamine excess as an underlying cause in a patient with depression who exhibits these symptoms simultaneously? And why not call it “dopamine excess syndrome”? We already have “serotonin syndrome” for a patient experiencing a serotonin storm. However, using the same logic, it should be called “serotonin excess syndrome.” And if we know of “serotonin excess syndrome,” why not consider “serotonin deficiency syndrome”?
In Part 1 of this article, we discuss serotonin and dopamine. Table 1 outlines medical and psychiatric symptoms that likely reflect serotonin excess2-18 and deficiency,14,19-29 and Table 2 lists symptoms that likely reflect dopamine excess14,30-41 and deficiency.4,14,20,38,40-43 In Part 2 we will touch on endorphins and norepinephrine, and in Part 3 we will conclude by looking at GABA and glutamate.
Serotonin excess (Table 12-18)
On a recent office visit, Ms. H reports that most of the time she does not feel much of anything, but she still experiences panic attacks8,9,13,15 and is easily agitated.6,8 Her mother died recently, and Ms. H is concerned that she did not grieve.15-18 She failed her last semester in college and was indifferent to her failure.18 She sleeps poorly,8 is failing her creative classes, and wonders why she has lost her artistic inclination.16-18 Ms. H has difficulty with amotivation, planning, social interactions, and speech.16,17 All of those symptoms worsened after she was prescribed fluoxetine approximately 1 year ago for her “blues.” Ms. H is obese and continues to gain weight,2 though she frequently has diarrhea,3,4,7,8 loud peristalsis, and abdominal cramps.4,7,8 She sweats easily6-8 and her heart frequently races.8,9 Additionally, Ms. H’s primary care physician told her that she has “borderline diabetes.”2 She is prone to frequent bruising11 and is easy to shake, even when she is experiencing minimal anxiety.6-9 Ms. H had consulted with a neurologist because of unusual electrical “zapping” in her brain and muscle twitches.5,8,9,13 She had experienced a seizure as a child, but this was possibly related to hypernatremia,2 and she has not taken any anticonvulsant medication for several years.8 She exhibits hyperactive deep tendon reflexes and tremors5,7,9 and blinks frequently.6,9 She experiences hot flashes,3,6-8,14 does not tolerate heat, and prefers cooler weather.8,9 Her pains and aches,12,14 to which she has been prone all of her life, have recently become much worse, and she was diagnosed with fibromyalgia in part because she frequently feels stiff all over.10 She complains of strange tingling and prickling sensations in her hands and feet, especially when anxious.7,9,10 Her headaches also worsened and may be precipitated by bright light, as her pupils are usually dilated.5,7,9 Her hypertension is fairly controlled with medication.6,8-10 Ms. H says she experienced a psychotic episode when she was in her mid-teens,6,8 but reassures you that “she is not that bad now,” although she remains hypervigilant.13 Also while in her teens, Ms. H was treated with paroxetine and experienced restlessness, agitation, delirium, tachycardia, fluctuating blood pressure, diaphoresis, diarrhea, and neuromuscular excitation, which prompted discontinuation of the antidepressant.5-7,9,10
Impression. Ms. H exhibits symptoms associated with serotonin hyperactivity. Discontinuing and avoiding selective serotonin reuptake inhibitors (SSRIs) would be prudent; prescribing an anticonvulsant would be reasonable. Using a GABAergic medication to suppress serotonin (eg, baclofen) is likely to help. Avoiding dopaminergic medications is a must. Antidepressive antipsychotics would be logical to use. The use of serotonin-suppressing medications may be considered. One may argue for the use of beta-blockers in such a patient.
Continue to: Serotonin deficiency
Serotonin deficiency (Table 114,19-29)
Mr. A is chronically depressed, hopeless,19 and easily angered.21 He does not believe anyone can help him.19 You are concerned for his safety because he had attempted to end his life by shooting himself in the chest.19,21,22,25 Even when he’s not particularly depressed, Mr. A does not enjoy much of anything.21,26,27 He becomes particularly agitated when he drinks alcohol,25 which unfortunately is common for him.29 He engages in binge eating to feel better; he knows this is not healthy but he cannot control his behavior.20,29 Mr. A is poorly compliant with his medications, even with a blood thinner, which he was prescribed due to an episode of deep vein thrombosis. He complains of chronic daily headaches and episodic migraines.23,24 He rarely blinks,23,28 his skin is dry and cool, his hair is brittle,23 his mouth is dry,14,23,27 and he constantly licks his chapped lips.14,26,27 Mr. A frequently has general body pain26,31 but is dismissive of his body aches and completely stops reporting pain when his depression gets particularly severe. When depressed, he is slow in movement and thinking.14,21,26,27 He is more concerned with anxiety than depression.21 Mr. A is plagued by constipation, abdominal pain, muscle tension, and episodes of shaking.14,26,27 He also frequently complains about chronic tinnitus.28
Impression. Mr. A shows symptoms associated with serotonin hypoactivity. SSRIs and any other antidepressants with serotonin activity would be an obvious choice for treatment. A mood-stabilizing antipsychotic with serotonin activity would be welcome in treatment. Thyroid hormone supplementation may be of value, especially if thyroid stimulating hormone level is high. Light therapy, a diet with food that contains tryptophan, psychotherapy, and exercise are desirable. Avoiding benzodiazepines would be a good idea.
Dopamine excess (Table 214,30-41)
Ms. L presents with complaints of “fibromyalgia” and “daily headaches,”14 and also dissociation (finding herself in places when she does not know how she got there) and “out-of-body experiences.”32 She is odd, and states that people do not understand her and that she is “different.”38 Her friend, who is present at the appointment, elaborates on Ms. L’s bizarreness and oddness in behavior, out-of-context emotions, suspiciousness, paranoia, and possible hallucinations.35,36,38 Ms. L discloses frequent diffuse body pains, headaches, nausea, excessive salivation, and tongue burning, as well as muscle twitching.14 Sex worsens her headaches and body pain. She reports seizures that are not registered on EEG. In the office, she is suspicious, exhibits odd posturing, tends to misinterpret your words, and makes you feel uncomfortable. Anxiety38 and multiple obsessive-compulsive symptoms, especially excessive cleaning and grooming, complicate Ms. L’s life.31,32,34 On examination, she is hypertensive, and she has scars caused by self-cutting and skin picking on her arms.30-32 An electrocardiogram shows an elevated heart rate, widened QRS complex, and ectopic heartbeats.14 Ms. L has experienced trichotillomania since adolescence32-34 and her fingernails are bitten to the skin.34 She has difficulty with impulse control, and thrill-seeking is a prominent part of her life, mainly via gambling, compulsive sex, and compulsive buying.35,36 She also says she experiences indigestion and delayed gastric emptying.37
Impression. Ms. L exhibits multiple symptoms associated with dopamine excess. Dopamine antagonists should be considered and may help not only with her psychiatric symptoms but also with her pain symptoms. Bupropion (as a dopamine agonist), caffeine, and stimulants should be avoided.
Excessive dopamine is, in extreme cases, associated with somatic psychosis, somatic symptom disorder, factitious disorder, pain disorder, and hypochondria.39 It may come with odd and bizarre/peculiar symptoms out of proportion with objectively identified pathology. These symptoms are common in chronic pain and headache patients, and need to be addressed by appropriate use of dopamine antagonizing medications.39
Continue to: Dopamine deficiency
Dopamine deficiency (Table 24,14,20,38,40-43)
Mr. W experiences widespread pain, including chronic back pain, headaches, and abdominal pain. He also has substantial anhedonia, lack of interest, procrastination, and hypersomnia.41,42 He is apathetic and has difficulty getting up in the morning.41,42 Unusual tiredness and weakness drive him to overuse caffeine; he states that 5 Mountain Dews and 4 cups of regular coffee a day make his headaches bearable.38,41-43 Sex also improves his headaches. Since childhood, he has taken stimulants for attention-deficit/hyperactivity disorder. He reports that occasional use of cocaine helps ease his pain and depression. Mr. W’s wife is concerned with her husband’s low sexual drive and alcohol consumption, and discloses that he has periodic trouble with gambling. Mr. W was forced into psychotherapy but never was able to work productively with his therapist.38,41-43 He loves eating and cannot control his weight.40 This contrasts with episodic anorexia he experienced when he was younger.20 His face is usually emotionless.43 Mr. W is prone to constipation.14 His restless leg syndrome and periodic limb movement disorder are so bad that his wife refuses to share a bed with him.14 He is clumsy and has a problem with repetitive motor tasks.43 A paucity of speech, limited eye contact, poor grooming, and difficulty forming therapeutic alliances have long been part of Mr. W’s history.38,42,43 On physical examination, he has a dry mouth; he is stiff, tremulous, and hypotensive.14
Impression. Mr. W shows multiple symptoms associated with dopamine deficiency. Bupropion may be reasonable to consider. Dopamine augmentation via the use of stimulants is warranted in such patients, especially if stimulants had not been tried before (lisdexamfetamine would be a good choice to minimize addictive potential). For a patient with dopamine deficiency, levodopa may improve more than just restless legs. Amantadine may improve dopaminergic signaling through the accelerated dopamine release and decrease in presynaptic uptake, so this medication may be carefully tried.44 Pain treatment would not be successful for Mr. W without simultaneous treatment for his substance use.
Bottom Line
Both high and low levels of serotonin and dopamine may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.
Related Resources
- Abell SR, El-Mallakh RS. Serotonin-mediated anxiety: How to recognize and treat it. Current Psychiatry. 2021;20(11):37-40. doi:10.12788/cp.0168
Drug Brand Names
Amantadine • Gocovri
Baclofen • Ozobax
Bupropion • Wellbutrin
Fluoxetine • Prozac
Lisdexamfetamine • Vyvanse
Paroxetine • Paxil
It is unfortunate that, in some clinical areas, medical conditions are still treated by name and not based on the underlying pathological process. It would be odd in 2022 to treat “dropsy” instead of heart or kidney disease (2 very different causes of edema). Similarly, if the FDA had been approving drugs 150 years ago, we would have medications on label for “dementia praecox,” not schizophrenia or Alzheimer disease. With the help of DSM-5, psychiatry still resides in the descriptive symptomatic world of disorders.
In the United States, thanks to Freud, psychiatric symptoms became separated from medical symptoms, which made it more difficult to associate psychiatric manifestations with the underlying pathophysiology. Though the physical manifestations that parallel emotional symptoms—such as the dry mouth of anxiety, the tremor and leg weakness of fear, the constipation and blurry vision of depression, the breathing difficulty of anger, the abdominal pain of stress, the blushing of shyness, the palpitations of flashbacks, and endless others—are well known, the present classification of psychiatric disorders is blind to it. Neurochemical causes of gastrointestinal spasm or muscle tension are better researched than underlying central neurochemistry, though the same neurotransmitters drive them.
Can the biochemistry of psychiatric symptoms be judged on the basis of peripheral symptoms? Can the mental manifestations be connected to biological causation, and vice versa? Would psychiatrists be better off selecting treatments by recognizing involved neurotransmitters instead of addressing descriptive “depression, anxiety, and psychosis”? Each of these clinical syndromes may be caused by entirely different underlying neuronal mechanisms. Such mechanisms could be suggested if medical symptoms (which are measurable and objective) would become part of the psychiatric diagnosis. Is treating the “cough” sufficient, or would recognition that tuberculosis caused the cough guide better treatment? Is it time to abandon descriptive conditions and replace them with a specific “mechanism-based” viewpoint?
Ample research has shown that serotonin, dopamine, norepinephrine, endorphins, glutamate, and gamma aminobutyric acid (GABA) are the neurotransmitters most responsible in the process of both psychiatric disorders and chronic pain. These neurotransmitters are involved in much more than emotions (including the feeling of pain). An abundance of medical symptom clusters point toward which neurotransmitter dysfunction may be leading in specific cases of distinct types of depression, psychosis, anxiety, or “chronic pain.” Even presently, there are medications available (both for FDA-approved indications and off-label) that can be used to regulate these neurotransmitters, allowing practitioners to target the possible biological underlining of psychiatric or pain pathology. Hopefully, in the not-so-distant future, there will be specific medications for serotonin, dopamine, and noradrenergic depression as well as for GABAergic anxiety, endorphin psychosis, noradrenergic insomnia, and similar conditions.
Numerous neurotransmitters may be connected to both depression and pain in all their forms. These include (but are not limited to) prostaglandins, bradykinins, substance P, potassium, magnesium, calcium, histamine, adenosine triphosphate, calcitonin gene-related peptide (CGRP), nitric oxide (NO), cholecystokinin 7 (CCK7), neurotrophic growth factor (NGF), neurotensin, acetylcholine (Ach), oxytocin, cannabinoids, and others. These have not been researched sufficiently to identify their clinical presentation of excessive or insufficient availability at the sites of neurotransmission. It is difficult to draw conclusions about what kind of clinical symptoms they may cause (outside of pain), and therefore, they are not addressed in this article.
Both high and low levels of certain neurotransmitters may be associated with psychiatric conditions and chronic pain. Too much is as bad as too little.1 This applies to both quantity of neurotransmitters as well as quality of the corresponding receptor activity. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation. Reading indirect signs of bodily functions is a basic clinical skill that should not be forgotten, even in the time of advanced technology.
A different way of viewing psychiatric disorders
In this article, we present 4 hypothetical clinical cases to emphasize a possible way of analyzing symptoms to identify underlying pathology and guide more effective treatment. In no way do these descriptions reflect the entire set of symptoms caused by neurotransmitters; we created them based on what is presently known or suspected, and extensive research is required to confirm or disprove what we describe here.
Continue to: There are no well-recognized...
There are no well-recognized, well-established, reliable, or validated syndromes described in our work. Our goal is to suggest an alternative way of looking at psychiatric disorders by viewing syndromal presentation through the lens of specific neurotransmitters. The collection of symptoms associated with various neurotransmitters as presented in this hypothesis is not complete. We have assembled what is described in the literature as a suggestion for specific future research. We simplified these clinical presentations by omitting scenarios in which a specific neurotransmitter increases in one area but not another. For example, all the symptoms of dopamine excess we describe would not have to occur concurrently in the same patient, but they may develop in certain patients depending on which dopaminergic pathway is exhibiting excess activity. Such distinctions may be established only by exhaustive research not yet conducted.
Our proposal may seem radical, but it truly is not. For example, if we know that dopamine excess may cause seizures, psychosis, and blood pressure elevation, why not consider dopamine excess as an underlying cause in a patient with depression who exhibits these symptoms simultaneously? And why not call it “dopamine excess syndrome”? We already have “serotonin syndrome” for a patient experiencing a serotonin storm. However, using the same logic, it should be called “serotonin excess syndrome.” And if we know of “serotonin excess syndrome,” why not consider “serotonin deficiency syndrome”?
In Part 1 of this article, we discuss serotonin and dopamine. Table 1 outlines medical and psychiatric symptoms that likely reflect serotonin excess2-18 and deficiency,14,19-29 and Table 2 lists symptoms that likely reflect dopamine excess14,30-41 and deficiency.4,14,20,38,40-43 In Part 2 we will touch on endorphins and norepinephrine, and in Part 3 we will conclude by looking at GABA and glutamate.
Serotonin excess (Table 12-18)
On a recent office visit, Ms. H reports that most of the time she does not feel much of anything, but she still experiences panic attacks8,9,13,15 and is easily agitated.6,8 Her mother died recently, and Ms. H is concerned that she did not grieve.15-18 She failed her last semester in college and was indifferent to her failure.18 She sleeps poorly,8 is failing her creative classes, and wonders why she has lost her artistic inclination.16-18 Ms. H has difficulty with amotivation, planning, social interactions, and speech.16,17 All of those symptoms worsened after she was prescribed fluoxetine approximately 1 year ago for her “blues.” Ms. H is obese and continues to gain weight,2 though she frequently has diarrhea,3,4,7,8 loud peristalsis, and abdominal cramps.4,7,8 She sweats easily6-8 and her heart frequently races.8,9 Additionally, Ms. H’s primary care physician told her that she has “borderline diabetes.”2 She is prone to frequent bruising11 and is easy to shake, even when she is experiencing minimal anxiety.6-9 Ms. H had consulted with a neurologist because of unusual electrical “zapping” in her brain and muscle twitches.5,8,9,13 She had experienced a seizure as a child, but this was possibly related to hypernatremia,2 and she has not taken any anticonvulsant medication for several years.8 She exhibits hyperactive deep tendon reflexes and tremors5,7,9 and blinks frequently.6,9 She experiences hot flashes,3,6-8,14 does not tolerate heat, and prefers cooler weather.8,9 Her pains and aches,12,14 to which she has been prone all of her life, have recently become much worse, and she was diagnosed with fibromyalgia in part because she frequently feels stiff all over.10 She complains of strange tingling and prickling sensations in her hands and feet, especially when anxious.7,9,10 Her headaches also worsened and may be precipitated by bright light, as her pupils are usually dilated.5,7,9 Her hypertension is fairly controlled with medication.6,8-10 Ms. H says she experienced a psychotic episode when she was in her mid-teens,6,8 but reassures you that “she is not that bad now,” although she remains hypervigilant.13 Also while in her teens, Ms. H was treated with paroxetine and experienced restlessness, agitation, delirium, tachycardia, fluctuating blood pressure, diaphoresis, diarrhea, and neuromuscular excitation, which prompted discontinuation of the antidepressant.5-7,9,10
Impression. Ms. H exhibits symptoms associated with serotonin hyperactivity. Discontinuing and avoiding selective serotonin reuptake inhibitors (SSRIs) would be prudent; prescribing an anticonvulsant would be reasonable. Using a GABAergic medication to suppress serotonin (eg, baclofen) is likely to help. Avoiding dopaminergic medications is a must. Antidepressive antipsychotics would be logical to use. The use of serotonin-suppressing medications may be considered. One may argue for the use of beta-blockers in such a patient.
