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FDA approves new CAR T-cell treatment for multiple myeloma
A new treatment option for patients with refractory/relapsed multiple myeloma who have already tried four or more therapies has been approved by the U.S. Food and Drug Administration.
There are already two other therapies on the market that target BCMA – another CAR T cell, idecabtagene vicleucel (Abecma), which was approved by the FDA in March 2021, and a drug conjugate, belantamab mafodotin (Blenrep), which was approved in August 2020.
The approval of cilta-cel was based on clinical data from the CARTITUDE-1 study, which were initially presented in December 2020 at the annual meeting of the American Society of Hematology, as reported at the time by this news organization.
The trial involved 97 patients with relapsed/refractory multiple myeloma who had already received a median of six previous treatments (range, three to 18), including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
“The treatment journey for the majority of patients living with multiple myeloma is a relentless cycle of remission and relapse, with fewer patients achieving a deep response as they progress through later lines of therapy,” commented Sundar Jagannath, MBBS, professor of medicine, hematology, and medical oncology at Mount Sinai, who was a principal investigator on the pivotal study.
“That is why I have been really excited about the results from the CARTITUDE-1 study, which has demonstrated that cilta-cel can provide deep and durable responses and long-term treatment-free intervals, even in this heavily pretreated multiple myeloma patient population,” he said.
“Today’s approval of Carvykti helps address a great unmet need for these patients,” he commented in a press release from the manufacturer.
Like other CAR T-cell therapies, ciltacabtagene autoleucel is a one-time treatment. It involves collecting blood from the patient, extracting T cells, genetically engineering them, then transfusing them back to the patient, who in the meantime has undergone conditioning.
The results from CARTITUDE-1 show that this one-time treatment resulted in deep and durable responses.
The overall response rate was 98%, and the majority of patients (78%) achieved a stringent complete response, in which physicians are unable to observe any signs or symptoms of disease via imaging or other tests after treatment.
At a median of 18 months’ follow-up, the median duration of response was 21.8 months.
“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” commented Mr. Jagannath.
“The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time,” he added.
As with other CAR T-cell therapies, there were serious side effects, and these products are available only through restricted programs under a risk evaluation and mitigation strategy.
The product information for Cartykti includes a boxed warning that mentions cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome, parkinsonism, Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and/or recurrent cytopenias.
The most common adverse reactions (reported in greater than or equal to 20% of patients) are pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections–pathogens unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.
A version of this article first appeared on Medscape.com.
A new treatment option for patients with refractory/relapsed multiple myeloma who have already tried four or more therapies has been approved by the U.S. Food and Drug Administration.
There are already two other therapies on the market that target BCMA – another CAR T cell, idecabtagene vicleucel (Abecma), which was approved by the FDA in March 2021, and a drug conjugate, belantamab mafodotin (Blenrep), which was approved in August 2020.
The approval of cilta-cel was based on clinical data from the CARTITUDE-1 study, which were initially presented in December 2020 at the annual meeting of the American Society of Hematology, as reported at the time by this news organization.
The trial involved 97 patients with relapsed/refractory multiple myeloma who had already received a median of six previous treatments (range, three to 18), including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
“The treatment journey for the majority of patients living with multiple myeloma is a relentless cycle of remission and relapse, with fewer patients achieving a deep response as they progress through later lines of therapy,” commented Sundar Jagannath, MBBS, professor of medicine, hematology, and medical oncology at Mount Sinai, who was a principal investigator on the pivotal study.
“That is why I have been really excited about the results from the CARTITUDE-1 study, which has demonstrated that cilta-cel can provide deep and durable responses and long-term treatment-free intervals, even in this heavily pretreated multiple myeloma patient population,” he said.
“Today’s approval of Carvykti helps address a great unmet need for these patients,” he commented in a press release from the manufacturer.
Like other CAR T-cell therapies, ciltacabtagene autoleucel is a one-time treatment. It involves collecting blood from the patient, extracting T cells, genetically engineering them, then transfusing them back to the patient, who in the meantime has undergone conditioning.
The results from CARTITUDE-1 show that this one-time treatment resulted in deep and durable responses.
The overall response rate was 98%, and the majority of patients (78%) achieved a stringent complete response, in which physicians are unable to observe any signs or symptoms of disease via imaging or other tests after treatment.
At a median of 18 months’ follow-up, the median duration of response was 21.8 months.
“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” commented Mr. Jagannath.
“The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time,” he added.
As with other CAR T-cell therapies, there were serious side effects, and these products are available only through restricted programs under a risk evaluation and mitigation strategy.
The product information for Cartykti includes a boxed warning that mentions cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome, parkinsonism, Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and/or recurrent cytopenias.
The most common adverse reactions (reported in greater than or equal to 20% of patients) are pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections–pathogens unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.
A version of this article first appeared on Medscape.com.
A new treatment option for patients with refractory/relapsed multiple myeloma who have already tried four or more therapies has been approved by the U.S. Food and Drug Administration.
There are already two other therapies on the market that target BCMA – another CAR T cell, idecabtagene vicleucel (Abecma), which was approved by the FDA in March 2021, and a drug conjugate, belantamab mafodotin (Blenrep), which was approved in August 2020.
The approval of cilta-cel was based on clinical data from the CARTITUDE-1 study, which were initially presented in December 2020 at the annual meeting of the American Society of Hematology, as reported at the time by this news organization.
The trial involved 97 patients with relapsed/refractory multiple myeloma who had already received a median of six previous treatments (range, three to 18), including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
“The treatment journey for the majority of patients living with multiple myeloma is a relentless cycle of remission and relapse, with fewer patients achieving a deep response as they progress through later lines of therapy,” commented Sundar Jagannath, MBBS, professor of medicine, hematology, and medical oncology at Mount Sinai, who was a principal investigator on the pivotal study.
“That is why I have been really excited about the results from the CARTITUDE-1 study, which has demonstrated that cilta-cel can provide deep and durable responses and long-term treatment-free intervals, even in this heavily pretreated multiple myeloma patient population,” he said.
“Today’s approval of Carvykti helps address a great unmet need for these patients,” he commented in a press release from the manufacturer.
Like other CAR T-cell therapies, ciltacabtagene autoleucel is a one-time treatment. It involves collecting blood from the patient, extracting T cells, genetically engineering them, then transfusing them back to the patient, who in the meantime has undergone conditioning.
The results from CARTITUDE-1 show that this one-time treatment resulted in deep and durable responses.
The overall response rate was 98%, and the majority of patients (78%) achieved a stringent complete response, in which physicians are unable to observe any signs or symptoms of disease via imaging or other tests after treatment.
At a median of 18 months’ follow-up, the median duration of response was 21.8 months.
“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” commented Mr. Jagannath.
“The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time,” he added.
As with other CAR T-cell therapies, there were serious side effects, and these products are available only through restricted programs under a risk evaluation and mitigation strategy.
The product information for Cartykti includes a boxed warning that mentions cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome, parkinsonism, Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and/or recurrent cytopenias.
The most common adverse reactions (reported in greater than or equal to 20% of patients) are pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections–pathogens unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.
A version of this article first appeared on Medscape.com.
What is the healthiest salt for you?
When we refer to “regular table salt,” it is most commonly in the form of sodium chloride, which is also a major constituent of packaged and ultraprocessed foods.
The best approach to finding the “healthiest salt” – which really means the lowest in sodium – is to look for the amount on the label. “Sodium-free” usually indicates less than 5 mg of sodium per serving, and “low-sodium” usually means 140 mg or less per serving. In contrast, regular table salt can contain as much as 560 mg of sodium in one serving.
Other en vogue salts, such as pink Himalayan salt, sea salt, and kosher salt, are high in sodium content – like regular table salt – but because of their larger crystal size, less sodium is delivered per serving.
Most salt substitutes are reduced in sodium, with the addition of potassium chloride instead.
FDA issues guidance on reducing salt
Currently, the U.S. sodium dietary guidelines for persons older than 14 stipulate 2,300 mg/d, which is equivalent to 1 teaspoon a day. However it is estimated that the average person in the United States consumes more than this – around 3,400 mg of sodium daily.
In October 2021, the U.S. Food and Drug Administration published guidance on voluntary sodium limitations in commercially processed, packaged, and prepared food. The FDA’s short-term approach is to slowly reduce exposure to sodium in processed and restaurant food by 2025, on the basis that people will eventually get used to less salt, as has happened in the United Kingdom and other countries.
Such strategies to reduce salt intake are now being used in national programs in several countries. Many of these successful initiatives include active engagement with the food industry to reduce the amount of sodium added to processed food, as well as public awareness campaigns to alert consumers to the dangers of eating too much salt. This includes increasing potassium in manufactured foods, primarily to target hypertension and heart disease, as described by Clare Farrand, MSc, BSc, and colleagues, in the Journal of Clinical Hypertension. The authors also make several recommendations regarding salt reduction policies:
- Food manufacturers should gradually reduce sodium in food to the lowest possible levels and explore the use of potassium-based sodium replacers to reduce sodium levels even further.
- Governments should continue to monitor sodium and potassium levels in processed foods.
- Further consideration may need to be given to how best to label salt substitutes (namely potassium) in processed foods to ensure that people who may be adversely affected are aware.