Continue to: Serotonin deficiency
Serotonin deficiency (Table 114,19-29)
Mr. A is chronically depressed, hopeless,19 and easily angered.21 He does not believe anyone can help him.19 You are concerned for his safety because he had attempted to end his life by shooting himself in the chest.19,21,22,25 Even when he’s not particularly depressed, Mr. A does not enjoy much of anything.21,26,27 He becomes particularly agitated when he drinks alcohol,25 which unfortunately is common for him.29 He engages in binge eating to feel better; he knows this is not healthy but he cannot control his behavior.20,29 Mr. A is poorly compliant with his medications, even with a blood thinner, which he was prescribed due to an episode of deep vein thrombosis. He complains of chronic daily headaches and episodic migraines.23,24 He rarely blinks,23,28 his skin is dry and cool, his hair is brittle,23 his mouth is dry,14,23,27 and he constantly licks his chapped lips.14,26,27 Mr. A frequently has general body pain26,31 but is dismissive of his body aches and completely stops reporting pain when his depression gets particularly severe. When depressed, he is slow in movement and thinking.14,21,26,27 He is more concerned with anxiety than depression.21 Mr. A is plagued by constipation, abdominal pain, muscle tension, and episodes of shaking.14,26,27 He also frequently complains about chronic tinnitus.28
Impression. Mr. A shows symptoms associated with serotonin hypoactivity. SSRIs and any other antidepressants with serotonin activity would be an obvious choice for treatment. A mood-stabilizing antipsychotic with serotonin activity would be welcome in treatment. Thyroid hormone supplementation may be of value, especially if thyroid stimulating hormone level is high. Light therapy, a diet with food that contains tryptophan, psychotherapy, and exercise are desirable. Avoiding benzodiazepines would be a good idea.
Dopamine excess (Table 214,30-41)
Ms. L presents with complaints of “fibromyalgia” and “daily headaches,”14 and also dissociation (finding herself in places when she does not know how she got there) and “out-of-body experiences.”32 She is odd, and states that people do not understand her and that she is “different.”38 Her friend, who is present at the appointment, elaborates on Ms. L’s bizarreness and oddness in behavior, out-of-context emotions, suspiciousness, paranoia, and possible hallucinations.35,36,38 Ms. L discloses frequent diffuse body pains, headaches, nausea, excessive salivation, and tongue burning, as well as muscle twitching.14 Sex worsens her headaches and body pain. She reports seizures that are not registered on EEG. In the office, she is suspicious, exhibits odd posturing, tends to misinterpret your words, and makes you feel uncomfortable. Anxiety38 and multiple obsessive-compulsive symptoms, especially excessive cleaning and grooming, complicate Ms. L’s life.31,32,34 On examination, she is hypertensive, and she has scars caused by self-cutting and skin picking on her arms.30-32 An electrocardiogram shows an elevated heart rate, widened QRS complex, and ectopic heartbeats.14 Ms. L has experienced trichotillomania since adolescence32-34 and her fingernails are bitten to the skin.34 She has difficulty with impulse control, and thrill-seeking is a prominent part of her life, mainly via gambling, compulsive sex, and compulsive buying.35,36 She also says she experiences indigestion and delayed gastric emptying.37
Impression. Ms. L exhibits multiple symptoms associated with dopamine excess. Dopamine antagonists should be considered and may help not only with her psychiatric symptoms but also with her pain symptoms. Bupropion (as a dopamine agonist), caffeine, and stimulants should be avoided.
Excessive dopamine is, in extreme cases, associated with somatic psychosis, somatic symptom disorder, factitious disorder, pain disorder, and hypochondria.39 It may come with odd and bizarre/peculiar symptoms out of proportion with objectively identified pathology. These symptoms are common in chronic pain and headache patients, and need to be addressed by appropriate use of dopamine antagonizing medications.39
Continue to: Dopamine deficiency
Dopamine deficiency (Table 24,14,20,38,40-43)
Mr. W experiences widespread pain, including chronic back pain, headaches, and abdominal pain. He also has substantial anhedonia, lack of interest, procrastination, and hypersomnia.41,42 He is apathetic and has difficulty getting up in the morning.41,42 Unusual tiredness and weakness drive him to overuse caffeine; he states that 5 Mountain Dews and 4 cups of regular coffee a day make his headaches bearable.38,41-43 Sex also improves his headaches. Since childhood, he has taken stimulants for attention-deficit/hyperactivity disorder. He reports that occasional use of cocaine helps ease his pain and depression. Mr. W’s wife is concerned with her husband’s low sexual drive and alcohol consumption, and discloses that he has periodic trouble with gambling. Mr. W was forced into psychotherapy but never was able to work productively with his therapist.38,41-43 He loves eating and cannot control his weight.40 This contrasts with episodic anorexia he experienced when he was younger.20 His face is usually emotionless.43 Mr. W is prone to constipation.14 His restless leg syndrome and periodic limb movement disorder are so bad that his wife refuses to share a bed with him.14 He is clumsy and has a problem with repetitive motor tasks.43 A paucity of speech, limited eye contact, poor grooming, and difficulty forming therapeutic alliances have long been part of Mr. W’s history.38,42,43 On physical examination, he has a dry mouth; he is stiff, tremulous, and hypotensive.14
Impression. Mr. W shows multiple symptoms associated with dopamine deficiency. Bupropion may be reasonable to consider. Dopamine augmentation via the use of stimulants is warranted in such patients, especially if stimulants had not been tried before (lisdexamfetamine would be a good choice to minimize addictive potential). For a patient with dopamine deficiency, levodopa may improve more than just restless legs. Amantadine may improve dopaminergic signaling through the accelerated dopamine release and decrease in presynaptic uptake, so this medication may be carefully tried.44 Pain treatment would not be successful for Mr. W without simultaneous treatment for his substance use.
Bottom Line
Both high and low levels of serotonin and dopamine may be associated with certain psychiatric and medical symptoms and disorders. An astute clinician may judge which neurotransmitter is dysfunctional based on the patient’s presentation, and tailor treatment accordingly.
Related Resources
- Abell SR, El-Mallakh RS. Serotonin-mediated anxiety: How to recognize and treat it. Current Psychiatry. 2021;20(11):37-40. doi:10.12788/cp.0168
Drug Brand Names
Amantadine • Gocovri
Baclofen • Ozobax
Bupropion • Wellbutrin
Fluoxetine • Prozac
Lisdexamfetamine • Vyvanse
Paroxetine • Paxil
1. Stahl SM. Dazzled by the dominions of dopamine: clinical roles of D3, D2, and D1 receptors. CNS Spectr. 2017;22(4):305-311.
2. Young RL, Lumsden AL, Martin AM, et al. Augmented capacity for peripheral serotonin release in human obesity. Int J Obes (Lond). 2018;42(11):1880-1889.
3. Ahlman H. Serotonin and carcinoid tumors. J Cardiovasc Pharmacol. 1985;7(Suppl 7):S79-S85.
4. Terry N, Margolis KG. Serotonergic mechanisms regulating the GI tract: experimental evidence and therapeutic relevance. Handb Exp Pharmacol. 2017;239:319-342.
5. Prakash S, Belani P, Trivedi A. Headache as a presenting feature in patients with serotonin syndrome: a case series. Cephalalgia. 2014;34(2):148-153.
6. van Ewijk CE, Jacobs GE, Girbes ARJ. Unsuspected serotonin toxicity in the ICU. Ann Intensive Care. 2016;6(1):85.
7. Pedavally S, Fugate JE, Rabinstein AA. Serotonin syndrome in the intensive care unit: clinical presentations and precipitating medications. Neurocrit Care. 2014;21(1):108-113.
8. Nguyen H, Pan A, Smollin C, et al. An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California Poison Control System. J Clin Pharm Ther. 2019;44(2):327-334.
9. Ansari H, Kouti L. Drug interaction and serotonin toxicity with opioid use: another reason to avoid opioids in headache and migraine treatment. Curr Pain Headache Rep. 2016;20(8):50.
10. Ott M, Mannchen JK, Jamshidi F, et al. Management of severe arterial hypertension associated with serotonin syndrome: a case report analysis based on systematic review techniques. Ther Adv Psychopharmacol. 2019;9:2045125318818814. doi:10.1177/2045125318818814
11. Cerrito F, Lazzaro MP, Gaudio E, et al. 5HT2-receptors and serotonin release: their role in human platelet aggregation. Life Sci. 1993;53(3):209-215.
12. Ohayon MM. Pain sensitivity, depression, and sleep deprivation: links with serotoninergic dysfunction. J Psychiatr Res. 2009;43(16):1243-1245.
13. Maron E, Shlik J. Serotonin function in panic disorder: important, but why? Neuropsychopharmacology. 2006;31(1):1-11.
14. Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Spanish version. Elsevier; 2011:120,199,201-204,730-740.
15. Garland EJ, Baerg EA. Amotivational syndrome associated with selective serotonin reuptake inhibitors in children and adolescents. J Child Adolesc Psychopharmacol. 2001;11(2):181-186.
16. George MS, Trimble MR. A fluvoxamine-induced frontal lobe syndrome in a patient with comorbid Gilles de la Tourette’s syndrome and obsessive compulsive disorder. J Clin Psychiatry. 1992;53(10):379-380.
17. Hoehn-Saric R, Harris GJ, Pearlson GD, et al. A fluoxetine-induced frontal lobe syndrome in an obsessive compulsive patient. J Clin Psychiatry. 1991;52(3):131-133.
18. Hoehn-Saric R, Lipsey JR, McLeod DR. Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol. 1990;10(5):343-345.
19. Samuelsson M, Jokinen J, Nordström AL, et al. CSF 5-HIAA, suicide intent and hopelessness in the prediction of early suicide in male high-risk suicide attempters. Acta Psychiatr Scand. 2006;113(1):44-47.
20. Brewerton TD. Clinical Handbook of Eating Disorders: An Integrated Approach. CRC Press; 2004:257-281.
21. Mann JJ, Oquendo M, Underwood MD, et al. The neurobiology of suicide risk: a review for the clinician. J Clin Psychiatry. 1999;60 Suppl 2:7-116.
22. Mann JJ, Malone KM. Cerebrospinal fluid amines and higher-lethality suicide attempts in depressed inpatients. Biol Psychiatry. 1997;41(2):162-171.
23. Joseph R, Welch KM, D’Andrea G. Serotonergic hypofunction in migraine: a synthesis of evidence based on platelet dense body dysfunction. Cephalalgia. 1989;9(4):293-299.
24. Pakalnis A, Splaingard M, Splaingard D, et al. Serotonin effects on sleep and emotional disorders in adolescent migraine. Headache. 2009;49(10):1486-1492.
25. Virkkunen M, Goldman D, Nielsen DA, et al. Low brain serotonin turnover rate (low CSF 5-HIAA) and impulsive violence. J Psychiatry Neurosci. 1995;20(4):271-275.
26. Liu Y, Zhao J, Fan X, et al. Dysfunction in serotonergic and noradrenergic systems and somatic symptoms in psychiatric disorders. Front Psychiatry. 2019;10:286.
27. Ginsburg GS, Riddle MA, Davies M. Somatic symptoms in children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2006;45(10):1179-1187.
28. O’Malley PG, Jackson JL, Santoro J, et al. Antidepressant therapy for unexplained symptoms and symptom syndromes. J Fam Pract. 1999;48(12):980-990.
29. Fortuna JL. Sweet preference, sugar addiction and the familial history of alcohol dependence: shared neural pathways and genes. J Psychoactive Drugs. 2010;42(2):147-151.
30. Stanley B, Sher L, Wilson S, et al. Non-suicidal self-injurious behavior, endogenous opioids and monoamine neurotransmitters. J Affect Disord. 2010;124(1-2):134-140.
31. Graybiel AM, Saka E. A genetic basis for obsessive grooming. Neuron. 2002;33(1):1-2.
32. Tse W, Hälbig TD. Skin picking in Parkinson’s disease: a behavioral side-effect of dopaminergic treatment? Psychiatry Clin Neurosci. 2010;64(2):214.
33. Ayaydın H. Probable emergence of symptoms of trichotillomania by atomoxetine: a case report. Psychiatry and Clinical Psychopharmacology. 2019;29(2)220-222.
34. Paholpak P, Mendez MF. Trichotillomania as a manifestation of dementia. Case Rep Psychiatry. 2016;2016:9782702. doi:10.1155/2016/9782702
35. Clark CA, Dagher A. The role of dopamine in risk taking: a specific look at Parkinson’s disease and gambling. Front Behav Neurosci. 2014;8:196.
36. Norbury A, Husain M. Sensation-seeking: dopaminergic modulation and risk for psychopathology. Behav Brain Res. 2015;288:79-93.
37. Chen TS, Chang FY. Elevated serum dopamine increases while coffee consumption decreases the occurrence of reddish streaks in the intact stomach. J Gastroenterol Hepatol. 2013;28(12):1810-1814.
38. Wong-Riley MT. Neuroscience Secrets. 1st edition. Spanish version. Hanley & Belfus; 1999:420-429.
39. Arbuck DM. Antipsychotics, dopamine, and pain. Current Psychiatry. 2020;19(1):25-29,31.
40. Bello NT, Hajnal A. Dopamine and binge eating behaviors. Pharmacol Biochem Behav. 2010;97(1):25-33.
41. Velligan DI, Weiden PJ, Sajatovic M, et al; Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70 Suppl 4:1-46.
42. Milev P, Ho BC, Arndt S, et al. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry. 2005;162(3):495-506.
43. Gepshtein S, Li X, Snider J, et al. Dopamine function and the efficiency of human movement. J Cogn Neurosci. 2014;26(3):645-657.
44. Scarff JR. The ABCDs of treating tardive dyskinesia. Current Psychiatry. 2020;19(4):21,55.
1. Stahl SM. Dazzled by the dominions of dopamine: clinical roles of D3, D2, and D1 receptors. CNS Spectr. 2017;22(4):305-311.
2. Young RL, Lumsden AL, Martin AM, et al. Augmented capacity for peripheral serotonin release in human obesity. Int J Obes (Lond). 2018;42(11):1880-1889.
3. Ahlman H. Serotonin and carcinoid tumors. J Cardiovasc Pharmacol. 1985;7(Suppl 7):S79-S85.
4. Terry N, Margolis KG. Serotonergic mechanisms regulating the GI tract: experimental evidence and therapeutic relevance. Handb Exp Pharmacol. 2017;239:319-342.
5. Prakash S, Belani P, Trivedi A. Headache as a presenting feature in patients with serotonin syndrome: a case series. Cephalalgia. 2014;34(2):148-153.
6. van Ewijk CE, Jacobs GE, Girbes ARJ. Unsuspected serotonin toxicity in the ICU. Ann Intensive Care. 2016;6(1):85.
7. Pedavally S, Fugate JE, Rabinstein AA. Serotonin syndrome in the intensive care unit: clinical presentations and precipitating medications. Neurocrit Care. 2014;21(1):108-113.
8. Nguyen H, Pan A, Smollin C, et al. An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California Poison Control System. J Clin Pharm Ther. 2019;44(2):327-334.
9. Ansari H, Kouti L. Drug interaction and serotonin toxicity with opioid use: another reason to avoid opioids in headache and migraine treatment. Curr Pain Headache Rep. 2016;20(8):50.
10. Ott M, Mannchen JK, Jamshidi F, et al. Management of severe arterial hypertension associated with serotonin syndrome: a case report analysis based on systematic review techniques. Ther Adv Psychopharmacol. 2019;9:2045125318818814. doi:10.1177/2045125318818814
11. Cerrito F, Lazzaro MP, Gaudio E, et al. 5HT2-receptors and serotonin release: their role in human platelet aggregation. Life Sci. 1993;53(3):209-215.
12. Ohayon MM. Pain sensitivity, depression, and sleep deprivation: links with serotoninergic dysfunction. J Psychiatr Res. 2009;43(16):1243-1245.
13. Maron E, Shlik J. Serotonin function in panic disorder: important, but why? Neuropsychopharmacology. 2006;31(1):1-11.
14. Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Spanish version. Elsevier; 2011:120,199,201-204,730-740.
15. Garland EJ, Baerg EA. Amotivational syndrome associated with selective serotonin reuptake inhibitors in children and adolescents. J Child Adolesc Psychopharmacol. 2001;11(2):181-186.
16. George MS, Trimble MR. A fluvoxamine-induced frontal lobe syndrome in a patient with comorbid Gilles de la Tourette’s syndrome and obsessive compulsive disorder. J Clin Psychiatry. 1992;53(10):379-380.
17. Hoehn-Saric R, Harris GJ, Pearlson GD, et al. A fluoxetine-induced frontal lobe syndrome in an obsessive compulsive patient. J Clin Psychiatry. 1991;52(3):131-133.
18. Hoehn-Saric R, Lipsey JR, McLeod DR. Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol. 1990;10(5):343-345.
19. Samuelsson M, Jokinen J, Nordström AL, et al. CSF 5-HIAA, suicide intent and hopelessness in the prediction of early suicide in male high-risk suicide attempters. Acta Psychiatr Scand. 2006;113(1):44-47.
20. Brewerton TD. Clinical Handbook of Eating Disorders: An Integrated Approach. CRC Press; 2004:257-281.
21. Mann JJ, Oquendo M, Underwood MD, et al. The neurobiology of suicide risk: a review for the clinician. J Clin Psychiatry. 1999;60 Suppl 2:7-116.
22. Mann JJ, Malone KM. Cerebrospinal fluid amines and higher-lethality suicide attempts in depressed inpatients. Biol Psychiatry. 1997;41(2):162-171.
23. Joseph R, Welch KM, D’Andrea G. Serotonergic hypofunction in migraine: a synthesis of evidence based on platelet dense body dysfunction. Cephalalgia. 1989;9(4):293-299.
24. Pakalnis A, Splaingard M, Splaingard D, et al. Serotonin effects on sleep and emotional disorders in adolescent migraine. Headache. 2009;49(10):1486-1492.
25. Virkkunen M, Goldman D, Nielsen DA, et al. Low brain serotonin turnover rate (low CSF 5-HIAA) and impulsive violence. J Psychiatry Neurosci. 1995;20(4):271-275.
26. Liu Y, Zhao J, Fan X, et al. Dysfunction in serotonergic and noradrenergic systems and somatic symptoms in psychiatric disorders. Front Psychiatry. 2019;10:286.
27. Ginsburg GS, Riddle MA, Davies M. Somatic symptoms in children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2006;45(10):1179-1187.
28. O’Malley PG, Jackson JL, Santoro J, et al. Antidepressant therapy for unexplained symptoms and symptom syndromes. J Fam Pract. 1999;48(12):980-990.
29. Fortuna JL. Sweet preference, sugar addiction and the familial history of alcohol dependence: shared neural pathways and genes. J Psychoactive Drugs. 2010;42(2):147-151.
30. Stanley B, Sher L, Wilson S, et al. Non-suicidal self-injurious behavior, endogenous opioids and monoamine neurotransmitters. J Affect Disord. 2010;124(1-2):134-140.
31. Graybiel AM, Saka E. A genetic basis for obsessive grooming. Neuron. 2002;33(1):1-2.
32. Tse W, Hälbig TD. Skin picking in Parkinson’s disease: a behavioral side-effect of dopaminergic treatment? Psychiatry Clin Neurosci. 2010;64(2):214.
33. Ayaydın H. Probable emergence of symptoms of trichotillomania by atomoxetine: a case report. Psychiatry and Clinical Psychopharmacology. 2019;29(2)220-222.
34. Paholpak P, Mendez MF. Trichotillomania as a manifestation of dementia. Case Rep Psychiatry. 2016;2016:9782702. doi:10.1155/2016/9782702
35. Clark CA, Dagher A. The role of dopamine in risk taking: a specific look at Parkinson’s disease and gambling. Front Behav Neurosci. 2014;8:196.
36. Norbury A, Husain M. Sensation-seeking: dopaminergic modulation and risk for psychopathology. Behav Brain Res. 2015;288:79-93.
37. Chen TS, Chang FY. Elevated serum dopamine increases while coffee consumption decreases the occurrence of reddish streaks in the intact stomach. J Gastroenterol Hepatol. 2013;28(12):1810-1814.
38. Wong-Riley MT. Neuroscience Secrets. 1st edition. Spanish version. Hanley & Belfus; 1999:420-429.
39. Arbuck DM. Antipsychotics, dopamine, and pain. Current Psychiatry. 2020;19(1):25-29,31.
40. Bello NT, Hajnal A. Dopamine and binge eating behaviors. Pharmacol Biochem Behav. 2010;97(1):25-33.
41. Velligan DI, Weiden PJ, Sajatovic M, et al; Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70 Suppl 4:1-46.
42. Milev P, Ho BC, Arndt S, et al. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry. 2005;162(3):495-506.
43. Gepshtein S, Li X, Snider J, et al. Dopamine function and the efficiency of human movement. J Cogn Neurosci. 2014;26(3):645-657.
44. Scarff JR. The ABCDs of treating tardive dyskinesia. Current Psychiatry. 2020;19(4):21,55.
30 years of fake nursing ends with 7-year prison sentence
A Canadian woman who officials allege faked being a registered nurse for some 30 years in Canada and the United States is scheduled to appear in court next month after being sentenced to 7 years in prison.
She was previously sentenced April 22 in an Ontario court after she pled guilty in January to seven offenses, including impersonation, assault with a weapon, and assault, according to CBC Radio-Canada.
Ms. Cleroux, who uses several aliases, had a long history of deception in three provinces in Canada, as well as in Colorado and Florida. The sentencing in Ontario stemmed from incidents at a medical and dental clinic in Ottawa last year, which included administration of medications to patients through needle injections, Ottawa Police reported in a press statement obtained by this news organization.
Authorities charged Ms. Cleroux in September with assault with a weapon and criminal negligence causing bodily harm, along with “personation to gain advantage,” obtaining by false pretense, and using a forged document, this news organization reported.
Ms. Cleroux has been in custody since her arrest by Ottawa Police in August.
The Vancouver Police Department (VPD) charged Ms. Cleroux last year with fraud of over $5,000 and personation with intent. VPD investigated claims that an employee at BC Women’s Hospital fraudulently identified herself as a nurse while working there between June 2020 and June 2021, according to a VPD press release.
Nursing colleges in British Columbia and Ontario issued warnings that she had used aliases and purported to be a registered nurse to gain employment. The aliases included Melanie Thompson, Melanie Smith, and Melanie Cleroux.
Ms. Cleroux was believed to be a student in a nursing school in Colorado, but she only completed 2 years of a 4-year nursing course and was never certified as a nurse, according to CBC. Her criminal record dates back 30 years and includes 67 adult convictions and other convictions in her youth, CBC reported.
A version of this article first appeared on Medscape.com.
A Canadian woman who officials allege faked being a registered nurse for some 30 years in Canada and the United States is scheduled to appear in court next month after being sentenced to 7 years in prison.
She was previously sentenced April 22 in an Ontario court after she pled guilty in January to seven offenses, including impersonation, assault with a weapon, and assault, according to CBC Radio-Canada.
Ms. Cleroux, who uses several aliases, had a long history of deception in three provinces in Canada, as well as in Colorado and Florida. The sentencing in Ontario stemmed from incidents at a medical and dental clinic in Ottawa last year, which included administration of medications to patients through needle injections, Ottawa Police reported in a press statement obtained by this news organization.
Authorities charged Ms. Cleroux in September with assault with a weapon and criminal negligence causing bodily harm, along with “personation to gain advantage,” obtaining by false pretense, and using a forged document, this news organization reported.
Ms. Cleroux has been in custody since her arrest by Ottawa Police in August.
The Vancouver Police Department (VPD) charged Ms. Cleroux last year with fraud of over $5,000 and personation with intent. VPD investigated claims that an employee at BC Women’s Hospital fraudulently identified herself as a nurse while working there between June 2020 and June 2021, according to a VPD press release.
Nursing colleges in British Columbia and Ontario issued warnings that she had used aliases and purported to be a registered nurse to gain employment. The aliases included Melanie Thompson, Melanie Smith, and Melanie Cleroux.
Ms. Cleroux was believed to be a student in a nursing school in Colorado, but she only completed 2 years of a 4-year nursing course and was never certified as a nurse, according to CBC. Her criminal record dates back 30 years and includes 67 adult convictions and other convictions in her youth, CBC reported.
A version of this article first appeared on Medscape.com.
A Canadian woman who officials allege faked being a registered nurse for some 30 years in Canada and the United States is scheduled to appear in court next month after being sentenced to 7 years in prison.
She was previously sentenced April 22 in an Ontario court after she pled guilty in January to seven offenses, including impersonation, assault with a weapon, and assault, according to CBC Radio-Canada.
Ms. Cleroux, who uses several aliases, had a long history of deception in three provinces in Canada, as well as in Colorado and Florida. The sentencing in Ontario stemmed from incidents at a medical and dental clinic in Ottawa last year, which included administration of medications to patients through needle injections, Ottawa Police reported in a press statement obtained by this news organization.
Authorities charged Ms. Cleroux in September with assault with a weapon and criminal negligence causing bodily harm, along with “personation to gain advantage,” obtaining by false pretense, and using a forged document, this news organization reported.
Ms. Cleroux has been in custody since her arrest by Ottawa Police in August.
The Vancouver Police Department (VPD) charged Ms. Cleroux last year with fraud of over $5,000 and personation with intent. VPD investigated claims that an employee at BC Women’s Hospital fraudulently identified herself as a nurse while working there between June 2020 and June 2021, according to a VPD press release.
Nursing colleges in British Columbia and Ontario issued warnings that she had used aliases and purported to be a registered nurse to gain employment. The aliases included Melanie Thompson, Melanie Smith, and Melanie Cleroux.
Ms. Cleroux was believed to be a student in a nursing school in Colorado, but she only completed 2 years of a 4-year nursing course and was never certified as a nurse, according to CBC. Her criminal record dates back 30 years and includes 67 adult convictions and other convictions in her youth, CBC reported.
A version of this article first appeared on Medscape.com.
FDA approves oteseconazole for chronic yeast infections
The Food and Drug Administration has approved oteseconazole capsules (Vivjoa), an azole antifungal agent, for the prevention of recurrent yeast infections in women who are not of reproductive potential.
Oteseconazole inhibits CYP51, an enzyme fungi require to preserve the integrity of their cell walls and to grow properly, according to Mycovia, the drug’s manufacturer. It is the first FDA-approved product for the treatment of recurrent vulvovaginal candidiasis (RVVC).
Recurrent vulvovaginal candidiasis, or chronic yeast infection, affects an estimated 138 million women worldwide annually. The condition is defined as three or more symptomatic acute episodes of yeast infection within a 12-month period. The primary symptoms of RVVC include vaginal itching, burning, irritation, and inflammation. Some patients may also experience abnormal vaginal discharge and pain during sex or urination.
“A medicine with Vivjoa’s sustained efficacy combined with the clinical safety profile has been long needed, as until now, physicians and their patients have had no FDA-approved medications for RVVC,” Stephen Brand, PhD, chief development officer of Mycovia, said in a statement. “We are excited to be the first to offer a medication designed specifically for RVVC, a challenging and chronic condition that is expected to increase in prevalence over the next decade.”
Approval for oteseconazole was based on results of three phase 3 trials involving 875 patients at 232 sites across 11 countries. In the U.S.-only ultraVIOLET trial, 89.7% of women with RVVC who received oteseconazole cleared their initial yeast infection and did not experience a recurrence during the 50-week maintenance period, compared with 57.1% of those who received fluconazole (Diflucan) followed by placebo (P < .001), according to Mycovia.
The most common side effects reported in phase 3 clinical studies were headache (7.4%) and nausea (3.6%), the company said. Patients with a hypersensitivity to oteseconazole should not take the drug, nor should those who are of reproductive potential, pregnant, or lactating.
Mycovia said it plans to launch the drug in the second quarter of 2022.
Full prescribing information is available online.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved oteseconazole capsules (Vivjoa), an azole antifungal agent, for the prevention of recurrent yeast infections in women who are not of reproductive potential.
Oteseconazole inhibits CYP51, an enzyme fungi require to preserve the integrity of their cell walls and to grow properly, according to Mycovia, the drug’s manufacturer. It is the first FDA-approved product for the treatment of recurrent vulvovaginal candidiasis (RVVC).
Recurrent vulvovaginal candidiasis, or chronic yeast infection, affects an estimated 138 million women worldwide annually. The condition is defined as three or more symptomatic acute episodes of yeast infection within a 12-month period. The primary symptoms of RVVC include vaginal itching, burning, irritation, and inflammation. Some patients may also experience abnormal vaginal discharge and pain during sex or urination.
“A medicine with Vivjoa’s sustained efficacy combined with the clinical safety profile has been long needed, as until now, physicians and their patients have had no FDA-approved medications for RVVC,” Stephen Brand, PhD, chief development officer of Mycovia, said in a statement. “We are excited to be the first to offer a medication designed specifically for RVVC, a challenging and chronic condition that is expected to increase in prevalence over the next decade.”
Approval for oteseconazole was based on results of three phase 3 trials involving 875 patients at 232 sites across 11 countries. In the U.S.-only ultraVIOLET trial, 89.7% of women with RVVC who received oteseconazole cleared their initial yeast infection and did not experience a recurrence during the 50-week maintenance period, compared with 57.1% of those who received fluconazole (Diflucan) followed by placebo (P < .001), according to Mycovia.
The most common side effects reported in phase 3 clinical studies were headache (7.4%) and nausea (3.6%), the company said. Patients with a hypersensitivity to oteseconazole should not take the drug, nor should those who are of reproductive potential, pregnant, or lactating.
Mycovia said it plans to launch the drug in the second quarter of 2022.
Full prescribing information is available online.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved oteseconazole capsules (Vivjoa), an azole antifungal agent, for the prevention of recurrent yeast infections in women who are not of reproductive potential.
Oteseconazole inhibits CYP51, an enzyme fungi require to preserve the integrity of their cell walls and to grow properly, according to Mycovia, the drug’s manufacturer. It is the first FDA-approved product for the treatment of recurrent vulvovaginal candidiasis (RVVC).
Recurrent vulvovaginal candidiasis, or chronic yeast infection, affects an estimated 138 million women worldwide annually. The condition is defined as three or more symptomatic acute episodes of yeast infection within a 12-month period. The primary symptoms of RVVC include vaginal itching, burning, irritation, and inflammation. Some patients may also experience abnormal vaginal discharge and pain during sex or urination.
“A medicine with Vivjoa’s sustained efficacy combined with the clinical safety profile has been long needed, as until now, physicians and their patients have had no FDA-approved medications for RVVC,” Stephen Brand, PhD, chief development officer of Mycovia, said in a statement. “We are excited to be the first to offer a medication designed specifically for RVVC, a challenging and chronic condition that is expected to increase in prevalence over the next decade.”
Approval for oteseconazole was based on results of three phase 3 trials involving 875 patients at 232 sites across 11 countries. In the U.S.-only ultraVIOLET trial, 89.7% of women with RVVC who received oteseconazole cleared their initial yeast infection and did not experience a recurrence during the 50-week maintenance period, compared with 57.1% of those who received fluconazole (Diflucan) followed by placebo (P < .001), according to Mycovia.
The most common side effects reported in phase 3 clinical studies were headache (7.4%) and nausea (3.6%), the company said. Patients with a hypersensitivity to oteseconazole should not take the drug, nor should those who are of reproductive potential, pregnant, or lactating.
Mycovia said it plans to launch the drug in the second quarter of 2022.
Full prescribing information is available online.
A version of this article first appeared on Medscape.com.
Hospital readmission remains common for teens with nonfatal drug overdose
Approximately 1 in 5 adolescents hospitalized for nonfatal drug overdoses were readmitted within 6 months, based on data from more than 12,000 individuals.
Previous studies suggest that many adolescents fail to receive timely treatment for addiction after a nonfatal overdose, but the rates of hospital readmission in this population have not been examined, according to Julie Gaither, PhD, of Yale University, New Haven, Conn.
In a study presented at the annual meeting of the Pediatric Academic Societies, Dr. Gaither and her colleague, John M. Leventhal, MD, also of Yale University, used data from the 2016 Nationwide Readmissions Database to examine incidence and recurrent hospitalizations for nonfatal drug overdoses in adolescents. The study population included 12,952 patients aged 11-21 years who were admitted to a hospital after a nonfatal drug overdose in 2016. Of these, 15% were younger than 15 years, and 52.1% were females.
Overall, 76.2% of the overdoses involved opioids; 77.9% involved a prescription opioid, 15.3% involved heroin, and 7.9% involved fentanyl.
Across all drug overdoses, the majority (86.5%) were attributed to accidental intent and 11.8% were attributed to self-harm. Notably, females were nearly four times more likely than males to attempt suicide (odds ratio, 3.57). After the initial hospitalization, 79.3% of the patients were discharged home, and 11.5% went to a short-term care facility.
The 6-month hospital readmission rate was 21.4%. Of the patients readmitted for any cause, 18.2% of readmissions were for recurrent overdoses, and 92.1% of these were attributed to opioids.
The median cost of the initial hospital admission was $23,705 (ranging from $11,902 to $54,682) and the median cost of the first readmission was $25,416 (ranging from $13,905 to $48,810). In 42.1% of all hospitalizations, Medicaid was the primary payer.
The study findings were limited by the relatively high number of Medicaid patients, which may limit generalizability, but is strengthened by the large sample size.
The findings highlight not only the need for prevention efforts to limit opioid use among adolescents, but also “speak to the need for timely evidenced-based addiction treatment and appropriate follow-up care for teens following hospitalization for a nonfatal drug overdose,” the researchers wrote in their abstract.
Potential for postpandemic surge in drug use
Interestingly, some recent research has shown a decline in teens’ substance use during the pandemic, Kelly Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview.