- Governments should systematically monitor potassium intake at the population level, including for specific susceptible groups.
- Governments should continue to systematically monitor sodium (salt) intake and iodine intake at the population level to adjust salt iodization over time as necessary, depending on observed salt intake in specific targeted groups, to ensure that they have sufficient but not excessive iodine intakes as salt intakes are reduced.
- Governments should consider opportunities for promoting and subsidizing salt substitutes, particularly in countries where salt added during cooking or at the table is the major source of salt in the diet.
The new FDA document includes 163 subcategories of foods in its voluntary salt reduction strategy.
Salt substitutes, high blood pressure, and mortality
Lowering sodium intake is almost certainly beneficial for persons with high blood pressure. In 2020, a review in Hypertension highlighted the benefit of salt substitutes in reducing hypertension, reporting that they lower systolic blood pressure by 5.58 mm Hg and diastolic blood pressure by 2.88 mm Hg.
And changes to dietary sodium intake can potentially reduce or obviate the need for medications for essential hypertension in some individuals. Although there are only a few studies on this topic, a study by Bruce Neal, MB, ChB, PhD, and colleagues, revealed a reduction in stroke, cardiovascular events, and deaths with the use of potassium-based salt substitutes.
Salt substitutes and sodium and potassium handling in the kidneys
Many studies have shown that potassium-rich salt substitutes are safe in individuals with normal kidney function, but are they safe and beneficial for people with chronic kidney disease (CKD)?
For anyone who is on a renal diet, potassium and sodium intake goals are limited according to their absolute level of kidney function.
There have been case reports of life-threatening blood potassium levels (hyperkalemia) due to potassium-rich salt substitutes in people with CKD, but no larger published studies on this topic can be found.
A diet modeling study by Rebecca Morrison and colleagues evaluated varying degrees of potassium-enriched salt substituted bread products and their impact on dietary intake in persons with CKD. They used dietary data from the National Nutrition and Physical Activity Survey 2011-2012 in Australia for 12,152 participants, 154 of whom had CKD. Replacing the sodium in bread with varying amounts of potassium chloride (20%, 30%, and 40%) would result in one-third of people with CKD exceeding the safe limits for dietary potassium consumption (31.8%, 32.6%, and 33%, respectively), they found.
“Potassium chloride substitution in staple foods such as bread and bread products have serious and potentially fatal consequences for people who need to restrict dietary potassium. Improved food labelling is required for consumers to avoid excessive consumption,” Ms. Morrison and colleagues concluded. They added that more studies are needed to further understand the risks of potassium dietary intake and hyperkalemia in CKD from potassium-based salt substitutes.
The American Heart Association recommends no more than 1,500 mg of sodium intake daily for persons with CKD, diabetes, or high blood pressure; those older than 51; and African American persons of any age.
The recommended daily intake of potassium in persons with CKD can range from 2,000 mg to 4,000 mg, depending on the individual and their degree of CKD. The potassium content in some salt substitutes varies from 440 mg to 2,800 mg per teaspoon.
The best recommendation for individuals with CKD and a goal to reduce their sodium intake is to use herbs and lower-sodium seasonings as a substitute, but these should always be reviewed with their physician and renal nutritionist.
Dr. Brookins is a board-certified nephrologist and internist practicing in Georgia. She is the founder and owner of Remote Renal Care, a telehealth kidney practice. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
When we refer to “regular table salt,” it is most commonly in the form of sodium chloride, which is also a major constituent of packaged and ultraprocessed foods.
The best approach to finding the “healthiest salt” – which really means the lowest in sodium – is to look for the amount on the label. “Sodium-free” usually indicates less than 5 mg of sodium per serving, and “low-sodium” usually means 140 mg or less per serving. In contrast, regular table salt can contain as much as 560 mg of sodium in one serving.
Other en vogue salts, such as pink Himalayan salt, sea salt, and kosher salt, are high in sodium content – like regular table salt – but because of their larger crystal size, less sodium is delivered per serving.
Most salt substitutes are reduced in sodium, with the addition of potassium chloride instead.
FDA issues guidance on reducing salt
Currently, the U.S. sodium dietary guidelines for persons older than 14 stipulate 2,300 mg/d, which is equivalent to 1 teaspoon a day. However it is estimated that the average person in the United States consumes more than this – around 3,400 mg of sodium daily.
In October 2021, the U.S. Food and Drug Administration published guidance on voluntary sodium limitations in commercially processed, packaged, and prepared food. The FDA’s short-term approach is to slowly reduce exposure to sodium in processed and restaurant food by 2025, on the basis that people will eventually get used to less salt, as has happened in the United Kingdom and other countries.
Such strategies to reduce salt intake are now being used in national programs in several countries. Many of these successful initiatives include active engagement with the food industry to reduce the amount of sodium added to processed food, as well as public awareness campaigns to alert consumers to the dangers of eating too much salt. This includes increasing potassium in manufactured foods, primarily to target hypertension and heart disease, as described by Clare Farrand, MSc, BSc, and colleagues, in the Journal of Clinical Hypertension. The authors also make several recommendations regarding salt reduction policies:
- Food manufacturers should gradually reduce sodium in food to the lowest possible levels and explore the use of potassium-based sodium replacers to reduce sodium levels even further.
- Governments should continue to monitor sodium and potassium levels in processed foods.
- Further consideration may need to be given to how best to label salt substitutes (namely potassium) in processed foods to ensure that people who may be adversely affected are aware.
- Governments should systematically monitor potassium intake at the population level, including for specific susceptible groups.
- Governments should continue to systematically monitor sodium (salt) intake and iodine intake at the population level to adjust salt iodization over time as necessary, depending on observed salt intake in specific targeted groups, to ensure that they have sufficient but not excessive iodine intakes as salt intakes are reduced.
- Governments should consider opportunities for promoting and subsidizing salt substitutes, particularly in countries where salt added during cooking or at the table is the major source of salt in the diet.
The new FDA document includes 163 subcategories of foods in its voluntary salt reduction strategy.
Salt substitutes, high blood pressure, and mortality
Lowering sodium intake is almost certainly beneficial for persons with high blood pressure. In 2020, a review in Hypertension highlighted the benefit of salt substitutes in reducing hypertension, reporting that they lower systolic blood pressure by 5.58 mm Hg and diastolic blood pressure by 2.88 mm Hg.
And changes to dietary sodium intake can potentially reduce or obviate the need for medications for essential hypertension in some individuals. Although there are only a few studies on this topic, a study by Bruce Neal, MB, ChB, PhD, and colleagues, revealed a reduction in stroke, cardiovascular events, and deaths with the use of potassium-based salt substitutes.
Salt substitutes and sodium and potassium handling in the kidneys
Many studies have shown that potassium-rich salt substitutes are safe in individuals with normal kidney function, but are they safe and beneficial for people with chronic kidney disease (CKD)?
For anyone who is on a renal diet, potassium and sodium intake goals are limited according to their absolute level of kidney function.
There have been case reports of life-threatening blood potassium levels (hyperkalemia) due to potassium-rich salt substitutes in people with CKD, but no larger published studies on this topic can be found.
A diet modeling study by Rebecca Morrison and colleagues evaluated varying degrees of potassium-enriched salt substituted bread products and their impact on dietary intake in persons with CKD. They used dietary data from the National Nutrition and Physical Activity Survey 2011-2012 in Australia for 12,152 participants, 154 of whom had CKD. Replacing the sodium in bread with varying amounts of potassium chloride (20%, 30%, and 40%) would result in one-third of people with CKD exceeding the safe limits for dietary potassium consumption (31.8%, 32.6%, and 33%, respectively), they found.
“Potassium chloride substitution in staple foods such as bread and bread products have serious and potentially fatal consequences for people who need to restrict dietary potassium. Improved food labelling is required for consumers to avoid excessive consumption,” Ms. Morrison and colleagues concluded. They added that more studies are needed to further understand the risks of potassium dietary intake and hyperkalemia in CKD from potassium-based salt substitutes.
The American Heart Association recommends no more than 1,500 mg of sodium intake daily for persons with CKD, diabetes, or high blood pressure; those older than 51; and African American persons of any age.
The recommended daily intake of potassium in persons with CKD can range from 2,000 mg to 4,000 mg, depending on the individual and their degree of CKD. The potassium content in some salt substitutes varies from 440 mg to 2,800 mg per teaspoon.
The best recommendation for individuals with CKD and a goal to reduce their sodium intake is to use herbs and lower-sodium seasonings as a substitute, but these should always be reviewed with their physician and renal nutritionist.
Dr. Brookins is a board-certified nephrologist and internist practicing in Georgia. She is the founder and owner of Remote Renal Care, a telehealth kidney practice. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
When we refer to “regular table salt,” it is most commonly in the form of sodium chloride, which is also a major constituent of packaged and ultraprocessed foods.
The best approach to finding the “healthiest salt” – which really means the lowest in sodium – is to look for the amount on the label. “Sodium-free” usually indicates less than 5 mg of sodium per serving, and “low-sodium” usually means 140 mg or less per serving. In contrast, regular table salt can contain as much as 560 mg of sodium in one serving.
Other en vogue salts, such as pink Himalayan salt, sea salt, and kosher salt, are high in sodium content – like regular table salt – but because of their larger crystal size, less sodium is delivered per serving.