“However, as the world begins ‘opening up’ again, I suspect rates of drug use will rise – especially with the significant burden of mental health issues adolescents have struggled with during the last few years,” said Dr. Curran, who was not involved with the current study.
“Sadly, I am not surprised by this study’s findings. Too often, teens with substance abuse issues are not connected to effective, evidenced-based treatment, and for those who are, the wait list can be long,” she said.
“Teens who are misusing drugs – either to get high or to attempt suicide – who are admitted for nonfatal overdose have a high rate of readmission for recurrent drug overdose,” Dr. Curran said. “This high rate of readmission has serious social and financial implications,” she added. “This study is part of a growing body of literature that supports the importance of getting adolescents into effective, evidence-based substance abuse treatment, such as medication-assisted treatment in opioid abuse. However, we also should be advocating for improved funding for and access to these treatments for all individuals.”
The study received no outside funding. Dr. Gaither had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
Approximately 1 in 5 adolescents hospitalized for nonfatal drug overdoses were readmitted within 6 months, based on data from more than 12,000 individuals.
Previous studies suggest that many adolescents fail to receive timely treatment for addiction after a nonfatal overdose, but the rates of hospital readmission in this population have not been examined, according to Julie Gaither, PhD, of Yale University, New Haven, Conn.
In a study presented at the annual meeting of the Pediatric Academic Societies, Dr. Gaither and her colleague, John M. Leventhal, MD, also of Yale University, used data from the 2016 Nationwide Readmissions Database to examine incidence and recurrent hospitalizations for nonfatal drug overdoses in adolescents. The study population included 12,952 patients aged 11-21 years who were admitted to a hospital after a nonfatal drug overdose in 2016. Of these, 15% were younger than 15 years, and 52.1% were females.
Overall, 76.2% of the overdoses involved opioids; 77.9% involved a prescription opioid, 15.3% involved heroin, and 7.9% involved fentanyl.
Across all drug overdoses, the majority (86.5%) were attributed to accidental intent and 11.8% were attributed to self-harm. Notably, females were nearly four times more likely than males to attempt suicide (odds ratio, 3.57). After the initial hospitalization, 79.3% of the patients were discharged home, and 11.5% went to a short-term care facility.
The 6-month hospital readmission rate was 21.4%. Of the patients readmitted for any cause, 18.2% of readmissions were for recurrent overdoses, and 92.1% of these were attributed to opioids.
The median cost of the initial hospital admission was $23,705 (ranging from $11,902 to $54,682) and the median cost of the first readmission was $25,416 (ranging from $13,905 to $48,810). In 42.1% of all hospitalizations, Medicaid was the primary payer.
The study findings were limited by the relatively high number of Medicaid patients, which may limit generalizability, but is strengthened by the large sample size.
The findings highlight not only the need for prevention efforts to limit opioid use among adolescents, but also “speak to the need for timely evidenced-based addiction treatment and appropriate follow-up care for teens following hospitalization for a nonfatal drug overdose,” the researchers wrote in their abstract.
Potential for postpandemic surge in drug use
Interestingly, some recent research has shown a decline in teens’ substance use during the pandemic, Kelly Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview.
“However, as the world begins ‘opening up’ again, I suspect rates of drug use will rise – especially with the significant burden of mental health issues adolescents have struggled with during the last few years,” said Dr. Curran, who was not involved with the current study.
“Sadly, I am not surprised by this study’s findings. Too often, teens with substance abuse issues are not connected to effective, evidenced-based treatment, and for those who are, the wait list can be long,” she said.
“Teens who are misusing drugs – either to get high or to attempt suicide – who are admitted for nonfatal overdose have a high rate of readmission for recurrent drug overdose,” Dr. Curran said. “This high rate of readmission has serious social and financial implications,” she added. “This study is part of a growing body of literature that supports the importance of getting adolescents into effective, evidence-based substance abuse treatment, such as medication-assisted treatment in opioid abuse. However, we also should be advocating for improved funding for and access to these treatments for all individuals.”
The study received no outside funding. Dr. Gaither had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
Approximately 1 in 5 adolescents hospitalized for nonfatal drug overdoses were readmitted within 6 months, based on data from more than 12,000 individuals.
Previous studies suggest that many adolescents fail to receive timely treatment for addiction after a nonfatal overdose, but the rates of hospital readmission in this population have not been examined, according to Julie Gaither, PhD, of Yale University, New Haven, Conn.
In a study presented at the annual meeting of the Pediatric Academic Societies, Dr. Gaither and her colleague, John M. Leventhal, MD, also of Yale University, used data from the 2016 Nationwide Readmissions Database to examine incidence and recurrent hospitalizations for nonfatal drug overdoses in adolescents. The study population included 12,952 patients aged 11-21 years who were admitted to a hospital after a nonfatal drug overdose in 2016. Of these, 15% were younger than 15 years, and 52.1% were females.
Overall, 76.2% of the overdoses involved opioids; 77.9% involved a prescription opioid, 15.3% involved heroin, and 7.9% involved fentanyl.
Across all drug overdoses, the majority (86.5%) were attributed to accidental intent and 11.8% were attributed to self-harm. Notably, females were nearly four times more likely than males to attempt suicide (odds ratio, 3.57). After the initial hospitalization, 79.3% of the patients were discharged home, and 11.5% went to a short-term care facility.
The 6-month hospital readmission rate was 21.4%. Of the patients readmitted for any cause, 18.2% of readmissions were for recurrent overdoses, and 92.1% of these were attributed to opioids.
The median cost of the initial hospital admission was $23,705 (ranging from $11,902 to $54,682) and the median cost of the first readmission was $25,416 (ranging from $13,905 to $48,810). In 42.1% of all hospitalizations, Medicaid was the primary payer.
The study findings were limited by the relatively high number of Medicaid patients, which may limit generalizability, but is strengthened by the large sample size.
The findings highlight not only the need for prevention efforts to limit opioid use among adolescents, but also “speak to the need for timely evidenced-based addiction treatment and appropriate follow-up care for teens following hospitalization for a nonfatal drug overdose,” the researchers wrote in their abstract.
Potential for postpandemic surge in drug use
Interestingly, some recent research has shown a decline in teens’ substance use during the pandemic, Kelly Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview.
“However, as the world begins ‘opening up’ again, I suspect rates of drug use will rise – especially with the significant burden of mental health issues adolescents have struggled with during the last few years,” said Dr. Curran, who was not involved with the current study.
“Sadly, I am not surprised by this study’s findings. Too often, teens with substance abuse issues are not connected to effective, evidenced-based treatment, and for those who are, the wait list can be long,” she said.
“Teens who are misusing drugs – either to get high or to attempt suicide – who are admitted for nonfatal overdose have a high rate of readmission for recurrent drug overdose,” Dr. Curran said. “This high rate of readmission has serious social and financial implications,” she added. “This study is part of a growing body of literature that supports the importance of getting adolescents into effective, evidence-based substance abuse treatment, such as medication-assisted treatment in opioid abuse. However, we also should be advocating for improved funding for and access to these treatments for all individuals.”
The study received no outside funding. Dr. Gaither had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
FROM PAS 2022
Nap length linked to cognitive changes
No wonder we feel worse after naps
Some of us have hectic schedules that may make a nap feel more necessary. It’s common knowledge that naps shouldn’t be too long – maybe 20 minutes or so – but if you frequently take 3-hour naps and wake up thinking you’re late for school even though you’re 47 and have your PhD, this LOTME is for you.
Studies have shown that there is a link between napping during the day and Alzheimer’s/cognitive decline, but now we’ve got a double whammy for you: Longer and more frequent napping is linked to worse cognition after a year, and in turn, those with cognitive decline and Alzheimer’s are known to nap longer and more frequently during the day.
“We now know that the pathology related to cognitive decline can cause other changes in function,” he said. “It’s really a multisystem disorder, also including difficulty sleeping, changes in movement, changes in body composition, depression symptoms, behavioral changes, etc.,” coauthor Aron Buchman, MD, said in a statement from Rush University Medical Center.
The investigators monitored 1,400 patients over the course of 14 years with wrist bracelets that recorded when a person was not active during the day and considered that a nap.
At the beginning of the study, 75% of the study subjects had no cognitive impairment, 19.5% had some cognitive impairment, and approximately 4% had Alzheimer’s. Napping during the day only increased about 11 minutes a year for those with no signs of cognitive impairment, but those who showed significantly more signs of cognitive decline doubled their nap time and those actually diagnosed with Alzheimer’s tripled theirs.
The investigators did not imply that napping causes Alzheimer’s, but they noted that people who are older and nap more than an hour a day are 40% more likely to be at risk. It is something to consider and monitor.
Sometimes, after all, a nap seems like the best idea ever, but more often than not we wake up feeling 10 times worse. Our bodies may be giving us a heads up.
Pokemon Go away depression
The summer of 2016 was a great time if you happened to be a fan of Pokemon. Which is quite a lot of people. For almost 20 years millions have enjoyed the games and animated series, but Pokemon Go brought the thrill of catching Pokemon to life in a whole new way. For the first time, you could go out into the world and pretend you were a real Pokemon trainer, and everywhere you went, there would be others like you.
The ability to chase after Pikachu and Charizard in real life (well, augmented reality, but close enough) seemed to bring people a lot of joy, but seemed is never good enough for science. Can’t have anecdotes, we need data! So researchers at the London School of Economics and Political Science conducted a study into how Pokemon Go affected local Internet search rates of depression as the game was released slowly around the world.
Through analyzing Google Trend data of words like “depression,” “anxiety,” and “stress,” the researchers found that the release of Pokemon Go was significantly associated with a noticeable, though short-term, drop in depression-related Internet searches. Location-based augmented reality games may alleviate symptoms of mild depression, the researchers said, as they encourage physical activity, face-to-face socialization, and exposure to nature, though they added that simply going outside is likely not enough to combat clinical cases of severe depression.
Still, augmented reality games represent a viable target for public health investment, since they’re easy to use and inexpensive to make. That said, we’re not sure we want the FDA or CDC making a new Pokemon Go game. They’d probably end up filling the streets with Mr. Mime. And no one would leave their house for that.
And now a word from our sponsor
How many times has this happened to you? You need to repair a jet engine, inspect a nuclear reactor cooling system, AND perform bowel surgery, but you can’t carry around all the heavy, old-fashioned tools needed for those jobs.
Well, we’ve got one tool that can do it all! And that tool is a snake. No, it’s a robot.
It’s both! It’s the COntinuum roBot for Remote Applications. COBRA is the robot that looks like a snake! A snake that’s 5 meters long but only as thick as a pencil (about 9 mm in diameter). A robot with “extraordinary manoeuvrability and responsiveness due to … a compliant-joint structure and multiple continuous sections that enable it to bend at around 90 degrees,” according to the team at the University of Nottingham (England) that developed it.
COBRA comes equipped with a stereovision camera and a miniature cutting tool to perform complex industrial repair, but other devices can be interchanged for possible medical use.
COBRA and its joystick-like controller were designed to be easy to use. Dr. Oladejo Olaleye, the ear, nose, and throat and robotic surgeon at University Hospitals of Leicester who is directing its surgical development, was able to use COBRA on a dummy after just 5 minutes of training. He called it “the future of diagnostic endoscopy and therapeutic surgery.”
Don’t be the last aircraft engineer/nuclear technician/surgeon on your block to have this ultraslender, ultramaneuverable reptilian repair robot. Get your COBRA now! Operators are standing by.
Disclaimer: Robot is still under development and not yet on sale.
Rule, (worm) Britannia!
As long as there have been people, there have been parasitic worms living in their guts. Helminth infection is a continuing and largely ignored crisis in poor, tropical nations, though worm-based diseases have been basically eliminated from wealthier countries.
This wasn’t always the case, however, as a study published in PLOS Neglected Tropical Diseases (now there’s a specific topic) has found. The researchers detail the glorious history of helminth infestation in the United Kingdom from the Victorian era all the way back to prehistory, scouring hundreds of skeletons found in 17 sites across the country for eggs, which can remain intact for thousands of years.
The researchers found that two eras in particular had very high rates of infection. Unsurprisingly, the late medieval era was one of them, but the other is less obvious. The Romans were famous for their hygiene, their baths, and their plumbing, but maybe they also should be famous for the abundance of worms in their bellies. That doesn’t make sense at first: Shouldn’t good hygiene lower infection? The benefits of a good sewer system, however, are lessened when the waste containing said infectious organisms is used to fertilize crops. Recycling is generally a good thing, but less so when you’re recycling parasitic worms.
Curiously, of the three sites from the industrial age, only the one in London had high levels of worm infestation. Considering how dirty and cramped 19th-century British cities were, one might expect disease to run rampant (tuberculosis certainly did), but the sites in Oxford and Birmingham were almost devoid of worms. The researchers theorized that this was because of access to clean well water. Or maybe worms just have a thing for London. [Editor’s note: It’s probably not that.]
No wonder we feel worse after naps
Some of us have hectic schedules that may make a nap feel more necessary. It’s common knowledge that naps shouldn’t be too long – maybe 20 minutes or so – but if you frequently take 3-hour naps and wake up thinking you’re late for school even though you’re 47 and have your PhD, this LOTME is for you.
Studies have shown that there is a link between napping during the day and Alzheimer’s/cognitive decline, but now we’ve got a double whammy for you: Longer and more frequent napping is linked to worse cognition after a year, and in turn, those with cognitive decline and Alzheimer’s are known to nap longer and more frequently during the day.
“We now know that the pathology related to cognitive decline can cause other changes in function,” he said. “It’s really a multisystem disorder, also including difficulty sleeping, changes in movement, changes in body composition, depression symptoms, behavioral changes, etc.,” coauthor Aron Buchman, MD, said in a statement from Rush University Medical Center.
The investigators monitored 1,400 patients over the course of 14 years with wrist bracelets that recorded when a person was not active during the day and considered that a nap.
At the beginning of the study, 75% of the study subjects had no cognitive impairment, 19.5% had some cognitive impairment, and approximately 4% had Alzheimer’s. Napping during the day only increased about 11 minutes a year for those with no signs of cognitive impairment, but those who showed significantly more signs of cognitive decline doubled their nap time and those actually diagnosed with Alzheimer’s tripled theirs.
The investigators did not imply that napping causes Alzheimer’s, but they noted that people who are older and nap more than an hour a day are 40% more likely to be at risk. It is something to consider and monitor.
Sometimes, after all, a nap seems like the best idea ever, but more often than not we wake up feeling 10 times worse. Our bodies may be giving us a heads up.
Pokemon Go away depression
The summer of 2016 was a great time if you happened to be a fan of Pokemon. Which is quite a lot of people. For almost 20 years millions have enjoyed the games and animated series, but Pokemon Go brought the thrill of catching Pokemon to life in a whole new way. For the first time, you could go out into the world and pretend you were a real Pokemon trainer, and everywhere you went, there would be others like you.
The ability to chase after Pikachu and Charizard in real life (well, augmented reality, but close enough) seemed to bring people a lot of joy, but seemed is never good enough for science. Can’t have anecdotes, we need data! So researchers at the London School of Economics and Political Science conducted a study into how Pokemon Go affected local Internet search rates of depression as the game was released slowly around the world.
Through analyzing Google Trend data of words like “depression,” “anxiety,” and “stress,” the researchers found that the release of Pokemon Go was significantly associated with a noticeable, though short-term, drop in depression-related Internet searches. Location-based augmented reality games may alleviate symptoms of mild depression, the researchers said, as they encourage physical activity, face-to-face socialization, and exposure to nature, though they added that simply going outside is likely not enough to combat clinical cases of severe depression.
Still, augmented reality games represent a viable target for public health investment, since they’re easy to use and inexpensive to make. That said, we’re not sure we want the FDA or CDC making a new Pokemon Go game. They’d probably end up filling the streets with Mr. Mime. And no one would leave their house for that.
And now a word from our sponsor
How many times has this happened to you? You need to repair a jet engine, inspect a nuclear reactor cooling system, AND perform bowel surgery, but you can’t carry around all the heavy, old-fashioned tools needed for those jobs.
Well, we’ve got one tool that can do it all! And that tool is a snake. No, it’s a robot.
It’s both! It’s the COntinuum roBot for Remote Applications. COBRA is the robot that looks like a snake! A snake that’s 5 meters long but only as thick as a pencil (about 9 mm in diameter). A robot with “extraordinary manoeuvrability and responsiveness due to … a compliant-joint structure and multiple continuous sections that enable it to bend at around 90 degrees,” according to the team at the University of Nottingham (England) that developed it.
COBRA comes equipped with a stereovision camera and a miniature cutting tool to perform complex industrial repair, but other devices can be interchanged for possible medical use.
COBRA and its joystick-like controller were designed to be easy to use. Dr. Oladejo Olaleye, the ear, nose, and throat and robotic surgeon at University Hospitals of Leicester who is directing its surgical development, was able to use COBRA on a dummy after just 5 minutes of training. He called it “the future of diagnostic endoscopy and therapeutic surgery.”
Don’t be the last aircraft engineer/nuclear technician/surgeon on your block to have this ultraslender, ultramaneuverable reptilian repair robot. Get your COBRA now! Operators are standing by.
Disclaimer: Robot is still under development and not yet on sale.
Rule, (worm) Britannia!
As long as there have been people, there have been parasitic worms living in their guts. Helminth infection is a continuing and largely ignored crisis in poor, tropical nations, though worm-based diseases have been basically eliminated from wealthier countries.
This wasn’t always the case, however, as a study published in PLOS Neglected Tropical Diseases (now there’s a specific topic) has found. The researchers detail the glorious history of helminth infestation in the United Kingdom from the Victorian era all the way back to prehistory, scouring hundreds of skeletons found in 17 sites across the country for eggs, which can remain intact for thousands of years.
The researchers found that two eras in particular had very high rates of infection. Unsurprisingly, the late medieval era was one of them, but the other is less obvious. The Romans were famous for their hygiene, their baths, and their plumbing, but maybe they also should be famous for the abundance of worms in their bellies. That doesn’t make sense at first: Shouldn’t good hygiene lower infection? The benefits of a good sewer system, however, are lessened when the waste containing said infectious organisms is used to fertilize crops. Recycling is generally a good thing, but less so when you’re recycling parasitic worms.
Curiously, of the three sites from the industrial age, only the one in London had high levels of worm infestation. Considering how dirty and cramped 19th-century British cities were, one might expect disease to run rampant (tuberculosis certainly did), but the sites in Oxford and Birmingham were almost devoid of worms. The researchers theorized that this was because of access to clean well water. Or maybe worms just have a thing for London. [Editor’s note: It’s probably not that.]
No wonder we feel worse after naps
Some of us have hectic schedules that may make a nap feel more necessary. It’s common knowledge that naps shouldn’t be too long – maybe 20 minutes or so – but if you frequently take 3-hour naps and wake up thinking you’re late for school even though you’re 47 and have your PhD, this LOTME is for you.
Studies have shown that there is a link between napping during the day and Alzheimer’s/cognitive decline, but now we’ve got a double whammy for you: Longer and more frequent napping is linked to worse cognition after a year, and in turn, those with cognitive decline and Alzheimer’s are known to nap longer and more frequently during the day.
“We now know that the pathology related to cognitive decline can cause other changes in function,” he said. “It’s really a multisystem disorder, also including difficulty sleeping, changes in movement, changes in body composition, depression symptoms, behavioral changes, etc.,” coauthor Aron Buchman, MD, said in a statement from Rush University Medical Center.
The investigators monitored 1,400 patients over the course of 14 years with wrist bracelets that recorded when a person was not active during the day and considered that a nap.
At the beginning of the study, 75% of the study subjects had no cognitive impairment, 19.5% had some cognitive impairment, and approximately 4% had Alzheimer’s. Napping during the day only increased about 11 minutes a year for those with no signs of cognitive impairment, but those who showed significantly more signs of cognitive decline doubled their nap time and those actually diagnosed with Alzheimer’s tripled theirs.
The investigators did not imply that napping causes Alzheimer’s, but they noted that people who are older and nap more than an hour a day are 40% more likely to be at risk. It is something to consider and monitor.
Sometimes, after all, a nap seems like the best idea ever, but more often than not we wake up feeling 10 times worse. Our bodies may be giving us a heads up.
Pokemon Go away depression
The summer of 2016 was a great time if you happened to be a fan of Pokemon. Which is quite a lot of people. For almost 20 years millions have enjoyed the games and animated series, but Pokemon Go brought the thrill of catching Pokemon to life in a whole new way. For the first time, you could go out into the world and pretend you were a real Pokemon trainer, and everywhere you went, there would be others like you.
The ability to chase after Pikachu and Charizard in real life (well, augmented reality, but close enough) seemed to bring people a lot of joy, but seemed is never good enough for science. Can’t have anecdotes, we need data! So researchers at the London School of Economics and Political Science conducted a study into how Pokemon Go affected local Internet search rates of depression as the game was released slowly around the world.
Through analyzing Google Trend data of words like “depression,” “anxiety,” and “stress,” the researchers found that the release of Pokemon Go was significantly associated with a noticeable, though short-term, drop in depression-related Internet searches. Location-based augmented reality games may alleviate symptoms of mild depression, the researchers said, as they encourage physical activity, face-to-face socialization, and exposure to nature, though they added that simply going outside is likely not enough to combat clinical cases of severe depression.
Still, augmented reality games represent a viable target for public health investment, since they’re easy to use and inexpensive to make. That said, we’re not sure we want the FDA or CDC making a new Pokemon Go game. They’d probably end up filling the streets with Mr. Mime. And no one would leave their house for that.
And now a word from our sponsor
How many times has this happened to you? You need to repair a jet engine, inspect a nuclear reactor cooling system, AND perform bowel surgery, but you can’t carry around all the heavy, old-fashioned tools needed for those jobs.
Well, we’ve got one tool that can do it all! And that tool is a snake. No, it’s a robot.
It’s both! It’s the COntinuum roBot for Remote Applications. COBRA is the robot that looks like a snake! A snake that’s 5 meters long but only as thick as a pencil (about 9 mm in diameter). A robot with “extraordinary manoeuvrability and responsiveness due to … a compliant-joint structure and multiple continuous sections that enable it to bend at around 90 degrees,” according to the team at the University of Nottingham (England) that developed it.
COBRA comes equipped with a stereovision camera and a miniature cutting tool to perform complex industrial repair, but other devices can be interchanged for possible medical use.
COBRA and its joystick-like controller were designed to be easy to use. Dr. Oladejo Olaleye, the ear, nose, and throat and robotic surgeon at University Hospitals of Leicester who is directing its surgical development, was able to use COBRA on a dummy after just 5 minutes of training. He called it “the future of diagnostic endoscopy and therapeutic surgery.”
Don’t be the last aircraft engineer/nuclear technician/surgeon on your block to have this ultraslender, ultramaneuverable reptilian repair robot. Get your COBRA now! Operators are standing by.
Disclaimer: Robot is still under development and not yet on sale.
Rule, (worm) Britannia!
As long as there have been people, there have been parasitic worms living in their guts. Helminth infection is a continuing and largely ignored crisis in poor, tropical nations, though worm-based diseases have been basically eliminated from wealthier countries.
This wasn’t always the case, however, as a study published in PLOS Neglected Tropical Diseases (now there’s a specific topic) has found. The researchers detail the glorious history of helminth infestation in the United Kingdom from the Victorian era all the way back to prehistory, scouring hundreds of skeletons found in 17 sites across the country for eggs, which can remain intact for thousands of years.
The researchers found that two eras in particular had very high rates of infection. Unsurprisingly, the late medieval era was one of them, but the other is less obvious. The Romans were famous for their hygiene, their baths, and their plumbing, but maybe they also should be famous for the abundance of worms in their bellies. That doesn’t make sense at first: Shouldn’t good hygiene lower infection? The benefits of a good sewer system, however, are lessened when the waste containing said infectious organisms is used to fertilize crops. Recycling is generally a good thing, but less so when you’re recycling parasitic worms.
Curiously, of the three sites from the industrial age, only the one in London had high levels of worm infestation. Considering how dirty and cramped 19th-century British cities were, one might expect disease to run rampant (tuberculosis certainly did), but the sites in Oxford and Birmingham were almost devoid of worms. The researchers theorized that this was because of access to clean well water. Or maybe worms just have a thing for London. [Editor’s note: It’s probably not that.]
Facial Follicular Spicules: A Rare Cutaneous Presentation of Trichodysplasia Spinulosa
To the Editor:
A 57-year-old man with hypertension, dyslipidemia, and congestive heart failure presented with a disfiguring eruption comprised of asymptomatic papules on the face that appeared 12 months post–heart transplantation. Immunosuppressive medications included mycophenolic acid and tacrolimus ointment (FK506). The pinpoint papules spread from the central face to the ears, arms, and legs. Physical examination revealed multiple 0.5- to 1-mm flesh-colored papules over the glabella, nose, nasolabial folds, philtrum, chin, ears, arms, and legs sparing the trunk. The initial appearance of the facial rash resembled the surface of a nutmeg grater with central white spiny excrescences overlying fine papules (spinulosism)(Figure 1). In addition, eyebrow alopecia was present.
A 3-mm punch biopsy of a papule with a central spine was performed on the left thigh. Microscopic examination revealed marked dilatation of anagen hair follicles with a proliferation of haphazard inner root sheath cells replacing the follicular lumen. Hair shafts were absent, and plugged infundibula were observed (Figure 2). The inner root sheath keratinocytes were enlarged and dystrophic with deeply eosinophilic trichohyalin granules (Figure 3). The epidermis, outer root sheath epithelium, and eccrine structures were unremarkable.
Transmission electron microscopy (TEM) confirmed the presence of intranuclear viral inclusions within affected inner root sheath keratinocytes composed of nonenveloped icosahedral viral particles measuring 33 to 38 nm in diameter (Figure 4). These findings morphologically were consistent with a polyomavirus. No intracytoplasmic or extracellular viral particles were identified. The clinical history, physical examination, histopathology, and electron microscopy features strongly supported the diagnosis of trichodysplasia spinulosa (TS) despite insufficient material being retrieved for polymerase chain reaction identification.
Trichodysplasia spinulosa was first described by Haycox et al1 in 1999. The authors suggested a viral etiology. Eleven years later, TS-associated polyomavirus (TSPyV) was identified by van der Meijden et al.2 Follicular keratinocytes are the specific target for TSPyV.3 Evidence has been presented suggesting that TS is caused by a primary infection or reactivation of TSPyV in the setting of immunosuppression.4,5
Patients with TS present with papular eruptions that appear on the central face with spiny excrescences and various degrees of alopecia involving the eyebrows or eyelashes. Histopathologic features include distended hair follicles with expansion of inner root sheath cells, eosinophilic trichohyalin granules, and the absence of hair shafts. The viral protein can be verified through immunohistochemistry TSPyV VP1 staining that demonstrates co-localization with trichohyalin. Viral particles also can be visualized as 35- to 38-nm intranuclear particles with an organized crystalloid morphology on TEM.6,7 The negative polymerase chain reaction in our patient could be the result of suboptimal template DNA concentration extracted from the limited amount of tissue remaining in the block after hematoxylin and eosin staining.
The clinical differential diagnosis of central facial spinulosism includes the follicular spicules of multiple myeloma (FSMM). In fact, FSMM and TS can only be differentiated after obtaining a blood profile and bone marrow biopsy that excludes the diagnosis of FSMM. A history of immunosuppression typically suggests TS. Histopathology often is equivocal in FSMM8; however, TEM reveals viral particles (TSPyV) in TS. Transmission electron microscopy in FSMM demonstrates fibrillary structures arranged in a paracrystalline configuration with unknown significance instead of viral particles. Despite the absence of viral particles on TEM, a low mean copy number of Merkel cell polyomavirus was isolated from a patient with FSMM who responded dramatically to treatment with topical cidofovir gel 1%.8 In addition to treating the underlying multiple myeloma in FSMM, topical cidofovir gel 1% also may have a role in treatment of these patients, suggesting a possible viral rather than simply paraneoplastic etiology of FSMM. Therefore, polyomavirus infection should be considered in the initial workup of any patient with fine facial follicular spicules.
The most effective management of TS in transplant recipients is to reduce immunosuppression to the lowest level possible without jeopardizing the transplanted organ.9 In our case, reduction of immunosuppressive drugs was not possible. In fact, immunosuppression in our patient was increased following evidence of early rejection of the heart transplant. Although manual extraction of the keratin spicules resulted in considerable improvement in a similar facial eruption in a patient with pediatric pre–B-cell acute lymphoblastic leukemia developing TS,10 it is impossible to apply this approach to patients such as ours who have thousands of tiny lesions. Fortunately, custom-compounded cidofovir gel 1% applied twice daily to the patient’s face and ears for 4 weeks led to near-complete clearance at follow-up (Figure 5). Due to the high cost of the medication (approaching $700 for one tube), our patient applied this medication to the face only several times weekly with excellent improvement. Thus, it appears that it is possible to suppress this virus with topical medication alone.
Polyomavirus infection should be considered in patients presenting with fine follicular spiny papules, especially those who are immunosuppressed. The possibility of coexisting multiple myeloma should be excluded.
Acknowledgment—We sincerely thank Glenn A. Hoskins (Jackson, Mississippi), the electron microscopy technologist, for the detection of viral particles and the electron microscope photographs.
- Haycox CL, Kim S, Fleckman P, et al. Trichodysplasia spinulosa: a newly described folliculocentric viral infection in an immunocompromised host. J Investig Dermatol Symp Proc. 1999;4:268-271.
- van der Meijden E, Janssens RWA, Lauber C, et al. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient. PLoS Pathog. 2010;6:E1001024.
- Rouanet J, Aubin F, Gaboriaud P, et al. Trichodysplasia spinulosa: a polyomavirus infection specifically targeting follicular keratinocytes in immunocompromised patients. Br J Dermatol. 2016;174:629-632.
- van der Meijden E, Kazem S, Burgers MM, et al. Seroprevalence of trichodysplasia spinulosa-associated polyomavirus. Emerg Infect Dis. 2011;17:1355-1363.
- van der Meijden E, Horváth B, Nijland M, et al. Primary polyomavirus infection, not reactivation, as the cause of trichodysplasia spinulosa in immunocompromised patients. J Infect Dis. 2017;215:1080-1084.
- Fischer MK, Kao GF, Nguyen HP, et al. Specific detection of trichodysplasia spinulosa-associated polyomavirus DNA in skin and renal allograft tissues in a patient with trichodysplasia spinulosa. Arch Dermatol. 2012;148:726-733.
- Kazem S, van der Meijden E, Feltkamp MC. The trichodysplasia spinulosa-associated polyomavirus: virological background and clinical implications. APMIS. 2013;121:770-782.
- van Boheemen S, Jones T, Muhlemann B, et al. Cidofovir gel as treatment of follicular spicules in multiple myeloma. JAMA Dermatol. 2015;151:82-84.
- DeCrescenzo AJ, Philips RC, Wilkerson MG. Trichodysplasia spinulosa: a rare complication of immunosuppression. JAAD Case Rep. 2016;2:307-309.
- Barton M, Lockhart S, Sidbury R, et al. Trichodysplasia spinulosa in a 7-year-old boy managed using physical extraction of keratin spicules. Pediatr Dermatol. 2017;34:E74-E76.
To the Editor:
A 57-year-old man with hypertension, dyslipidemia, and congestive heart failure presented with a disfiguring eruption comprised of asymptomatic papules on the face that appeared 12 months post–heart transplantation. Immunosuppressive medications included mycophenolic acid and tacrolimus ointment (FK506). The pinpoint papules spread from the central face to the ears, arms, and legs. Physical examination revealed multiple 0.5- to 1-mm flesh-colored papules over the glabella, nose, nasolabial folds, philtrum, chin, ears, arms, and legs sparing the trunk. The initial appearance of the facial rash resembled the surface of a nutmeg grater with central white spiny excrescences overlying fine papules (spinulosism)(Figure 1). In addition, eyebrow alopecia was present.
A 3-mm punch biopsy of a papule with a central spine was performed on the left thigh. Microscopic examination revealed marked dilatation of anagen hair follicles with a proliferation of haphazard inner root sheath cells replacing the follicular lumen. Hair shafts were absent, and plugged infundibula were observed (Figure 2). The inner root sheath keratinocytes were enlarged and dystrophic with deeply eosinophilic trichohyalin granules (Figure 3). The epidermis, outer root sheath epithelium, and eccrine structures were unremarkable.
Transmission electron microscopy (TEM) confirmed the presence of intranuclear viral inclusions within affected inner root sheath keratinocytes composed of nonenveloped icosahedral viral particles measuring 33 to 38 nm in diameter (Figure 4). These findings morphologically were consistent with a polyomavirus. No intracytoplasmic or extracellular viral particles were identified. The clinical history, physical examination, histopathology, and electron microscopy features strongly supported the diagnosis of trichodysplasia spinulosa (TS) despite insufficient material being retrieved for polymerase chain reaction identification.
Trichodysplasia spinulosa was first described by Haycox et al1 in 1999. The authors suggested a viral etiology. Eleven years later, TS-associated polyomavirus (TSPyV) was identified by van der Meijden et al.2 Follicular keratinocytes are the specific target for TSPyV.3 Evidence has been presented suggesting that TS is caused by a primary infection or reactivation of TSPyV in the setting of immunosuppression.4,5
Patients with TS present with papular eruptions that appear on the central face with spiny excrescences and various degrees of alopecia involving the eyebrows or eyelashes. Histopathologic features include distended hair follicles with expansion of inner root sheath cells, eosinophilic trichohyalin granules, and the absence of hair shafts. The viral protein can be verified through immunohistochemistry TSPyV VP1 staining that demonstrates co-localization with trichohyalin. Viral particles also can be visualized as 35- to 38-nm intranuclear particles with an organized crystalloid morphology on TEM.6,7 The negative polymerase chain reaction in our patient could be the result of suboptimal template DNA concentration extracted from the limited amount of tissue remaining in the block after hematoxylin and eosin staining.