Most salt substitutes are reduced in sodium, with the addition of potassium chloride instead.
FDA issues guidance on reducing salt
Currently, the U.S. sodium dietary guidelines for persons older than 14 stipulate 2,300 mg/d, which is equivalent to 1 teaspoon a day. However it is estimated that the average person in the United States consumes more than this – around 3,400 mg of sodium daily.
In October 2021, the U.S. Food and Drug Administration published guidance on voluntary sodium limitations in commercially processed, packaged, and prepared food. The FDA’s short-term approach is to slowly reduce exposure to sodium in processed and restaurant food by 2025, on the basis that people will eventually get used to less salt, as has happened in the United Kingdom and other countries.
Such strategies to reduce salt intake are now being used in national programs in several countries. Many of these successful initiatives include active engagement with the food industry to reduce the amount of sodium added to processed food, as well as public awareness campaigns to alert consumers to the dangers of eating too much salt. This includes increasing potassium in manufactured foods, primarily to target hypertension and heart disease, as described by Clare Farrand, MSc, BSc, and colleagues, in the Journal of Clinical Hypertension. The authors also make several recommendations regarding salt reduction policies:
- Food manufacturers should gradually reduce sodium in food to the lowest possible levels and explore the use of potassium-based sodium replacers to reduce sodium levels even further.
- Governments should continue to monitor sodium and potassium levels in processed foods.
- Further consideration may need to be given to how best to label salt substitutes (namely potassium) in processed foods to ensure that people who may be adversely affected are aware.
- Governments should systematically monitor potassium intake at the population level, including for specific susceptible groups.
- Governments should continue to systematically monitor sodium (salt) intake and iodine intake at the population level to adjust salt iodization over time as necessary, depending on observed salt intake in specific targeted groups, to ensure that they have sufficient but not excessive iodine intakes as salt intakes are reduced.
- Governments should consider opportunities for promoting and subsidizing salt substitutes, particularly in countries where salt added during cooking or at the table is the major source of salt in the diet.
The new FDA document includes 163 subcategories of foods in its voluntary salt reduction strategy.
Salt substitutes, high blood pressure, and mortality
Lowering sodium intake is almost certainly beneficial for persons with high blood pressure. In 2020, a review in Hypertension highlighted the benefit of salt substitutes in reducing hypertension, reporting that they lower systolic blood pressure by 5.58 mm Hg and diastolic blood pressure by 2.88 mm Hg.
And changes to dietary sodium intake can potentially reduce or obviate the need for medications for essential hypertension in some individuals. Although there are only a few studies on this topic, a study by Bruce Neal, MB, ChB, PhD, and colleagues, revealed a reduction in stroke, cardiovascular events, and deaths with the use of potassium-based salt substitutes.
Salt substitutes and sodium and potassium handling in the kidneys
Many studies have shown that potassium-rich salt substitutes are safe in individuals with normal kidney function, but are they safe and beneficial for people with chronic kidney disease (CKD)?
For anyone who is on a renal diet, potassium and sodium intake goals are limited according to their absolute level of kidney function.
There have been case reports of life-threatening blood potassium levels (hyperkalemia) due to potassium-rich salt substitutes in people with CKD, but no larger published studies on this topic can be found.
A diet modeling study by Rebecca Morrison and colleagues evaluated varying degrees of potassium-enriched salt substituted bread products and their impact on dietary intake in persons with CKD. They used dietary data from the National Nutrition and Physical Activity Survey 2011-2012 in Australia for 12,152 participants, 154 of whom had CKD. Replacing the sodium in bread with varying amounts of potassium chloride (20%, 30%, and 40%) would result in one-third of people with CKD exceeding the safe limits for dietary potassium consumption (31.8%, 32.6%, and 33%, respectively), they found.
“Potassium chloride substitution in staple foods such as bread and bread products have serious and potentially fatal consequences for people who need to restrict dietary potassium. Improved food labelling is required for consumers to avoid excessive consumption,” Ms. Morrison and colleagues concluded. They added that more studies are needed to further understand the risks of potassium dietary intake and hyperkalemia in CKD from potassium-based salt substitutes.
The American Heart Association recommends no more than 1,500 mg of sodium intake daily for persons with CKD, diabetes, or high blood pressure; those older than 51; and African American persons of any age.
The recommended daily intake of potassium in persons with CKD can range from 2,000 mg to 4,000 mg, depending on the individual and their degree of CKD. The potassium content in some salt substitutes varies from 440 mg to 2,800 mg per teaspoon.
The best recommendation for individuals with CKD and a goal to reduce their sodium intake is to use herbs and lower-sodium seasonings as a substitute, but these should always be reviewed with their physician and renal nutritionist.
Dr. Brookins is a board-certified nephrologist and internist practicing in Georgia. She is the founder and owner of Remote Renal Care, a telehealth kidney practice. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Mycoplasma genitalium: The Smallest Pathogen Becoming a Big Concern
This supplement reviews key aspects of Mycoplasma genitalium and further testing and treatment options for the STI. To read more about this click the link below.
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This supplement reviews key aspects of Mycoplasma genitalium and further testing and treatment options for the STI. To read more about this click the link below.
Click Here to Read More
This supplement reviews key aspects of Mycoplasma genitalium and further testing and treatment options for the STI. To read more about this click the link below.
Click Here to Read More
New data explore risk of magnetic interference with implantable devices
Building on several previous reports that the newest models of mobile telephones and other electronics that use magnets pose a threat to the function of defibrillators and other implantable cardiovascular devices, a new study implicates any device that emits a 10-gauss (G) magnetic field more than a couple of inches.
“Beside the devices described in our manuscript, this can be any portable consumer product [with magnets] like electric cigarettes or smart watches,” explained study author Sven Knecht, DSc, a research electrophysiologist associated with the department of cardiology, University Hospital Basel (Switzerland).
In the newly published article, the investigators evaluated earphones, earphone charging cases, and two electronic pens used to draw on electronic tablets. These particular devices are of interest because, like mobile phones, they are of a size and shape to fit in a breast pocket adjacent to where many cardiovascular devices are implanted.
The study joins several previous studies that have shown the same risk, but this study used three-dimensional (3D) mapping of the magnetic field rather than a one-axis sensor, which is a standard adopted by the U.S. Food and Drug Administration, according to the investigators.
3D mapping assessment used
Because of the 3D nature of magnetic fields, 3D mapping serves as a better tool to assess the risk of the magnetic force as the intensity gradient diminishes with distance from the source, the authors contended. The 3D maps used in this study have a resolution to 2 mm.
The ex vivo measurements of the magnetic field, which could be displayed in a configurable 3D volume in relation to the electronic products were performed on five different explanted cardioverter defibrillators from two manufacturers.
In the ex vivo setting, the ability of the earphones, earphone charging cases, and electronic pens to interfere with defibrillator function was compared to that of the Apple iPhone 12 Max, which was the subject of a small in vivo study published in 2021. When the iPhone 12 Max was placed on the skin over a cardiac implantable device in that study, clinically identifiable interference could be detected in all 3 patients evaluated.
Based on previous work, the International Organization for Standardization has established that a minimal field strength of 10 G is needed to interfere with an implantable device, but the actual risk from any specific device is determined by the distance at which this strength of magnetic field is projected.
In the 3D analysis, the 10-G intensity was found to project 20 mm from the surface of the ear phones, ear phone charging case, and one of the electronic pens and to project 29 mm from the other electronic pen. When tested against the five defibrillators, magnetic reversion mode was triggered by the portable electronics at distances ranging from 8 to 18 mm.
In an interview, Dr. Knecht explained that this study adds more devices to the list of those associated with potential for interfering with implantable cardiovascular devices, but added that the more important point is that any device that contains magnets emitting a force of 10 G or greater for more than a few inches can be expected to be associated with clinically meaningful interference. The devices tested in this study were produced by Apple and Microsoft, but a focus on specific devices obscures the main message.
“All portable electronics with an embedded permanent magnet creating a 10-G magnetic field have a theoretical capability of triggering implantable devices,” he said.
For pacemakers, the interference is likely to trigger constant pacing, which would not be expected to pose a significant health threat if detected with a reasonable period, according to Dr. Knecht. Interference is potentially more serious for defibrillators, which might fail during magnetic interference to provide the shock needed to terminate a serious arrhythmia.
The combination of events – interference at the time of an arrhythmia – make this risk “very low,” but Dr. Knecht said it is sufficient to mean that patients receiving an implantable cardiovascular device should be made aware of the risk and the need to avoid placing portable electronic products near the implanted device.
When in vivo evidence of a disturbance with the iPhone 12 was reported in 2021, it amplified existing concern. The American Heart Association maintains a list of electronic products with the potential to interfere with implantable devices on its website. But, again, understanding the potential for risk and the need to keep electronic products with magnets at a safe distance from cardiovascular implantable devices is more important than trying to memorize the ever-growing list of devices with this capability.
“Prudent education of patients receiving an implantable device is important,” said N.A. Mark Estes III, MD, professor of medicine in the division of cardiology at the University of Pittsburgh. However, in an interview, he warned that the growing list of implicated devices makes a complete survey impractical, and, even if achievable, likely to leave patients “feeling overwhelmed.”