The clinical differential diagnosis of central facial spinulosism includes the follicular spicules of multiple myeloma (FSMM). In fact, FSMM and TS can only be differentiated after obtaining a blood profile and bone marrow biopsy that excludes the diagnosis of FSMM. A history of immunosuppression typically suggests TS. Histopathology often is equivocal in FSMM8; however, TEM reveals viral particles (TSPyV) in TS. Transmission electron microscopy in FSMM demonstrates fibrillary structures arranged in a paracrystalline configuration with unknown significance instead of viral particles. Despite the absence of viral particles on TEM, a low mean copy number of Merkel cell polyomavirus was isolated from a patient with FSMM who responded dramatically to treatment with topical cidofovir gel 1%.8 In addition to treating the underlying multiple myeloma in FSMM, topical cidofovir gel 1% also may have a role in treatment of these patients, suggesting a possible viral rather than simply paraneoplastic etiology of FSMM. Therefore, polyomavirus infection should be considered in the initial workup of any patient with fine facial follicular spicules.
The most effective management of TS in transplant recipients is to reduce immunosuppression to the lowest level possible without jeopardizing the transplanted organ.9 In our case, reduction of immunosuppressive drugs was not possible. In fact, immunosuppression in our patient was increased following evidence of early rejection of the heart transplant. Although manual extraction of the keratin spicules resulted in considerable improvement in a similar facial eruption in a patient with pediatric pre–B-cell acute lymphoblastic leukemia developing TS,10 it is impossible to apply this approach to patients such as ours who have thousands of tiny lesions. Fortunately, custom-compounded cidofovir gel 1% applied twice daily to the patient’s face and ears for 4 weeks led to near-complete clearance at follow-up (Figure 5). Due to the high cost of the medication (approaching $700 for one tube), our patient applied this medication to the face only several times weekly with excellent improvement. Thus, it appears that it is possible to suppress this virus with topical medication alone.
Polyomavirus infection should be considered in patients presenting with fine follicular spiny papules, especially those who are immunosuppressed. The possibility of coexisting multiple myeloma should be excluded.
Acknowledgment—We sincerely thank Glenn A. Hoskins (Jackson, Mississippi), the electron microscopy technologist, for the detection of viral particles and the electron microscope photographs.
To the Editor:
A 57-year-old man with hypertension, dyslipidemia, and congestive heart failure presented with a disfiguring eruption comprised of asymptomatic papules on the face that appeared 12 months post–heart transplantation. Immunosuppressive medications included mycophenolic acid and tacrolimus ointment (FK506). The pinpoint papules spread from the central face to the ears, arms, and legs. Physical examination revealed multiple 0.5- to 1-mm flesh-colored papules over the glabella, nose, nasolabial folds, philtrum, chin, ears, arms, and legs sparing the trunk. The initial appearance of the facial rash resembled the surface of a nutmeg grater with central white spiny excrescences overlying fine papules (spinulosism)(Figure 1). In addition, eyebrow alopecia was present.
A 3-mm punch biopsy of a papule with a central spine was performed on the left thigh. Microscopic examination revealed marked dilatation of anagen hair follicles with a proliferation of haphazard inner root sheath cells replacing the follicular lumen. Hair shafts were absent, and plugged infundibula were observed (Figure 2). The inner root sheath keratinocytes were enlarged and dystrophic with deeply eosinophilic trichohyalin granules (Figure 3). The epidermis, outer root sheath epithelium, and eccrine structures were unremarkable.
Transmission electron microscopy (TEM) confirmed the presence of intranuclear viral inclusions within affected inner root sheath keratinocytes composed of nonenveloped icosahedral viral particles measuring 33 to 38 nm in diameter (Figure 4). These findings morphologically were consistent with a polyomavirus. No intracytoplasmic or extracellular viral particles were identified. The clinical history, physical examination, histopathology, and electron microscopy features strongly supported the diagnosis of trichodysplasia spinulosa (TS) despite insufficient material being retrieved for polymerase chain reaction identification.
Trichodysplasia spinulosa was first described by Haycox et al1 in 1999. The authors suggested a viral etiology. Eleven years later, TS-associated polyomavirus (TSPyV) was identified by van der Meijden et al.2 Follicular keratinocytes are the specific target for TSPyV.3 Evidence has been presented suggesting that TS is caused by a primary infection or reactivation of TSPyV in the setting of immunosuppression.4,5
Patients with TS present with papular eruptions that appear on the central face with spiny excrescences and various degrees of alopecia involving the eyebrows or eyelashes. Histopathologic features include distended hair follicles with expansion of inner root sheath cells, eosinophilic trichohyalin granules, and the absence of hair shafts. The viral protein can be verified through immunohistochemistry TSPyV VP1 staining that demonstrates co-localization with trichohyalin. Viral particles also can be visualized as 35- to 38-nm intranuclear particles with an organized crystalloid morphology on TEM.6,7 The negative polymerase chain reaction in our patient could be the result of suboptimal template DNA concentration extracted from the limited amount of tissue remaining in the block after hematoxylin and eosin staining.
The clinical differential diagnosis of central facial spinulosism includes the follicular spicules of multiple myeloma (FSMM). In fact, FSMM and TS can only be differentiated after obtaining a blood profile and bone marrow biopsy that excludes the diagnosis of FSMM. A history of immunosuppression typically suggests TS. Histopathology often is equivocal in FSMM8; however, TEM reveals viral particles (TSPyV) in TS. Transmission electron microscopy in FSMM demonstrates fibrillary structures arranged in a paracrystalline configuration with unknown significance instead of viral particles. Despite the absence of viral particles on TEM, a low mean copy number of Merkel cell polyomavirus was isolated from a patient with FSMM who responded dramatically to treatment with topical cidofovir gel 1%.8 In addition to treating the underlying multiple myeloma in FSMM, topical cidofovir gel 1% also may have a role in treatment of these patients, suggesting a possible viral rather than simply paraneoplastic etiology of FSMM. Therefore, polyomavirus infection should be considered in the initial workup of any patient with fine facial follicular spicules.
The most effective management of TS in transplant recipients is to reduce immunosuppression to the lowest level possible without jeopardizing the transplanted organ.9 In our case, reduction of immunosuppressive drugs was not possible. In fact, immunosuppression in our patient was increased following evidence of early rejection of the heart transplant. Although manual extraction of the keratin spicules resulted in considerable improvement in a similar facial eruption in a patient with pediatric pre–B-cell acute lymphoblastic leukemia developing TS,10 it is impossible to apply this approach to patients such as ours who have thousands of tiny lesions. Fortunately, custom-compounded cidofovir gel 1% applied twice daily to the patient’s face and ears for 4 weeks led to near-complete clearance at follow-up (Figure 5). Due to the high cost of the medication (approaching $700 for one tube), our patient applied this medication to the face only several times weekly with excellent improvement. Thus, it appears that it is possible to suppress this virus with topical medication alone.
Polyomavirus infection should be considered in patients presenting with fine follicular spiny papules, especially those who are immunosuppressed. The possibility of coexisting multiple myeloma should be excluded.
Acknowledgment—We sincerely thank Glenn A. Hoskins (Jackson, Mississippi), the electron microscopy technologist, for the detection of viral particles and the electron microscope photographs.
- Haycox CL, Kim S, Fleckman P, et al. Trichodysplasia spinulosa: a newly described folliculocentric viral infection in an immunocompromised host. J Investig Dermatol Symp Proc. 1999;4:268-271.
- van der Meijden E, Janssens RWA, Lauber C, et al. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient. PLoS Pathog. 2010;6:E1001024.
- Rouanet J, Aubin F, Gaboriaud P, et al. Trichodysplasia spinulosa: a polyomavirus infection specifically targeting follicular keratinocytes in immunocompromised patients. Br J Dermatol. 2016;174:629-632.
- van der Meijden E, Kazem S, Burgers MM, et al. Seroprevalence of trichodysplasia spinulosa-associated polyomavirus. Emerg Infect Dis. 2011;17:1355-1363.
- van der Meijden E, Horváth B, Nijland M, et al. Primary polyomavirus infection, not reactivation, as the cause of trichodysplasia spinulosa in immunocompromised patients. J Infect Dis. 2017;215:1080-1084.
- Fischer MK, Kao GF, Nguyen HP, et al. Specific detection of trichodysplasia spinulosa-associated polyomavirus DNA in skin and renal allograft tissues in a patient with trichodysplasia spinulosa. Arch Dermatol. 2012;148:726-733.
- Kazem S, van der Meijden E, Feltkamp MC. The trichodysplasia spinulosa-associated polyomavirus: virological background and clinical implications. APMIS. 2013;121:770-782.
- van Boheemen S, Jones T, Muhlemann B, et al. Cidofovir gel as treatment of follicular spicules in multiple myeloma. JAMA Dermatol. 2015;151:82-84.
- DeCrescenzo AJ, Philips RC, Wilkerson MG. Trichodysplasia spinulosa: a rare complication of immunosuppression. JAAD Case Rep. 2016;2:307-309.
- Barton M, Lockhart S, Sidbury R, et al. Trichodysplasia spinulosa in a 7-year-old boy managed using physical extraction of keratin spicules. Pediatr Dermatol. 2017;34:E74-E76.
- Haycox CL, Kim S, Fleckman P, et al. Trichodysplasia spinulosa: a newly described folliculocentric viral infection in an immunocompromised host. J Investig Dermatol Symp Proc. 1999;4:268-271.
- van der Meijden E, Janssens RWA, Lauber C, et al. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient. PLoS Pathog. 2010;6:E1001024.
- Rouanet J, Aubin F, Gaboriaud P, et al. Trichodysplasia spinulosa: a polyomavirus infection specifically targeting follicular keratinocytes in immunocompromised patients. Br J Dermatol. 2016;174:629-632.
- van der Meijden E, Kazem S, Burgers MM, et al. Seroprevalence of trichodysplasia spinulosa-associated polyomavirus. Emerg Infect Dis. 2011;17:1355-1363.
- van der Meijden E, Horváth B, Nijland M, et al. Primary polyomavirus infection, not reactivation, as the cause of trichodysplasia spinulosa in immunocompromised patients. J Infect Dis. 2017;215:1080-1084.
- Fischer MK, Kao GF, Nguyen HP, et al. Specific detection of trichodysplasia spinulosa-associated polyomavirus DNA in skin and renal allograft tissues in a patient with trichodysplasia spinulosa. Arch Dermatol. 2012;148:726-733.
- Kazem S, van der Meijden E, Feltkamp MC. The trichodysplasia spinulosa-associated polyomavirus: virological background and clinical implications. APMIS. 2013;121:770-782.
- van Boheemen S, Jones T, Muhlemann B, et al. Cidofovir gel as treatment of follicular spicules in multiple myeloma. JAMA Dermatol. 2015;151:82-84.
- DeCrescenzo AJ, Philips RC, Wilkerson MG. Trichodysplasia spinulosa: a rare complication of immunosuppression. JAAD Case Rep. 2016;2:307-309.
- Barton M, Lockhart S, Sidbury R, et al. Trichodysplasia spinulosa in a 7-year-old boy managed using physical extraction of keratin spicules. Pediatr Dermatol. 2017;34:E74-E76.
Practice Points
- Trichodysplasia spinulosa (TS) is a rare skin disease caused by primary TS-associated polyomavirus (TSPyV) infecting follicular keratinocytes in immunocompromised patients.
- Trichodysplasia spinulosa typically presents with papular eruptions that appear on the central face with spiny excrescences and various degrees of alopecia involving the eyebrows or eyelashes.
- The viral protein can be verified through immunohistochemistry TSPyV major capsid protein VP1 staining or can be visualized on transmission electron microscopy.
- Follicular spicules of multiple myeloma should be ruled out before initiating treatment with cidofovir gel 1% for TS.
NB-UVB phototherapy plays a key role in psoriasis treatment, expert says
BOSTON – In 2012, about 50% of patients receiving phototherapy at Brigham and Women’s Hospital in Boston were being treated for psoriasis. A decade later, that proportion has dropped to 20%.
Several factors have contributed to this trend, namely, the development of biologics, the COVID-19 pandemic, “and the rise of home phototherapy options,” Elizabeth A. Buzney, MD, codirector of the phototherapy center at Brigham and Women’s department of dermatology, said at the annual meeting of the American Academy of Dermatology. In her clinical opinion, phototherapy plays an essential role in the treatment of psoriasis.
“It is medically and financially responsible to review the option of phototherapy with every psoriasis patient,” Dr. Buzney said. “Many patients are not medical or financial candidates for biologic/apremilast therapy, or just would prefer nonsystemic therapy.”
In one meta-analysis, the proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 with NB-UVB therapy was 70% after 20-40 sessions, just below the efficacy of newer biologics – but better than ustekinumab and adalimumab.
“Phototherapy is not so far out of range as you might think it is,” she said, noting that other studies of NB-UVB therapy show PASI 75 responses of 62% and PASI 90 responses of 40%.
Phototherapy can also be an appealing option because biologics aren’t the best option for all patients with psoriasis. They are expensive for the health care system and potentially for patients, require initial and potentially continued lab testing and monitoring, and require injections, “which some patients don’t like,” said Dr. Buzney, who is also vice-chair of clinical affairs at the Brigham and Women’s Hospital department of dermatology. “There’s an infrequent risk of serious infection and there is risk in patients with HIV, TB, and hepatitis that you have to address. There is also concern for the impact of biologics on patients with a recent cancer.”
On the other hand, few contraindications to NB-UVB exist. According to joint American Academy of Dermatology-National Psoriasis Foundation guidelines on the management and treatment of psoriasis with phototherapy, published in 2019, NB-UVB therapy is only contraindicated in patients with xeroderma pigmentosa and other photosensitive disorders. Concurrent use of cyclosporine and NB-UVB treatment is also contraindicated because of the calculated increase in risk of skin cancer, extrapolated from data on risk with cyclosporine and PUVA (psoralen and ultraviolet A therapy).
The guidelines state that NB-UVB can be used with caution in lupus patients with no history of photosensitivity and who are SS-A negative, as well as patients with a history of melanoma or multiple nonmelanoma skin cancers, a history of recurrent oral herpes simplex virus infection, a history of arsenic intake, prior exposure to ionizing radiation, and those taking photosensitizing medications (since NB-UVB lamps emit “negligible” UVA).
It’s also safe to use during pregnancy and in children. “It’s safe and effective for the right patient,” Dr. Buzney said, discussing how phototherapy can be modified to accommodate children. “You can consider a slower dose-increased regimen. Will children keep the eye protection on? That’s a tricky one. How are you going to manage their anxiety during treatment and involve their family?”
Subgroups of patients who demonstrate a better response to NB-UVB treatment include those with guttate psoriasis, compared with plaque psoriasis, nonsmokers, those with a lower BMI, those with a higher baseline PASI, and those who demonstrate a faster trajectory of clinical response over the first 2-3 weeks of treatment.
Why would one not use phototherapy for psoriasis? “Cost and convenience,” Dr. Buzney said. “There is lost time/revenue to commute to treatment, which may involve multiple times per week. Coming to a public space when COVID-19 is still lingering is another concern, as are the out-of-pocket costs for copays and parking.”
For these reasons, she considers home phototherapy as a transformative option for many patients. Home phototherapy booths provide a safe and effective way to use NB-UVB phototherapy while minimizing copays and commuting costs. The one-time price tag of home NB-UVB booths runs between $5,000 and $7,000, but that is “much less expensive than the biologics,” which can cost $40,000-$50,000 per year, she said.
A small cross-sectional study of office- versus home-based NB-UVB in patients with vitiligo found a cost savings for home-based NB-UVB after 3 months.
One of the challenges with home phototherapy is the lack of long-term studies on patient use. In a small study Dr. Buzney conducted of 30 patients who were prescribed home phototherapy in the last 5 years, 65% practiced (or had practiced) conservative dosing, 83% had continued care with a dermatologist, 19% reported sunburns (5 mild and 1 severe), and 50% had discontinued the therapy at the time of survey because of a perceived lack of efficacy and inconvenience. But 30% of those who had stopped had done so within one month of getting their home booth.
“This tells me that we have to educate our patients better about what expectations should be and make sure they understand how to use their booths,” she said. “Home phototherapy has changed my practice, but not everyone is a candidate for it. Some patients are not dependable. Others are unable to understand instructions.”
Cost to purchase a NB-UVB booth is also an issue, she noted. “Typically, a percentage of cost is covered by insurance, but it’s problematic to purchase a booth if patients don’t know it’s going to work for them or not. Then you have college students who don’t have the space in their apartment or dorm room for a booth.”
Dr. Buzney reported having no relevant financial conflicts.
BOSTON – In 2012, about 50% of patients receiving phototherapy at Brigham and Women’s Hospital in Boston were being treated for psoriasis. A decade later, that proportion has dropped to 20%.
Several factors have contributed to this trend, namely, the development of biologics, the COVID-19 pandemic, “and the rise of home phototherapy options,” Elizabeth A. Buzney, MD, codirector of the phototherapy center at Brigham and Women’s department of dermatology, said at the annual meeting of the American Academy of Dermatology. In her clinical opinion, phototherapy plays an essential role in the treatment of psoriasis.
“It is medically and financially responsible to review the option of phototherapy with every psoriasis patient,” Dr. Buzney said. “Many patients are not medical or financial candidates for biologic/apremilast therapy, or just would prefer nonsystemic therapy.”
In one meta-analysis, the proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 with NB-UVB therapy was 70% after 20-40 sessions, just below the efficacy of newer biologics – but better than ustekinumab and adalimumab.