In Dr. Estes’s practice, he does provide printed information about the risks of electronics to interfere with implantable devices as well as a list of dos and don’ts. He agreed that the absolute risk of interference from a device causing significant clinical complications is low, but the goal is to “bring it as close to zero as possible.”
“No clinical case of a meaningful interaction of an electronic product and dysfunction of an implantable device has ever been documented,” he said. Given the widespread use of the new generation of cellphones that contain magnets powerful enough to induce dysfunction in an implantable device, “this speaks to the fact that the risk continues to be very low.”
Dr. Knecht and coinvestigators, along with Dr. Estes, reported no potential conflicts of interest.
Building on several previous reports that the newest models of mobile telephones and other electronics that use magnets pose a threat to the function of defibrillators and other implantable cardiovascular devices, a new study implicates any device that emits a 10-gauss (G) magnetic field more than a couple of inches.
“Beside the devices described in our manuscript, this can be any portable consumer product [with magnets] like electric cigarettes or smart watches,” explained study author Sven Knecht, DSc, a research electrophysiologist associated with the department of cardiology, University Hospital Basel (Switzerland).
In the newly published article, the investigators evaluated earphones, earphone charging cases, and two electronic pens used to draw on electronic tablets. These particular devices are of interest because, like mobile phones, they are of a size and shape to fit in a breast pocket adjacent to where many cardiovascular devices are implanted.
The study joins several previous studies that have shown the same risk, but this study used three-dimensional (3D) mapping of the magnetic field rather than a one-axis sensor, which is a standard adopted by the U.S. Food and Drug Administration, according to the investigators.
3D mapping assessment used
Because of the 3D nature of magnetic fields, 3D mapping serves as a better tool to assess the risk of the magnetic force as the intensity gradient diminishes with distance from the source, the authors contended. The 3D maps used in this study have a resolution to 2 mm.
The ex vivo measurements of the magnetic field, which could be displayed in a configurable 3D volume in relation to the electronic products were performed on five different explanted cardioverter defibrillators from two manufacturers.
In the ex vivo setting, the ability of the earphones, earphone charging cases, and electronic pens to interfere with defibrillator function was compared to that of the Apple iPhone 12 Max, which was the subject of a small in vivo study published in 2021. When the iPhone 12 Max was placed on the skin over a cardiac implantable device in that study, clinically identifiable interference could be detected in all 3 patients evaluated.
Based on previous work, the International Organization for Standardization has established that a minimal field strength of 10 G is needed to interfere with an implantable device, but the actual risk from any specific device is determined by the distance at which this strength of magnetic field is projected.
In the 3D analysis, the 10-G intensity was found to project 20 mm from the surface of the ear phones, ear phone charging case, and one of the electronic pens and to project 29 mm from the other electronic pen. When tested against the five defibrillators, magnetic reversion mode was triggered by the portable electronics at distances ranging from 8 to 18 mm.
In an interview, Dr. Knecht explained that this study adds more devices to the list of those associated with potential for interfering with implantable cardiovascular devices, but added that the more important point is that any device that contains magnets emitting a force of 10 G or greater for more than a few inches can be expected to be associated with clinically meaningful interference. The devices tested in this study were produced by Apple and Microsoft, but a focus on specific devices obscures the main message.
“All portable electronics with an embedded permanent magnet creating a 10-G magnetic field have a theoretical capability of triggering implantable devices,” he said.
For pacemakers, the interference is likely to trigger constant pacing, which would not be expected to pose a significant health threat if detected with a reasonable period, according to Dr. Knecht. Interference is potentially more serious for defibrillators, which might fail during magnetic interference to provide the shock needed to terminate a serious arrhythmia.
The combination of events – interference at the time of an arrhythmia – make this risk “very low,” but Dr. Knecht said it is sufficient to mean that patients receiving an implantable cardiovascular device should be made aware of the risk and the need to avoid placing portable electronic products near the implanted device.
When in vivo evidence of a disturbance with the iPhone 12 was reported in 2021, it amplified existing concern. The American Heart Association maintains a list of electronic products with the potential to interfere with implantable devices on its website. But, again, understanding the potential for risk and the need to keep electronic products with magnets at a safe distance from cardiovascular implantable devices is more important than trying to memorize the ever-growing list of devices with this capability.
“Prudent education of patients receiving an implantable device is important,” said N.A. Mark Estes III, MD, professor of medicine in the division of cardiology at the University of Pittsburgh. However, in an interview, he warned that the growing list of implicated devices makes a complete survey impractical, and, even if achievable, likely to leave patients “feeling overwhelmed.”
In Dr. Estes’s practice, he does provide printed information about the risks of electronics to interfere with implantable devices as well as a list of dos and don’ts. He agreed that the absolute risk of interference from a device causing significant clinical complications is low, but the goal is to “bring it as close to zero as possible.”
“No clinical case of a meaningful interaction of an electronic product and dysfunction of an implantable device has ever been documented,” he said. Given the widespread use of the new generation of cellphones that contain magnets powerful enough to induce dysfunction in an implantable device, “this speaks to the fact that the risk continues to be very low.”
Dr. Knecht and coinvestigators, along with Dr. Estes, reported no potential conflicts of interest.
Building on several previous reports that the newest models of mobile telephones and other electronics that use magnets pose a threat to the function of defibrillators and other implantable cardiovascular devices, a new study implicates any device that emits a 10-gauss (G) magnetic field more than a couple of inches.
“Beside the devices described in our manuscript, this can be any portable consumer product [with magnets] like electric cigarettes or smart watches,” explained study author Sven Knecht, DSc, a research electrophysiologist associated with the department of cardiology, University Hospital Basel (Switzerland).
In the newly published article, the investigators evaluated earphones, earphone charging cases, and two electronic pens used to draw on electronic tablets. These particular devices are of interest because, like mobile phones, they are of a size and shape to fit in a breast pocket adjacent to where many cardiovascular devices are implanted.
The study joins several previous studies that have shown the same risk, but this study used three-dimensional (3D) mapping of the magnetic field rather than a one-axis sensor, which is a standard adopted by the U.S. Food and Drug Administration, according to the investigators.
3D mapping assessment used
Because of the 3D nature of magnetic fields, 3D mapping serves as a better tool to assess the risk of the magnetic force as the intensity gradient diminishes with distance from the source, the authors contended. The 3D maps used in this study have a resolution to 2 mm.
The ex vivo measurements of the magnetic field, which could be displayed in a configurable 3D volume in relation to the electronic products were performed on five different explanted cardioverter defibrillators from two manufacturers.
In the ex vivo setting, the ability of the earphones, earphone charging cases, and electronic pens to interfere with defibrillator function was compared to that of the Apple iPhone 12 Max, which was the subject of a small in vivo study published in 2021. When the iPhone 12 Max was placed on the skin over a cardiac implantable device in that study, clinically identifiable interference could be detected in all 3 patients evaluated.
Based on previous work, the International Organization for Standardization has established that a minimal field strength of 10 G is needed to interfere with an implantable device, but the actual risk from any specific device is determined by the distance at which this strength of magnetic field is projected.
In the 3D analysis, the 10-G intensity was found to project 20 mm from the surface of the ear phones, ear phone charging case, and one of the electronic pens and to project 29 mm from the other electronic pen. When tested against the five defibrillators, magnetic reversion mode was triggered by the portable electronics at distances ranging from 8 to 18 mm.
In an interview, Dr. Knecht explained that this study adds more devices to the list of those associated with potential for interfering with implantable cardiovascular devices, but added that the more important point is that any device that contains magnets emitting a force of 10 G or greater for more than a few inches can be expected to be associated with clinically meaningful interference. The devices tested in this study were produced by Apple and Microsoft, but a focus on specific devices obscures the main message.
“All portable electronics with an embedded permanent magnet creating a 10-G magnetic field have a theoretical capability of triggering implantable devices,” he said.
For pacemakers, the interference is likely to trigger constant pacing, which would not be expected to pose a significant health threat if detected with a reasonable period, according to Dr. Knecht. Interference is potentially more serious for defibrillators, which might fail during magnetic interference to provide the shock needed to terminate a serious arrhythmia.
The combination of events – interference at the time of an arrhythmia – make this risk “very low,” but Dr. Knecht said it is sufficient to mean that patients receiving an implantable cardiovascular device should be made aware of the risk and the need to avoid placing portable electronic products near the implanted device.
When in vivo evidence of a disturbance with the iPhone 12 was reported in 2021, it amplified existing concern. The American Heart Association maintains a list of electronic products with the potential to interfere with implantable devices on its website. But, again, understanding the potential for risk and the need to keep electronic products with magnets at a safe distance from cardiovascular implantable devices is more important than trying to memorize the ever-growing list of devices with this capability.
“Prudent education of patients receiving an implantable device is important,” said N.A. Mark Estes III, MD, professor of medicine in the division of cardiology at the University of Pittsburgh. However, in an interview, he warned that the growing list of implicated devices makes a complete survey impractical, and, even if achievable, likely to leave patients “feeling overwhelmed.”
In Dr. Estes’s practice, he does provide printed information about the risks of electronics to interfere with implantable devices as well as a list of dos and don’ts. He agreed that the absolute risk of interference from a device causing significant clinical complications is low, but the goal is to “bring it as close to zero as possible.”
“No clinical case of a meaningful interaction of an electronic product and dysfunction of an implantable device has ever been documented,” he said. Given the widespread use of the new generation of cellphones that contain magnets powerful enough to induce dysfunction in an implantable device, “this speaks to the fact that the risk continues to be very low.”
Dr. Knecht and coinvestigators, along with Dr. Estes, reported no potential conflicts of interest.
FROM CIRCULATION: ARRHYTHMIAS & ELECTROPHYSIOLOGY
New studies indicate COVID pandemic began in Wuhan market
Two preprint studies released on Feb. 26 offer additional evidence that the coronavirus pandemic started at a market in Wuhan, China.
By analyzing data from several sources, scientists concluded that the virus came from animals and spread to humans in late 2019 at the Huanan Seafood Market. They added that no evidence supported a theory that the virus came from a laboratory in Wuhan.
“When you look at all the evidence together, it’s an extraordinarily clear picture that the pandemic started at the Huanan market,” Michael Worobey, D.Phil., a co-author on both studies and an evolutionary biologist at the University of Arizona, told the New York Times.
The two reports haven’t yet been peer-reviewed or published in a scientific journal. They were posted on Zenodo, an open-access research repository operated by CERN.
In one study, researchers used spatial analysis to show that the earliest COVID-19 cases, which were diagnosed in December 2019, were linked to the market. Researchers also found that environmental samples that tested positive for the SARS-CoV-2 virus were associated with animal vendors.
In another study, researchers found that two major viral lineages of the coronavirus resulted from at least two events when the virus spread from animals into humans. The first transmission most likely happened in late November or early December 2019, they wrote, and the other likely happened a few weeks later.
Several of the researchers behind the new studies also published a review last summer that said the pandemic originated in an animal, likely at a wildlife market. At that time, they said the first known case was a vendor at the Huanan market.
The new findings provide the strongest evidence yet that the pandemic had animal-related origins, Dr. Worobey told CNN. He called the results a “game, set and match” for the theory that the pandemic began in a lab.
“It’s no longer something that makes sense to imagine that this started any other way,” he said.
In a separate line of research, scientists at the Chinese CDC conducted a new analysis of samples collected at the market in January. They found that the samples included the two main lineages of the coronavirus. They posted the results in a report on the Research Square preprint server Feb. 26.
“The beauty of it is how simply it all adds up now,” Jeremy Kamil, a virologist at Louisiana State University Health Sciences, who wasn’t involved with the new studies, told the New York Times.
The initial spread of the coronavirus was like a firework, Dr. Worobey told CNN, starting at the market and exploding outward. The “overwhelming majority” of cases were specifically linked to the western section of the market, where most of the live-mammal vendors were located, the study authors wrote. Then COVID-19 cases spread into the community from there, and the pattern of transmission changed by January or February 2020.
When researchers tested surfaces at the market for coronavirus genetic material, one stall had the most positives, including a cage where raccoon dogs had been kept.
The study authors said the findings highlight the urgent need to pay attention to situations where wild animals and humans interact closely on a daily basis.
“We need to do a better job of farming and regulating these wild animals,” Robert Garry, one of the co-authors and a professor of microbiology and immunology at the Tulane University School of Medicine, told CNN.
That could include better infrastructure in places like markets where viruses spill over from animals to humans, he said. Surveillance is also key in preventing future pandemics by detecting new respiratory diseases in humans, isolating patients, and sequencing new virus strains.
“This is not the last time this happens,” he said.
A version of this article first appeared on WebMD.com.
Two preprint studies released on Feb. 26 offer additional evidence that the coronavirus pandemic started at a market in Wuhan, China.
By analyzing data from several sources, scientists concluded that the virus came from animals and spread to humans in late 2019 at the Huanan Seafood Market. They added that no evidence supported a theory that the virus came from a laboratory in Wuhan.
“When you look at all the evidence together, it’s an extraordinarily clear picture that the pandemic started at the Huanan market,” Michael Worobey, D.Phil., a co-author on both studies and an evolutionary biologist at the University of Arizona, told the New York Times.
The two reports haven’t yet been peer-reviewed or published in a scientific journal. They were posted on Zenodo, an open-access research repository operated by CERN.
In one study, researchers used spatial analysis to show that the earliest COVID-19 cases, which were diagnosed in December 2019, were linked to the market. Researchers also found that environmental samples that tested positive for the SARS-CoV-2 virus were associated with animal vendors.
In another study, researchers found that two major viral lineages of the coronavirus resulted from at least two events when the virus spread from animals into humans. The first transmission most likely happened in late November or early December 2019, they wrote, and the other likely happened a few weeks later.
Several of the researchers behind the new studies also published a review last summer that said the pandemic originated in an animal, likely at a wildlife market. At that time, they said the first known case was a vendor at the Huanan market.
The new findings provide the strongest evidence yet that the pandemic had animal-related origins, Dr. Worobey told CNN. He called the results a “game, set and match” for the theory that the pandemic began in a lab.
“It’s no longer something that makes sense to imagine that this started any other way,” he said.
In a separate line of research, scientists at the Chinese CDC conducted a new analysis of samples collected at the market in January. They found that the samples included the two main lineages of the coronavirus. They posted the results in a report on the Research Square preprint server Feb. 26.
“The beauty of it is how simply it all adds up now,” Jeremy Kamil, a virologist at Louisiana State University Health Sciences, who wasn’t involved with the new studies, told the New York Times.
The initial spread of the coronavirus was like a firework, Dr. Worobey told CNN, starting at the market and exploding outward. The “overwhelming majority” of cases were specifically linked to the western section of the market, where most of the live-mammal vendors were located, the study authors wrote. Then COVID-19 cases spread into the community from there, and the pattern of transmission changed by January or February 2020.
When researchers tested surfaces at the market for coronavirus genetic material, one stall had the most positives, including a cage where raccoon dogs had been kept.
The study authors said the findings highlight the urgent need to pay attention to situations where wild animals and humans interact closely on a daily basis.
“We need to do a better job of farming and regulating these wild animals,” Robert Garry, one of the co-authors and a professor of microbiology and immunology at the Tulane University School of Medicine, told CNN.
That could include better infrastructure in places like markets where viruses spill over from animals to humans, he said. Surveillance is also key in preventing future pandemics by detecting new respiratory diseases in humans, isolating patients, and sequencing new virus strains.
“This is not the last time this happens,” he said.
A version of this article first appeared on WebMD.com.
Two preprint studies released on Feb. 26 offer additional evidence that the coronavirus pandemic started at a market in Wuhan, China.
By analyzing data from several sources, scientists concluded that the virus came from animals and spread to humans in late 2019 at the Huanan Seafood Market. They added that no evidence supported a theory that the virus came from a laboratory in Wuhan.
“When you look at all the evidence together, it’s an extraordinarily clear picture that the pandemic started at the Huanan market,” Michael Worobey, D.Phil., a co-author on both studies and an evolutionary biologist at the University of Arizona, told the New York Times.
The two reports haven’t yet been peer-reviewed or published in a scientific journal. They were posted on Zenodo, an open-access research repository operated by CERN.
In one study, researchers used spatial analysis to show that the earliest COVID-19 cases, which were diagnosed in December 2019, were linked to the market. Researchers also found that environmental samples that tested positive for the SARS-CoV-2 virus were associated with animal vendors.
In another study, researchers found that two major viral lineages of the coronavirus resulted from at least two events when the virus spread from animals into humans. The first transmission most likely happened in late November or early December 2019, they wrote, and the other likely happened a few weeks later.
Several of the researchers behind the new studies also published a review last summer that said the pandemic originated in an animal, likely at a wildlife market. At that time, they said the first known case was a vendor at the Huanan market.
The new findings provide the strongest evidence yet that the pandemic had animal-related origins, Dr. Worobey told CNN. He called the results a “game, set and match” for the theory that the pandemic began in a lab.
“It’s no longer something that makes sense to imagine that this started any other way,” he said.
In a separate line of research, scientists at the Chinese CDC conducted a new analysis of samples collected at the market in January. They found that the samples included the two main lineages of the coronavirus. They posted the results in a report on the Research Square preprint server Feb. 26.
“The beauty of it is how simply it all adds up now,” Jeremy Kamil, a virologist at Louisiana State University Health Sciences, who wasn’t involved with the new studies, told the New York Times.
The initial spread of the coronavirus was like a firework, Dr. Worobey told CNN, starting at the market and exploding outward. The “overwhelming majority” of cases were specifically linked to the western section of the market, where most of the live-mammal vendors were located, the study authors wrote. Then COVID-19 cases spread into the community from there, and the pattern of transmission changed by January or February 2020.
When researchers tested surfaces at the market for coronavirus genetic material, one stall had the most positives, including a cage where raccoon dogs had been kept.
The study authors said the findings highlight the urgent need to pay attention to situations where wild animals and humans interact closely on a daily basis.
“We need to do a better job of farming and regulating these wild animals,” Robert Garry, one of the co-authors and a professor of microbiology and immunology at the Tulane University School of Medicine, told CNN.
That could include better infrastructure in places like markets where viruses spill over from animals to humans, he said. Surveillance is also key in preventing future pandemics by detecting new respiratory diseases in humans, isolating patients, and sequencing new virus strains.
“This is not the last time this happens,” he said.