“Phototherapy is not so far out of range as you might think it is,” she said, noting that other studies of NB-UVB therapy show PASI 75 responses of 62% and PASI 90 responses of 40%.
Phototherapy can also be an appealing option because biologics aren’t the best option for all patients with psoriasis. They are expensive for the health care system and potentially for patients, require initial and potentially continued lab testing and monitoring, and require injections, “which some patients don’t like,” said Dr. Buzney, who is also vice-chair of clinical affairs at the Brigham and Women’s Hospital department of dermatology. “There’s an infrequent risk of serious infection and there is risk in patients with HIV, TB, and hepatitis that you have to address. There is also concern for the impact of biologics on patients with a recent cancer.”
On the other hand, few contraindications to NB-UVB exist. According to joint American Academy of Dermatology-National Psoriasis Foundation guidelines on the management and treatment of psoriasis with phototherapy, published in 2019, NB-UVB therapy is only contraindicated in patients with xeroderma pigmentosa and other photosensitive disorders. Concurrent use of cyclosporine and NB-UVB treatment is also contraindicated because of the calculated increase in risk of skin cancer, extrapolated from data on risk with cyclosporine and PUVA (psoralen and ultraviolet A therapy).
The guidelines state that NB-UVB can be used with caution in lupus patients with no history of photosensitivity and who are SS-A negative, as well as patients with a history of melanoma or multiple nonmelanoma skin cancers, a history of recurrent oral herpes simplex virus infection, a history of arsenic intake, prior exposure to ionizing radiation, and those taking photosensitizing medications (since NB-UVB lamps emit “negligible” UVA).
It’s also safe to use during pregnancy and in children. “It’s safe and effective for the right patient,” Dr. Buzney said, discussing how phototherapy can be modified to accommodate children. “You can consider a slower dose-increased regimen. Will children keep the eye protection on? That’s a tricky one. How are you going to manage their anxiety during treatment and involve their family?”
Subgroups of patients who demonstrate a better response to NB-UVB treatment include those with guttate psoriasis, compared with plaque psoriasis, nonsmokers, those with a lower BMI, those with a higher baseline PASI, and those who demonstrate a faster trajectory of clinical response over the first 2-3 weeks of treatment.
Why would one not use phototherapy for psoriasis? “Cost and convenience,” Dr. Buzney said. “There is lost time/revenue to commute to treatment, which may involve multiple times per week. Coming to a public space when COVID-19 is still lingering is another concern, as are the out-of-pocket costs for copays and parking.”
For these reasons, she considers home phototherapy as a transformative option for many patients. Home phototherapy booths provide a safe and effective way to use NB-UVB phototherapy while minimizing copays and commuting costs. The one-time price tag of home NB-UVB booths runs between $5,000 and $7,000, but that is “much less expensive than the biologics,” which can cost $40,000-$50,000 per year, she said.
A small cross-sectional study of office- versus home-based NB-UVB in patients with vitiligo found a cost savings for home-based NB-UVB after 3 months.
One of the challenges with home phototherapy is the lack of long-term studies on patient use. In a small study Dr. Buzney conducted of 30 patients who were prescribed home phototherapy in the last 5 years, 65% practiced (or had practiced) conservative dosing, 83% had continued care with a dermatologist, 19% reported sunburns (5 mild and 1 severe), and 50% had discontinued the therapy at the time of survey because of a perceived lack of efficacy and inconvenience. But 30% of those who had stopped had done so within one month of getting their home booth.
“This tells me that we have to educate our patients better about what expectations should be and make sure they understand how to use their booths,” she said. “Home phototherapy has changed my practice, but not everyone is a candidate for it. Some patients are not dependable. Others are unable to understand instructions.”
Cost to purchase a NB-UVB booth is also an issue, she noted. “Typically, a percentage of cost is covered by insurance, but it’s problematic to purchase a booth if patients don’t know it’s going to work for them or not. Then you have college students who don’t have the space in their apartment or dorm room for a booth.”
Dr. Buzney reported having no relevant financial conflicts.
BOSTON – In 2012, about 50% of patients receiving phototherapy at Brigham and Women’s Hospital in Boston were being treated for psoriasis. A decade later, that proportion has dropped to 20%.
Several factors have contributed to this trend, namely, the development of biologics, the COVID-19 pandemic, “and the rise of home phototherapy options,” Elizabeth A. Buzney, MD, codirector of the phototherapy center at Brigham and Women’s department of dermatology, said at the annual meeting of the American Academy of Dermatology. In her clinical opinion, phototherapy plays an essential role in the treatment of psoriasis.
“It is medically and financially responsible to review the option of phototherapy with every psoriasis patient,” Dr. Buzney said. “Many patients are not medical or financial candidates for biologic/apremilast therapy, or just would prefer nonsystemic therapy.”
In one meta-analysis, the proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 with NB-UVB therapy was 70% after 20-40 sessions, just below the efficacy of newer biologics – but better than ustekinumab and adalimumab.
“Phototherapy is not so far out of range as you might think it is,” she said, noting that other studies of NB-UVB therapy show PASI 75 responses of 62% and PASI 90 responses of 40%.
Phototherapy can also be an appealing option because biologics aren’t the best option for all patients with psoriasis. They are expensive for the health care system and potentially for patients, require initial and potentially continued lab testing and monitoring, and require injections, “which some patients don’t like,” said Dr. Buzney, who is also vice-chair of clinical affairs at the Brigham and Women’s Hospital department of dermatology. “There’s an infrequent risk of serious infection and there is risk in patients with HIV, TB, and hepatitis that you have to address. There is also concern for the impact of biologics on patients with a recent cancer.”
On the other hand, few contraindications to NB-UVB exist. According to joint American Academy of Dermatology-National Psoriasis Foundation guidelines on the management and treatment of psoriasis with phototherapy, published in 2019, NB-UVB therapy is only contraindicated in patients with xeroderma pigmentosa and other photosensitive disorders. Concurrent use of cyclosporine and NB-UVB treatment is also contraindicated because of the calculated increase in risk of skin cancer, extrapolated from data on risk with cyclosporine and PUVA (psoralen and ultraviolet A therapy).
The guidelines state that NB-UVB can be used with caution in lupus patients with no history of photosensitivity and who are SS-A negative, as well as patients with a history of melanoma or multiple nonmelanoma skin cancers, a history of recurrent oral herpes simplex virus infection, a history of arsenic intake, prior exposure to ionizing radiation, and those taking photosensitizing medications (since NB-UVB lamps emit “negligible” UVA).
It’s also safe to use during pregnancy and in children. “It’s safe and effective for the right patient,” Dr. Buzney said, discussing how phototherapy can be modified to accommodate children. “You can consider a slower dose-increased regimen. Will children keep the eye protection on? That’s a tricky one. How are you going to manage their anxiety during treatment and involve their family?”
Subgroups of patients who demonstrate a better response to NB-UVB treatment include those with guttate psoriasis, compared with plaque psoriasis, nonsmokers, those with a lower BMI, those with a higher baseline PASI, and those who demonstrate a faster trajectory of clinical response over the first 2-3 weeks of treatment.
Why would one not use phototherapy for psoriasis? “Cost and convenience,” Dr. Buzney said. “There is lost time/revenue to commute to treatment, which may involve multiple times per week. Coming to a public space when COVID-19 is still lingering is another concern, as are the out-of-pocket costs for copays and parking.”
For these reasons, she considers home phototherapy as a transformative option for many patients. Home phototherapy booths provide a safe and effective way to use NB-UVB phototherapy while minimizing copays and commuting costs. The one-time price tag of home NB-UVB booths runs between $5,000 and $7,000, but that is “much less expensive than the biologics,” which can cost $40,000-$50,000 per year, she said.
A small cross-sectional study of office- versus home-based NB-UVB in patients with vitiligo found a cost savings for home-based NB-UVB after 3 months.
One of the challenges with home phototherapy is the lack of long-term studies on patient use. In a small study Dr. Buzney conducted of 30 patients who were prescribed home phototherapy in the last 5 years, 65% practiced (or had practiced) conservative dosing, 83% had continued care with a dermatologist, 19% reported sunburns (5 mild and 1 severe), and 50% had discontinued the therapy at the time of survey because of a perceived lack of efficacy and inconvenience. But 30% of those who had stopped had done so within one month of getting their home booth.
“This tells me that we have to educate our patients better about what expectations should be and make sure they understand how to use their booths,” she said. “Home phototherapy has changed my practice, but not everyone is a candidate for it. Some patients are not dependable. Others are unable to understand instructions.”
Cost to purchase a NB-UVB booth is also an issue, she noted. “Typically, a percentage of cost is covered by insurance, but it’s problematic to purchase a booth if patients don’t know it’s going to work for them or not. Then you have college students who don’t have the space in their apartment or dorm room for a booth.”
Dr. Buzney reported having no relevant financial conflicts.
AT AAD 22
IBD risk ‘uncertain’ in biologic-treated AxSpA patients
Considerable uncertainty surrounds whether people with axial spondyloarthritis (axSpA) who are treated with biologic drugs have an increased risk for developing inflammatory bowel disease (IBD) that is higher than if they receive other treatments, according to data reported at the annual meeting of the British Society for Rheumatology.
“We noticed two patterns,” Gary Macfarlane, MD, PhD, Dsc, of the University of Aberdeen (Scotland) said in presenting findings from an analysis of the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS) and a meta-analysis of available studies.
There was a “large excess risk in observational studies associated with biologic therapies, which was not replicated in RCTs [randomized, controlled trials],” he said, “and trials under extensions suggested a small absolute increased risk associated with etanercept and with [interleukin]-17 [inhibitors], although again with considerable uncertainty.”
While these data make it difficult to draw any firm conclusions, “we should be reassured that the patient groups receiving these specific biologics in routine clinical care have not demonstrated an excess risk of IBD,” Dr. Macfarlane told delegates at the meeting.
Addressing clinical questions
IBD is a known extra-articular manifestation of axSpA, with an estimated prevalence of about 7%, according to a 2015 meta-analysis of 69 studies involving more than 30,000 patients.
The idea that people being treated with biologics may be at higher risk for developing IBD than those taking other treatments was suggested by the results of a large (n = 80,326) Danish study in which patients who were treated with an anti–tumor necrosis factor (TNF)–alpha medication were found to be more likely to develop de novo ulcerative colitis or Crohn’s disease than were patients who did not receive biologics.
Notably, the risk for IBD seemed higher with etanercept than with other anti–TNF-alpha agents, such as infliximab and adalimumab.
The aim of the analyses that Dr. Macfarlane presented was therefore to see if there was a difference in IBD risk among patients treated with biologic agents versus other agents, and if etanercept really did pose a greater cause for concern.
“The reason that we are asking this question is that a clinician called us up and asked us if we had any data on it,” Dr. Macfarlane said. “I think that’s really important to say that one of the things the registers are designed for are to answer questions that clinicians may have.”
Looking for new-onset IBD
Although no longer recruiting patients, the BSRBR-AS provides a wealth of data on the real-life management of patients with axSpA who were or were not taking a biologic. Patients were recruited into the register between 2012 and 2017, with follow-up until 2018. Data analyses are still ongoing and expected to continue for another couple of years.
The current analysis of data from the BSRBR-AS included patients who did not already have IBD at enrollment into the register, and patients who had been treated with a biologic could have been treated only with a single agent. Of just over 1,800 eligible patients, 793 had been treated with a biologic and 1,058 had been given nonbiologic treatment.
As expected, there were some differences between the two groups of patients studied, with biologic-treated patients having a younger age than non–biologic-treated patients. Those who took a biologic also had higher disease activity, inflammatory scores, and rates of psoriasis, enthesitis, and peripheral joint involvement.
Incidence rates for new-onset IBD per 1,000 person-years of treatment were calculated as 17 (95% confidence interval, 10.7-25.8) for patients taking a biologic and 5.1 (95% CI, 2.7-8.7) for those not taking a biologic, giving an incidence rate difference of 11.9 (95% CI, 4.3-19.6).
There was some observed differences in the incidence of new-onset IBD associated with specific agents. Etanercept did not have a higher rate (13.9/1,000 patient-years; 95% CI, 5.1-30.3) than did other agents. But in comparison, the incidence of new-onset IBD for adalimumab was 20.4 (95% CI, 11.7-33.1) and zero for other anti-TNF agents such as certolizumab pegol and infliximab, although the duration of exposure to these drugs was much lower.
The IRDs for etanercept versus nonbiologic treatment and versus other anti-TNFs were 8.8 (95% CI, –2.7 to 20.3) and -6.4 (95% CI, –21.3 to 8.5), but with “considerable uncertainty” because the confidence intervals were very wide.
Uncertainty not helped by meta-analysis
“Given the uncertainty associated with the results from BSRBR-AS, we decided to undertake a meta-analysis to try to accumulate other data that could help us answer this question,” Dr. Macfarlane explained.
However, this didn’t really help clarify things because combining BSRBR-AS data with the results of a couple of observational studies suggested that the odds of of IBD doubled with any biologic treatment versus no biologic treatment (odds ratio, 2.19), and a 2.5-fold higher likelihood considering etanercept versus no biologic treatment, but no difference was seen comparing etanercept to other anti-TNF agents (OR, 0.93).
When the meta-analysis was restricted to RCTs, the rate of IBD per 1,000 person-years was 3.43 for placebo, 5.64 for all biologics, 8.14 for etanercept, 2.35 for other anti-TNFs, and 7.02 for IL-17 inhibitors.
For extensions of RCTs, IBD rates per 1,000 person-years of follow-up were 2.91 for etanercept, 0.83 for other anti-TNFs, 3.61 for IL-17 inhibitors, and 2.79 for all biologics.
“There was only a small difference in IBD incidence between the biologic therapy and the placebo groups” in the RCTs and associated studies, Dr. Macfarlane said, adding that “there was a small excess incidence associated with etanercept, compared to other anti-TNF agents, and [for] IL-17 therapy, compared to nonetanercept, anti–TNF-alpha therapies.”
Of course, the different study designs and durations of exposure to the various treatments raises significant methodological issues.
“Randomized, controlled trials should provide the highest quality evidence as a result of their design and randomizing patients to treatment,” Dr. Macfarlane said. “However, their relatively short follow-up, as well as their restrictive eligibility criteria, may work against finding a difference in IBD incidence if it were to exist.”
Observational studies are very valuable in the data they can provide but are also beset with problems, such as surveillance bias and confounding by indication.
The higher risk of IBD that was observed in observational studies could be an issue with study design, or perhaps, “in routine clinical practice, rheumatologists are taking on board factors that we have not measured, that are negating any slight increased risk,” Dr. Macfarlane said.
Session chair Nicola Goodson, MBChB, PhD, of Liverpool (England) University NHS Foundation Trust, commented: “I think that could well be a very reasonable explanation, because I think as a clinician, you do tend to channel drugs away from some people and channel drugs towards others.
However, Dr. Goodson noted that there was “a glimmer” of signal coming from the RCTs.
“Methodologically, that is what you would have to take as the most robust evidence,” Dr. Macfarlane said, “but even with all the evidence available, it’s still very hard for us to quantify; that has enormous uncertainty.”
Dr. Macfarlane and Dr. Goodson had no relevant conflicts of interest to disclose. The BSRBR-AS is supported by the BSR, which receives funds to support the registry from Pfizer, AbbVie, and UCB.
Considerable uncertainty surrounds whether people with axial spondyloarthritis (axSpA) who are treated with biologic drugs have an increased risk for developing inflammatory bowel disease (IBD) that is higher than if they receive other treatments, according to data reported at the annual meeting of the British Society for Rheumatology.
“We noticed two patterns,” Gary Macfarlane, MD, PhD, Dsc, of the University of Aberdeen (Scotland) said in presenting findings from an analysis of the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS) and a meta-analysis of available studies.
There was a “large excess risk in observational studies associated with biologic therapies, which was not replicated in RCTs [randomized, controlled trials],” he said, “and trials under extensions suggested a small absolute increased risk associated with etanercept and with [interleukin]-17 [inhibitors], although again with considerable uncertainty.”
While these data make it difficult to draw any firm conclusions, “we should be reassured that the patient groups receiving these specific biologics in routine clinical care have not demonstrated an excess risk of IBD,” Dr. Macfarlane told delegates at the meeting.
Addressing clinical questions
IBD is a known extra-articular manifestation of axSpA, with an estimated prevalence of about 7%, according to a 2015 meta-analysis of 69 studies involving more than 30,000 patients.
The idea that people being treated with biologics may be at higher risk for developing IBD than those taking other treatments was suggested by the results of a large (n = 80,326) Danish study in which patients who were treated with an anti–tumor necrosis factor (TNF)–alpha medication were found to be more likely to develop de novo ulcerative colitis or Crohn’s disease than were patients who did not receive biologics.
Notably, the risk for IBD seemed higher with etanercept than with other anti–TNF-alpha agents, such as infliximab and adalimumab.
The aim of the analyses that Dr. Macfarlane presented was therefore to see if there was a difference in IBD risk among patients treated with biologic agents versus other agents, and if etanercept really did pose a greater cause for concern.
“The reason that we are asking this question is that a clinician called us up and asked us if we had any data on it,” Dr. Macfarlane said. “I think that’s really important to say that one of the things the registers are designed for are to answer questions that clinicians may have.”