A version of this article first appeared on WebMD.com.
Sublingual dexmedetomidine may rapidly calm bipolar agitation
The phase 3 SERENITY II trial included almost 400 adults with bipolar I or II disorder and acute agitation.
Results showed relief from acute agitation kicked in beginning at 20 minutes after administration of the treatment and continued to 120 minutes, principal investigator Sheldon H. Preskorn, MD, professor, department of psychiatry and behavioral sciences, University of Kansas, Wichita, and colleagues reported.
“Patients who are mild to moderately agitated in whom there is the potential for escalation to more severe agitation,” are good candidates for sublingual dexmedetomidine, Dr. Preskorn told this news organization.
He noted that, while “comparative claims require comparative studies,” a key advantage is that it “can be self-administered by patients reliably because of the adherence of the film to the mucosa.”
The findings were published online Feb. 22, 2022 in JAMA.
Tough-to-manage symptom
Preliminary results were presented at the 2021 annual meeting of the American Psychiatric Association and reported by this news organization at that time.
Agitation is a common and tough-to-manage symptom associated with multiple neuropsychiatric conditions, including bipolar disorder.
The phase 3 SERENITY II trial enrolled 380 adults (mean age, 45 years; 55% women) with bipolar I or II disorder and acute agitation in the emergency department.
All participants had a total score of 14 or greater on the five items of the Positive and Negative Syndrome Scale–Excited Component (PEC) scale at baseline and a score of 4 or greater on at least one PEC item.
Patients were randomly allocated to a single dose of sublingual dexmedetomidine (120 mcg or 180 mcg) or placebo. All but two patients completed the study.
Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.
Rapid relief
Mean change from baseline in the PEC total score at 2 hours (primary endpoint) was –9 and –10.4 with the 120-mcg and 180-mcg doses of sublingual dexmedetomidine, respectively, versus –4.9 for placebo.
Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were statistically significant for both doses (both, P < .001 vs. placebo).
Statistically significant treatment effects were first evident 20 minutes after dosing for both of the dexmedetomidine doses versus placebo.
Patients in both active-treatment groups showed greater improvement in PEC total score than patients in the placebo group at all subsequent time points through 2 hours post dosing.
Sublingual dexmedetomidine was also associated with significant improvement on the secondary outcomes of Clinical Global Impressions–Improvement and Agitation-Calmness Evaluation Scale.
Adverse events occurred in 35.7% and 34.9% of patients taking 180 mcg and 120 mcg sublingual dexmedetomidine, respectively, compared with 17.5% of patients taking placebo. The most commonly reported adverse events were somnolence, dry mouth, hypotension, and dizziness. No treatment-related serious or severe adverse events were reported.
FDA action date: April 5
In an accompanying editorial, John K. Hsiao, MD, National Institutes of Health, Bethesda, Md., noted that an “out-of-control, agitated, possibly aggressive patient in a medical setting is a crisis demanding swift and safe resolution.
“Today, emergency departments now rival and perhaps surpass psychiatric units as settings where out-of-control, agitated patients must be managed,” Dr. Hsiao said.
The current study “provides evidence to support a novel, potentially important addition to the armamentarium for managing behavioral agitation,” he wrote.
BioXcel Therapeutics has submitted a new drug application to the Food and Drug Administration. The Prescription Drug User Fee Act target action date is April 5.
In a statement, Frank D. Yocca, PhD, chief scientific officer of BioXcel Therapeutics, said the company is looking forward to potential FDA approval of the treatment for agitation associated with bipolar disorders and schizophrenia.
“Building on the strength of these compelling data, we are also confidently progressing BXCL501 as a potential acute treatment for agitation associated with Alzheimer’s disease,” Dr. Yocca added.
The study was funded by BioXcel Therapeutics. Dr. Preskorn reported receiving consulting fees from BioXcel and receiving research grants from, serving as a consultant for, on advisory boards of, and on the speakers bureau of Alkermes, BioXcel Therapeutics, Eisai, Janssen, Novartis, Otsuka, Sunovion, and Usona Institute. Dr. Hsiao has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The phase 3 SERENITY II trial included almost 400 adults with bipolar I or II disorder and acute agitation.
Results showed relief from acute agitation kicked in beginning at 20 minutes after administration of the treatment and continued to 120 minutes, principal investigator Sheldon H. Preskorn, MD, professor, department of psychiatry and behavioral sciences, University of Kansas, Wichita, and colleagues reported.
“Patients who are mild to moderately agitated in whom there is the potential for escalation to more severe agitation,” are good candidates for sublingual dexmedetomidine, Dr. Preskorn told this news organization.
He noted that, while “comparative claims require comparative studies,” a key advantage is that it “can be self-administered by patients reliably because of the adherence of the film to the mucosa.”
The findings were published online Feb. 22, 2022 in JAMA.
Tough-to-manage symptom
Preliminary results were presented at the 2021 annual meeting of the American Psychiatric Association and reported by this news organization at that time.
Agitation is a common and tough-to-manage symptom associated with multiple neuropsychiatric conditions, including bipolar disorder.
The phase 3 SERENITY II trial enrolled 380 adults (mean age, 45 years; 55% women) with bipolar I or II disorder and acute agitation in the emergency department.
All participants had a total score of 14 or greater on the five items of the Positive and Negative Syndrome Scale–Excited Component (PEC) scale at baseline and a score of 4 or greater on at least one PEC item.
Patients were randomly allocated to a single dose of sublingual dexmedetomidine (120 mcg or 180 mcg) or placebo. All but two patients completed the study.
Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.
Rapid relief
Mean change from baseline in the PEC total score at 2 hours (primary endpoint) was –9 and –10.4 with the 120-mcg and 180-mcg doses of sublingual dexmedetomidine, respectively, versus –4.9 for placebo.
Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were statistically significant for both doses (both, P < .001 vs. placebo).
Statistically significant treatment effects were first evident 20 minutes after dosing for both of the dexmedetomidine doses versus placebo.
Patients in both active-treatment groups showed greater improvement in PEC total score than patients in the placebo group at all subsequent time points through 2 hours post dosing.
Sublingual dexmedetomidine was also associated with significant improvement on the secondary outcomes of Clinical Global Impressions–Improvement and Agitation-Calmness Evaluation Scale.
Adverse events occurred in 35.7% and 34.9% of patients taking 180 mcg and 120 mcg sublingual dexmedetomidine, respectively, compared with 17.5% of patients taking placebo. The most commonly reported adverse events were somnolence, dry mouth, hypotension, and dizziness. No treatment-related serious or severe adverse events were reported.
FDA action date: April 5
In an accompanying editorial, John K. Hsiao, MD, National Institutes of Health, Bethesda, Md., noted that an “out-of-control, agitated, possibly aggressive patient in a medical setting is a crisis demanding swift and safe resolution.
“Today, emergency departments now rival and perhaps surpass psychiatric units as settings where out-of-control, agitated patients must be managed,” Dr. Hsiao said.
The current study “provides evidence to support a novel, potentially important addition to the armamentarium for managing behavioral agitation,” he wrote.
BioXcel Therapeutics has submitted a new drug application to the Food and Drug Administration. The Prescription Drug User Fee Act target action date is April 5.
In a statement, Frank D. Yocca, PhD, chief scientific officer of BioXcel Therapeutics, said the company is looking forward to potential FDA approval of the treatment for agitation associated with bipolar disorders and schizophrenia.
“Building on the strength of these compelling data, we are also confidently progressing BXCL501 as a potential acute treatment for agitation associated with Alzheimer’s disease,” Dr. Yocca added.
The study was funded by BioXcel Therapeutics. Dr. Preskorn reported receiving consulting fees from BioXcel and receiving research grants from, serving as a consultant for, on advisory boards of, and on the speakers bureau of Alkermes, BioXcel Therapeutics, Eisai, Janssen, Novartis, Otsuka, Sunovion, and Usona Institute. Dr. Hsiao has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The phase 3 SERENITY II trial included almost 400 adults with bipolar I or II disorder and acute agitation.
Results showed relief from acute agitation kicked in beginning at 20 minutes after administration of the treatment and continued to 120 minutes, principal investigator Sheldon H. Preskorn, MD, professor, department of psychiatry and behavioral sciences, University of Kansas, Wichita, and colleagues reported.
“Patients who are mild to moderately agitated in whom there is the potential for escalation to more severe agitation,” are good candidates for sublingual dexmedetomidine, Dr. Preskorn told this news organization.
He noted that, while “comparative claims require comparative studies,” a key advantage is that it “can be self-administered by patients reliably because of the adherence of the film to the mucosa.”
The findings were published online Feb. 22, 2022 in JAMA.
Tough-to-manage symptom
Preliminary results were presented at the 2021 annual meeting of the American Psychiatric Association and reported by this news organization at that time.
Agitation is a common and tough-to-manage symptom associated with multiple neuropsychiatric conditions, including bipolar disorder.
The phase 3 SERENITY II trial enrolled 380 adults (mean age, 45 years; 55% women) with bipolar I or II disorder and acute agitation in the emergency department.
All participants had a total score of 14 or greater on the five items of the Positive and Negative Syndrome Scale–Excited Component (PEC) scale at baseline and a score of 4 or greater on at least one PEC item.
Patients were randomly allocated to a single dose of sublingual dexmedetomidine (120 mcg or 180 mcg) or placebo. All but two patients completed the study.
Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.
Rapid relief
Mean change from baseline in the PEC total score at 2 hours (primary endpoint) was –9 and –10.4 with the 120-mcg and 180-mcg doses of sublingual dexmedetomidine, respectively, versus –4.9 for placebo.
Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were statistically significant for both doses (both, P < .001 vs. placebo).
Statistically significant treatment effects were first evident 20 minutes after dosing for both of the dexmedetomidine doses versus placebo.
Patients in both active-treatment groups showed greater improvement in PEC total score than patients in the placebo group at all subsequent time points through 2 hours post dosing.
Sublingual dexmedetomidine was also associated with significant improvement on the secondary outcomes of Clinical Global Impressions–Improvement and Agitation-Calmness Evaluation Scale.
Adverse events occurred in 35.7% and 34.9% of patients taking 180 mcg and 120 mcg sublingual dexmedetomidine, respectively, compared with 17.5% of patients taking placebo. The most commonly reported adverse events were somnolence, dry mouth, hypotension, and dizziness. No treatment-related serious or severe adverse events were reported.
FDA action date: April 5
In an accompanying editorial, John K. Hsiao, MD, National Institutes of Health, Bethesda, Md., noted that an “out-of-control, agitated, possibly aggressive patient in a medical setting is a crisis demanding swift and safe resolution.
“Today, emergency departments now rival and perhaps surpass psychiatric units as settings where out-of-control, agitated patients must be managed,” Dr. Hsiao said.
The current study “provides evidence to support a novel, potentially important addition to the armamentarium for managing behavioral agitation,” he wrote.
BioXcel Therapeutics has submitted a new drug application to the Food and Drug Administration. The Prescription Drug User Fee Act target action date is April 5.
In a statement, Frank D. Yocca, PhD, chief scientific officer of BioXcel Therapeutics, said the company is looking forward to potential FDA approval of the treatment for agitation associated with bipolar disorders and schizophrenia.
“Building on the strength of these compelling data, we are also confidently progressing BXCL501 as a potential acute treatment for agitation associated with Alzheimer’s disease,” Dr. Yocca added.
The study was funded by BioXcel Therapeutics. Dr. Preskorn reported receiving consulting fees from BioXcel and receiving research grants from, serving as a consultant for, on advisory boards of, and on the speakers bureau of Alkermes, BioXcel Therapeutics, Eisai, Janssen, Novartis, Otsuka, Sunovion, and Usona Institute. Dr. Hsiao has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA
Left upper quadrant entry is often a reliable alternative to umbilicus
The choice of entry point for gynecologic laparoscopy is critical, considering that most laparoscopic injuries occur during initial entry into the abdomen. In addition, different abdominal access points may have differing utility and efficacy depending on the patient. (The overall rate of injuries to abdominal viscera and blood vessels at the time of entry is an estimated 1 per 1,000 cases.1)
The most conventional entry point for gynecologic laparoscopic surgeries has been the umbilicus, but there are contraindications to this choice and situations in which it may not be the best access site. It is important to have knowledge of alternate entry points and techniques that consider the patient’s current pathology, anatomy, and most importantly, surgical history to better facilitate a safe initial entry.
The left upper quadrant (LUQ) has been described as a preferred alternate site to the umbilicus, and some gynecologic surgeons even consider it as a routine mode of entry.2 In our practice, LUQ entry is a safe and commonly used technique that is chosen primarily based on a patient’s history of a midline vertical incision, the presence of abdominal mesh from a prior umbilical hernia repair, or repeated cesarean sections.
Our technique for LUQ entry is a modification of the traditional approach that employs Palmer’s point – the entry point described by Raoul Palmer, MD, in 1974 as 3-4 cm below the left subcostal margin at the midclavicular line.3 We choose to enter at the midclavicular level and directly under the last rib.
When the umbilicus is problematic
The umbilicus is a favored entry point not only for its operative access to pelvic structures but also because – in the absence of obesity – it has no or little subcutaneous fat and, therefore, provides the shortest distance from skin to peritoneum.
However, adhesive disease from a prior laparotomy involving the umbilicus is a risk factor for bowel injury during umbilical entry (direct trocar, Veress needle, or open technique). In a 1995 review of 360 women undergoing operative laparoscopy after a previous laparotomy, Brill et al. reported umbilical adhesions in 27% of those with prior horizontal suprapubic (Pfannenstiel) incisions, in 55% of those with prior incisions in the midline below the umbilicus, and 67% of those with prior midline incisions above the umbilicus.4
Of the 259 patients whose prior laparotomy was for gynecologic surgery (as opposed to obstetric or general surgery) adhesions were present in 70% of those who had midline incisions. (Direct injury to adherent omentum and bowel occurred during laparoscopic procedures in 21% of all women.)
Since the Brill paper, other studies have similarly reported significant adhesion rate, especially after midline incisions. For instance, one French study of patients undergoing laparoscopy reported umbilical adhesions in 51.7% of 89 patients who had previous laparotomy with a midline incision.5
Prior umbilical laparoscopy is not a risk factor for umbilical entry unless a hernia repair with mesh was performed at the umbilicus. Umbilical adhesions have been reported to occur in up to 15% of women who have had prior laparoscopic surgery, with more adhesions associated with larger trocar use (specifically 12-mm trocars).1 Still, the rate of those adhesions was very low.
Obesity is not necessarily a contraindication to umbilical entry; however, it can make successful entry more difficult, particularly in those with central obesity and a thicker layer of subcutaneous fat. It can be difficult in such cases to know when peritoneal access is achieved. Extra-long Veress needles or trocars may be needed, and it is important to enter the abdomen at a 90° angle to minimize risk to the great vessel vasculature.
LUQ entry is often a reliable alternative when central obesity is significant or when umbilical access proves to be difficult. Certainly, the subcutaneous fat layer is thinner at the LUQ than at the umbilicus, and in patients whose umbilicus is pulled very caudal because of a large pannus, the LUQ will also provide a better location for visualization of pelvic anatomy and for easier entry.
We still use umbilical entry in most patients with obesity, but if we are unsuccessful after two to three attempts, we proceed to the LUQ (barring any contraindications to this site).
LUQ entry: Our approach, contraindications
By entering at the midclavicular level and directly under the bottom of the rib cage, rather than 2-3 cm below the last rib as in traditional Palmer’s point LUQ entry, we benefit from the tenting up of the peritoneum by the last rib. Having space between the peritoneum and underlying omentum and stomach can facilitate an easier entry, as shown in the video.
We primarily utilize the Veress needle for entry. The needle is inserted directly perpendicular to the fascia, or at a slight angle toward the umbilicus. After the abdomen is insufflated to 15 mm Hg, we proceed with a visual peritoneal entry using a 5-mm trocar with a clear tip, which allows us to visualize both layers of fascia, and subsequently the peritoneum, as the trocar is advanced.
The fascia is not fused, so we can expect to feel three “pops” as the needle (or trocar) passes through the aponeuroses of the internal and external obliques, the aponeuroses of the internal oblique and transversus, and the peritoneum.
While successful peritoneal entry with umbilical access is generally confirmed with an intraperitoneal pressure measuring less than 7 mm Hg (which varies depending on abdominal wall thickness and adiposity), we have found that the opening pressure with LUQ entry is slightly higher. A recently published Canadian guideline for gynecologic laparoscopic entry recommends that an initial Veress intraperitoneal pressure of 10 mm Hg or below be considered an indicator of successful entry, regardless of the patient’s body habitus.1
LUQ entry can be helpful for surgeries involving large pelvic masses, for which there is little or no space to enter at the umbilicus or to optimally view the pathology. Utilizing the LUQ not only allows for an unobstructed entry and optimal viewing but also may become an extra operative port that can be used for the camera, allowing both surgeons to operate with two hands – a four-port technique. It also allows the surgeon to use a larger diameter port at the umbilicus without concern for cosmetics.
Additionally, there is a school of thought that LUQ entry is overall more successful, requiring less conversion to alternative sites and fewer attempts. This success may result from the presence of less adhesive disease in the LUQ, as well as clearer visualization of the anatomy while entering and confidence in entering the intraperitoneal space.
A prerequisite for LUQ entry is that the stomach be decompressed through placement of an oral gastric or nasogastric tube and suctioning of all gastric contents. An inability to decompress the stomach is a contraindication to LUQ entry, as is a history of splenectomy, an enlarged liver, gastric bypass surgery, or upper abdominal surgery.
Entry techniques, alternate sites
No single entry site or technique has been proven to be universally safer than another. A 2019 Cochrane review of laparoscopic entry techniques noted an advantage of direct trocar entry over Veress-needle entry for failed entry but concluded that, overall, evidence was insufficient to support the use of one entry technique over another to decrease complication rates.6
A more recently published review of randomized controlled trials, Cochrane reviews, and older descriptive accounts similarly concluded that, between the Veress needle (the oldest described technique), direct trocar insertion, and open entry (Hasson), there is no good evidence to suggest that any of these methods is universally superior.2 Surgeon comfort is, therefore, an important factor.