Looking for new-onset IBD
Although no longer recruiting patients, the BSRBR-AS provides a wealth of data on the real-life management of patients with axSpA who were or were not taking a biologic. Patients were recruited into the register between 2012 and 2017, with follow-up until 2018. Data analyses are still ongoing and expected to continue for another couple of years.
The current analysis of data from the BSRBR-AS included patients who did not already have IBD at enrollment into the register, and patients who had been treated with a biologic could have been treated only with a single agent. Of just over 1,800 eligible patients, 793 had been treated with a biologic and 1,058 had been given nonbiologic treatment.
As expected, there were some differences between the two groups of patients studied, with biologic-treated patients having a younger age than non–biologic-treated patients. Those who took a biologic also had higher disease activity, inflammatory scores, and rates of psoriasis, enthesitis, and peripheral joint involvement.
Incidence rates for new-onset IBD per 1,000 person-years of treatment were calculated as 17 (95% confidence interval, 10.7-25.8) for patients taking a biologic and 5.1 (95% CI, 2.7-8.7) for those not taking a biologic, giving an incidence rate difference of 11.9 (95% CI, 4.3-19.6).
There was some observed differences in the incidence of new-onset IBD associated with specific agents. Etanercept did not have a higher rate (13.9/1,000 patient-years; 95% CI, 5.1-30.3) than did other agents. But in comparison, the incidence of new-onset IBD for adalimumab was 20.4 (95% CI, 11.7-33.1) and zero for other anti-TNF agents such as certolizumab pegol and infliximab, although the duration of exposure to these drugs was much lower.
The IRDs for etanercept versus nonbiologic treatment and versus other anti-TNFs were 8.8 (95% CI, –2.7 to 20.3) and -6.4 (95% CI, –21.3 to 8.5), but with “considerable uncertainty” because the confidence intervals were very wide.
Uncertainty not helped by meta-analysis
“Given the uncertainty associated with the results from BSRBR-AS, we decided to undertake a meta-analysis to try to accumulate other data that could help us answer this question,” Dr. Macfarlane explained.
However, this didn’t really help clarify things because combining BSRBR-AS data with the results of a couple of observational studies suggested that the odds of of IBD doubled with any biologic treatment versus no biologic treatment (odds ratio, 2.19), and a 2.5-fold higher likelihood considering etanercept versus no biologic treatment, but no difference was seen comparing etanercept to other anti-TNF agents (OR, 0.93).
When the meta-analysis was restricted to RCTs, the rate of IBD per 1,000 person-years was 3.43 for placebo, 5.64 for all biologics, 8.14 for etanercept, 2.35 for other anti-TNFs, and 7.02 for IL-17 inhibitors.
For extensions of RCTs, IBD rates per 1,000 person-years of follow-up were 2.91 for etanercept, 0.83 for other anti-TNFs, 3.61 for IL-17 inhibitors, and 2.79 for all biologics.
“There was only a small difference in IBD incidence between the biologic therapy and the placebo groups” in the RCTs and associated studies, Dr. Macfarlane said, adding that “there was a small excess incidence associated with etanercept, compared to other anti-TNF agents, and [for] IL-17 therapy, compared to nonetanercept, anti–TNF-alpha therapies.”
Of course, the different study designs and durations of exposure to the various treatments raises significant methodological issues.
“Randomized, controlled trials should provide the highest quality evidence as a result of their design and randomizing patients to treatment,” Dr. Macfarlane said. “However, their relatively short follow-up, as well as their restrictive eligibility criteria, may work against finding a difference in IBD incidence if it were to exist.”
Observational studies are very valuable in the data they can provide but are also beset with problems, such as surveillance bias and confounding by indication.
The higher risk of IBD that was observed in observational studies could be an issue with study design, or perhaps, “in routine clinical practice, rheumatologists are taking on board factors that we have not measured, that are negating any slight increased risk,” Dr. Macfarlane said.
Session chair Nicola Goodson, MBChB, PhD, of Liverpool (England) University NHS Foundation Trust, commented: “I think that could well be a very reasonable explanation, because I think as a clinician, you do tend to channel drugs away from some people and channel drugs towards others.
However, Dr. Goodson noted that there was “a glimmer” of signal coming from the RCTs.
“Methodologically, that is what you would have to take as the most robust evidence,” Dr. Macfarlane said, “but even with all the evidence available, it’s still very hard for us to quantify; that has enormous uncertainty.”
Dr. Macfarlane and Dr. Goodson had no relevant conflicts of interest to disclose. The BSRBR-AS is supported by the BSR, which receives funds to support the registry from Pfizer, AbbVie, and UCB.
Considerable uncertainty surrounds whether people with axial spondyloarthritis (axSpA) who are treated with biologic drugs have an increased risk for developing inflammatory bowel disease (IBD) that is higher than if they receive other treatments, according to data reported at the annual meeting of the British Society for Rheumatology.
“We noticed two patterns,” Gary Macfarlane, MD, PhD, Dsc, of the University of Aberdeen (Scotland) said in presenting findings from an analysis of the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS) and a meta-analysis of available studies.
There was a “large excess risk in observational studies associated with biologic therapies, which was not replicated in RCTs [randomized, controlled trials],” he said, “and trials under extensions suggested a small absolute increased risk associated with etanercept and with [interleukin]-17 [inhibitors], although again with considerable uncertainty.”
While these data make it difficult to draw any firm conclusions, “we should be reassured that the patient groups receiving these specific biologics in routine clinical care have not demonstrated an excess risk of IBD,” Dr. Macfarlane told delegates at the meeting.
Addressing clinical questions
IBD is a known extra-articular manifestation of axSpA, with an estimated prevalence of about 7%, according to a 2015 meta-analysis of 69 studies involving more than 30,000 patients.
The idea that people being treated with biologics may be at higher risk for developing IBD than those taking other treatments was suggested by the results of a large (n = 80,326) Danish study in which patients who were treated with an anti–tumor necrosis factor (TNF)–alpha medication were found to be more likely to develop de novo ulcerative colitis or Crohn’s disease than were patients who did not receive biologics.
Notably, the risk for IBD seemed higher with etanercept than with other anti–TNF-alpha agents, such as infliximab and adalimumab.
The aim of the analyses that Dr. Macfarlane presented was therefore to see if there was a difference in IBD risk among patients treated with biologic agents versus other agents, and if etanercept really did pose a greater cause for concern.
“The reason that we are asking this question is that a clinician called us up and asked us if we had any data on it,” Dr. Macfarlane said. “I think that’s really important to say that one of the things the registers are designed for are to answer questions that clinicians may have.”
Looking for new-onset IBD
Although no longer recruiting patients, the BSRBR-AS provides a wealth of data on the real-life management of patients with axSpA who were or were not taking a biologic. Patients were recruited into the register between 2012 and 2017, with follow-up until 2018. Data analyses are still ongoing and expected to continue for another couple of years.
The current analysis of data from the BSRBR-AS included patients who did not already have IBD at enrollment into the register, and patients who had been treated with a biologic could have been treated only with a single agent. Of just over 1,800 eligible patients, 793 had been treated with a biologic and 1,058 had been given nonbiologic treatment.
As expected, there were some differences between the two groups of patients studied, with biologic-treated patients having a younger age than non–biologic-treated patients. Those who took a biologic also had higher disease activity, inflammatory scores, and rates of psoriasis, enthesitis, and peripheral joint involvement.
Incidence rates for new-onset IBD per 1,000 person-years of treatment were calculated as 17 (95% confidence interval, 10.7-25.8) for patients taking a biologic and 5.1 (95% CI, 2.7-8.7) for those not taking a biologic, giving an incidence rate difference of 11.9 (95% CI, 4.3-19.6).
There was some observed differences in the incidence of new-onset IBD associated with specific agents. Etanercept did not have a higher rate (13.9/1,000 patient-years; 95% CI, 5.1-30.3) than did other agents. But in comparison, the incidence of new-onset IBD for adalimumab was 20.4 (95% CI, 11.7-33.1) and zero for other anti-TNF agents such as certolizumab pegol and infliximab, although the duration of exposure to these drugs was much lower.
The IRDs for etanercept versus nonbiologic treatment and versus other anti-TNFs were 8.8 (95% CI, –2.7 to 20.3) and -6.4 (95% CI, –21.3 to 8.5), but with “considerable uncertainty” because the confidence intervals were very wide.
Uncertainty not helped by meta-analysis
“Given the uncertainty associated with the results from BSRBR-AS, we decided to undertake a meta-analysis to try to accumulate other data that could help us answer this question,” Dr. Macfarlane explained.
However, this didn’t really help clarify things because combining BSRBR-AS data with the results of a couple of observational studies suggested that the odds of of IBD doubled with any biologic treatment versus no biologic treatment (odds ratio, 2.19), and a 2.5-fold higher likelihood considering etanercept versus no biologic treatment, but no difference was seen comparing etanercept to other anti-TNF agents (OR, 0.93).
When the meta-analysis was restricted to RCTs, the rate of IBD per 1,000 person-years was 3.43 for placebo, 5.64 for all biologics, 8.14 for etanercept, 2.35 for other anti-TNFs, and 7.02 for IL-17 inhibitors.
For extensions of RCTs, IBD rates per 1,000 person-years of follow-up were 2.91 for etanercept, 0.83 for other anti-TNFs, 3.61 for IL-17 inhibitors, and 2.79 for all biologics.
“There was only a small difference in IBD incidence between the biologic therapy and the placebo groups” in the RCTs and associated studies, Dr. Macfarlane said, adding that “there was a small excess incidence associated with etanercept, compared to other anti-TNF agents, and [for] IL-17 therapy, compared to nonetanercept, anti–TNF-alpha therapies.”
Of course, the different study designs and durations of exposure to the various treatments raises significant methodological issues.
“Randomized, controlled trials should provide the highest quality evidence as a result of their design and randomizing patients to treatment,” Dr. Macfarlane said. “However, their relatively short follow-up, as well as their restrictive eligibility criteria, may work against finding a difference in IBD incidence if it were to exist.”
Observational studies are very valuable in the data they can provide but are also beset with problems, such as surveillance bias and confounding by indication.
The higher risk of IBD that was observed in observational studies could be an issue with study design, or perhaps, “in routine clinical practice, rheumatologists are taking on board factors that we have not measured, that are negating any slight increased risk,” Dr. Macfarlane said.
Session chair Nicola Goodson, MBChB, PhD, of Liverpool (England) University NHS Foundation Trust, commented: “I think that could well be a very reasonable explanation, because I think as a clinician, you do tend to channel drugs away from some people and channel drugs towards others.
However, Dr. Goodson noted that there was “a glimmer” of signal coming from the RCTs.
“Methodologically, that is what you would have to take as the most robust evidence,” Dr. Macfarlane said, “but even with all the evidence available, it’s still very hard for us to quantify; that has enormous uncertainty.”
Dr. Macfarlane and Dr. Goodson had no relevant conflicts of interest to disclose. The BSRBR-AS is supported by the BSR, which receives funds to support the registry from Pfizer, AbbVie, and UCB.
FROM BSR 2022
Unilateral eye irritation
Physical examination revealed an irregularly shaped conjunctival cyst on the lateral (temporal) field of the right eye. (This diagnosis is usually made based on the clinical examination alone.)
Primary care physicians encounter patients with a variety of eye conditions; pruritis and foreign body sensation are among the most common complaints.1 While viral or allergic conjunctivitis is often to blame for “itchy eyes,” the cause can also be a conjunctival mass.
Conjunctival masses can be divided into 2 groups: solid tumors or cysts.2 Conjunctival cysts form due to trauma, infection, or inflammation that disrupts the conjunctival epithelium. They can be congenital or acquired (more common) and are rarely caused by over-the-counter eye drops.2,3 The differential diagnosis for a conjunctival cyst includes conjunctival bleb, pinguecula, pterygium, pyogenic granuloma, and tumors of the conjunctiva. An external eye exam plus a slit-lamp examination can help confirm the diagnosis.
Small, asymptomatic conjunctival cysts will mostly resolve on their own and can be managed conservatively with lubricating eye drops.3 When inflammation surrounds the cyst, short-term use of a mild topical corticosteroid is reasonable.2 Simple needle aspiration can be performed but may lead to recurrence of the cyst. Lesions larger than 15 mm, or those that have grown or changed, should be evaluated by an ophthalmologist for biopsy and further management.2,3
After a discussion of the benefits and risks of different approaches, this patient decided on conservative management. Supportive care with lubricating eye drops was started. At her 1-month follow-up, all symptoms had resolved.
Photos courtesy of Morteza Khodaee, MD, MPH. Text courtesy of Amy S. Li, MD, Department of Internal Medicine, Jennifer Cogburn, MD, and Morteza Khodaee, MD, MPH, Department of Family Medicine, University of Colorado School of Medicine, Denver
1. Pflipsen M, Massaquoi M, Wolf S. Evaluation of the painful eye. Am Fam Physician. 2016 Jun 15;93:991-998.
2. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Indian J Ophthalmol. 2019;67:1930-1948. doi: 10.4103/ijo.IJO_2040_19
3. Olivier JF. Common conjunctival lesions. S Afr J CPD. 2013;31:134-137.
Physical examination revealed an irregularly shaped conjunctival cyst on the lateral (temporal) field of the right eye. (This diagnosis is usually made based on the clinical examination alone.)
Primary care physicians encounter patients with a variety of eye conditions; pruritis and foreign body sensation are among the most common complaints.1 While viral or allergic conjunctivitis is often to blame for “itchy eyes,” the cause can also be a conjunctival mass.
Conjunctival masses can be divided into 2 groups: solid tumors or cysts.2 Conjunctival cysts form due to trauma, infection, or inflammation that disrupts the conjunctival epithelium. They can be congenital or acquired (more common) and are rarely caused by over-the-counter eye drops.2,3 The differential diagnosis for a conjunctival cyst includes conjunctival bleb, pinguecula, pterygium, pyogenic granuloma, and tumors of the conjunctiva. An external eye exam plus a slit-lamp examination can help confirm the diagnosis.
Small, asymptomatic conjunctival cysts will mostly resolve on their own and can be managed conservatively with lubricating eye drops.3 When inflammation surrounds the cyst, short-term use of a mild topical corticosteroid is reasonable.2 Simple needle aspiration can be performed but may lead to recurrence of the cyst. Lesions larger than 15 mm, or those that have grown or changed, should be evaluated by an ophthalmologist for biopsy and further management.2,3
After a discussion of the benefits and risks of different approaches, this patient decided on conservative management. Supportive care with lubricating eye drops was started. At her 1-month follow-up, all symptoms had resolved.
Photos courtesy of Morteza Khodaee, MD, MPH. Text courtesy of Amy S. Li, MD, Department of Internal Medicine, Jennifer Cogburn, MD, and Morteza Khodaee, MD, MPH, Department of Family Medicine, University of Colorado School of Medicine, Denver
Physical examination revealed an irregularly shaped conjunctival cyst on the lateral (temporal) field of the right eye. (This diagnosis is usually made based on the clinical examination alone.)
Primary care physicians encounter patients with a variety of eye conditions; pruritis and foreign body sensation are among the most common complaints.1 While viral or allergic conjunctivitis is often to blame for “itchy eyes,” the cause can also be a conjunctival mass.
Conjunctival masses can be divided into 2 groups: solid tumors or cysts.2 Conjunctival cysts form due to trauma, infection, or inflammation that disrupts the conjunctival epithelium. They can be congenital or acquired (more common) and are rarely caused by over-the-counter eye drops.2,3 The differential diagnosis for a conjunctival cyst includes conjunctival bleb, pinguecula, pterygium, pyogenic granuloma, and tumors of the conjunctiva. An external eye exam plus a slit-lamp examination can help confirm the diagnosis.
Small, asymptomatic conjunctival cysts will mostly resolve on their own and can be managed conservatively with lubricating eye drops.3 When inflammation surrounds the cyst, short-term use of a mild topical corticosteroid is reasonable.2 Simple needle aspiration can be performed but may lead to recurrence of the cyst. Lesions larger than 15 mm, or those that have grown or changed, should be evaluated by an ophthalmologist for biopsy and further management.2,3
After a discussion of the benefits and risks of different approaches, this patient decided on conservative management. Supportive care with lubricating eye drops was started. At her 1-month follow-up, all symptoms had resolved.
Photos courtesy of Morteza Khodaee, MD, MPH. Text courtesy of Amy S. Li, MD, Department of Internal Medicine, Jennifer Cogburn, MD, and Morteza Khodaee, MD, MPH, Department of Family Medicine, University of Colorado School of Medicine, Denver
1. Pflipsen M, Massaquoi M, Wolf S. Evaluation of the painful eye. Am Fam Physician. 2016 Jun 15;93:991-998.
2. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Indian J Ophthalmol. 2019;67:1930-1948. doi: 10.4103/ijo.IJO_2040_19
3. Olivier JF. Common conjunctival lesions. S Afr J CPD. 2013;31:134-137.
1. Pflipsen M, Massaquoi M, Wolf S. Evaluation of the painful eye. Am Fam Physician. 2016 Jun 15;93:991-998.
2. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Indian J Ophthalmol. 2019;67:1930-1948. doi: 10.4103/ijo.IJO_2040_19
3. Olivier JF. Common conjunctival lesions. S Afr J CPD. 2013;31:134-137.