Regarding entry sites, we advocate use of the LUQ as an advantageous alternative site for access, but there are several other approaches described in the literature. These include right upper quadrant entry; the Lee Huang point, which is about 10 cm below the xiphoid; and uncommonly, vaginal, either posterior to the uterus into the pouch of Douglas or through the uterine fundus.2
The right upper quadrant approach is included in a recent video review in the Journal of Minimally Invasive Gynecology of safe entry techniques, along with umbilicus, LUQ, and supraumbilical entry.7
Another described entry site is the “Jain point,” located at the intersection of a vertical line drawn 2.5 cm medial to the anterior superior iliac spine, up to the level of the umbilicus, and a horizontal line at the upper margin of the umbilicus. In a retrospective study of 7,802 cases involving this method, the authors reported only one significant entry complication. Patients in the study had a wide range of BMIs and previous surgeries.8
With respect to entry techniques, we facilitate the Veress entry technique described by Frank E. Loeffler, MD, in the mid-1970s, unless there are contraindications such as second-trimester pregnancy. For umbilical entry, we first use a Kocher clamp to grasp the base of the umbilicus and then evert it. Using two towel clips, the surgeon and assistant apply countertraction by grasping the skin and fat on either side of the umbilicus. A horizontal incision is then made directly on the base of the umbilicus. The towel clips are used to elevate the anterior abdominal wall, and the Veress needle is attached to insufflation tubing, then inserted into the abdomen.
Alternatively, direct entry involves incising the skin, placing a laparoscope in a visual entry trocar, and directly visualizing each layer as the abdomen is entered. Once the trocar is intraperitoneal, insufflation is started.
In open laparoscopic/Hasson entry, the umbilical skin is incised, and the subcutaneous fat is dissected down until the rectal fascia is visualized. The fascia is then incised, the peritoneum is entered bluntly, and the Hasson trocar is placed. Insufflation is attached, and the laparoscope is inserted.
Dr. Sasaki is a partner, and Dr. McKenna is an AAGL MIGS fellow, in the private practice of Charles E. Miller, MD, & Associates in Chicago. They reported that they have no disclosures.
References
1. Vilos GA et al. J Obstet Gyneacol Can. 2021;43(3):376-89.
2. Recknagel JD and Goodman LR. J Minim Invasive Gynecol. 2021;28(3):467-74.
3. Palmer R. J Reprod Med. 1974;13:1-5.
4. Brill AI et al. Obstet Gynecol. 1995;85(2):269-72.
5. Audebert AJ and Gomel V. Fertil Steril. 2000;73(3):631-5.
6. Ahmad G et al. Cochrane Database of Systematic Reviews. 2019;1:CD006583.
7. Patzkowsky KE et al. J. Minim Invasive Gynecol. 2021;28(3):386.
8. Nutan J et al. Updates in Surgery. 2021;73(6):2321-9.
The choice of entry point for gynecologic laparoscopy is critical, considering that most laparoscopic injuries occur during initial entry into the abdomen. In addition, different abdominal access points may have differing utility and efficacy depending on the patient. (The overall rate of injuries to abdominal viscera and blood vessels at the time of entry is an estimated 1 per 1,000 cases.1)
The most conventional entry point for gynecologic laparoscopic surgeries has been the umbilicus, but there are contraindications to this choice and situations in which it may not be the best access site. It is important to have knowledge of alternate entry points and techniques that consider the patient’s current pathology, anatomy, and most importantly, surgical history to better facilitate a safe initial entry.
The left upper quadrant (LUQ) has been described as a preferred alternate site to the umbilicus, and some gynecologic surgeons even consider it as a routine mode of entry.2 In our practice, LUQ entry is a safe and commonly used technique that is chosen primarily based on a patient’s history of a midline vertical incision, the presence of abdominal mesh from a prior umbilical hernia repair, or repeated cesarean sections.
Our technique for LUQ entry is a modification of the traditional approach that employs Palmer’s point – the entry point described by Raoul Palmer, MD, in 1974 as 3-4 cm below the left subcostal margin at the midclavicular line.3 We choose to enter at the midclavicular level and directly under the last rib.
When the umbilicus is problematic
The umbilicus is a favored entry point not only for its operative access to pelvic structures but also because – in the absence of obesity – it has no or little subcutaneous fat and, therefore, provides the shortest distance from skin to peritoneum.
However, adhesive disease from a prior laparotomy involving the umbilicus is a risk factor for bowel injury during umbilical entry (direct trocar, Veress needle, or open technique). In a 1995 review of 360 women undergoing operative laparoscopy after a previous laparotomy, Brill et al. reported umbilical adhesions in 27% of those with prior horizontal suprapubic (Pfannenstiel) incisions, in 55% of those with prior incisions in the midline below the umbilicus, and 67% of those with prior midline incisions above the umbilicus.4
Of the 259 patients whose prior laparotomy was for gynecologic surgery (as opposed to obstetric or general surgery) adhesions were present in 70% of those who had midline incisions. (Direct injury to adherent omentum and bowel occurred during laparoscopic procedures in 21% of all women.)
Since the Brill paper, other studies have similarly reported significant adhesion rate, especially after midline incisions. For instance, one French study of patients undergoing laparoscopy reported umbilical adhesions in 51.7% of 89 patients who had previous laparotomy with a midline incision.5
Prior umbilical laparoscopy is not a risk factor for umbilical entry unless a hernia repair with mesh was performed at the umbilicus. Umbilical adhesions have been reported to occur in up to 15% of women who have had prior laparoscopic surgery, with more adhesions associated with larger trocar use (specifically 12-mm trocars).1 Still, the rate of those adhesions was very low.
Obesity is not necessarily a contraindication to umbilical entry; however, it can make successful entry more difficult, particularly in those with central obesity and a thicker layer of subcutaneous fat. It can be difficult in such cases to know when peritoneal access is achieved. Extra-long Veress needles or trocars may be needed, and it is important to enter the abdomen at a 90° angle to minimize risk to the great vessel vasculature.
LUQ entry is often a reliable alternative when central obesity is significant or when umbilical access proves to be difficult. Certainly, the subcutaneous fat layer is thinner at the LUQ than at the umbilicus, and in patients whose umbilicus is pulled very caudal because of a large pannus, the LUQ will also provide a better location for visualization of pelvic anatomy and for easier entry.
We still use umbilical entry in most patients with obesity, but if we are unsuccessful after two to three attempts, we proceed to the LUQ (barring any contraindications to this site).
LUQ entry: Our approach, contraindications
By entering at the midclavicular level and directly under the bottom of the rib cage, rather than 2-3 cm below the last rib as in traditional Palmer’s point LUQ entry, we benefit from the tenting up of the peritoneum by the last rib. Having space between the peritoneum and underlying omentum and stomach can facilitate an easier entry, as shown in the video.
We primarily utilize the Veress needle for entry. The needle is inserted directly perpendicular to the fascia, or at a slight angle toward the umbilicus. After the abdomen is insufflated to 15 mm Hg, we proceed with a visual peritoneal entry using a 5-mm trocar with a clear tip, which allows us to visualize both layers of fascia, and subsequently the peritoneum, as the trocar is advanced.
The fascia is not fused, so we can expect to feel three “pops” as the needle (or trocar) passes through the aponeuroses of the internal and external obliques, the aponeuroses of the internal oblique and transversus, and the peritoneum.
While successful peritoneal entry with umbilical access is generally confirmed with an intraperitoneal pressure measuring less than 7 mm Hg (which varies depending on abdominal wall thickness and adiposity), we have found that the opening pressure with LUQ entry is slightly higher. A recently published Canadian guideline for gynecologic laparoscopic entry recommends that an initial Veress intraperitoneal pressure of 10 mm Hg or below be considered an indicator of successful entry, regardless of the patient’s body habitus.1
LUQ entry can be helpful for surgeries involving large pelvic masses, for which there is little or no space to enter at the umbilicus or to optimally view the pathology. Utilizing the LUQ not only allows for an unobstructed entry and optimal viewing but also may become an extra operative port that can be used for the camera, allowing both surgeons to operate with two hands – a four-port technique. It also allows the surgeon to use a larger diameter port at the umbilicus without concern for cosmetics.
Additionally, there is a school of thought that LUQ entry is overall more successful, requiring less conversion to alternative sites and fewer attempts. This success may result from the presence of less adhesive disease in the LUQ, as well as clearer visualization of the anatomy while entering and confidence in entering the intraperitoneal space.
A prerequisite for LUQ entry is that the stomach be decompressed through placement of an oral gastric or nasogastric tube and suctioning of all gastric contents. An inability to decompress the stomach is a contraindication to LUQ entry, as is a history of splenectomy, an enlarged liver, gastric bypass surgery, or upper abdominal surgery.
Entry techniques, alternate sites
No single entry site or technique has been proven to be universally safer than another. A 2019 Cochrane review of laparoscopic entry techniques noted an advantage of direct trocar entry over Veress-needle entry for failed entry but concluded that, overall, evidence was insufficient to support the use of one entry technique over another to decrease complication rates.6
A more recently published review of randomized controlled trials, Cochrane reviews, and older descriptive accounts similarly concluded that, between the Veress needle (the oldest described technique), direct trocar insertion, and open entry (Hasson), there is no good evidence to suggest that any of these methods is universally superior.2 Surgeon comfort is, therefore, an important factor.
Regarding entry sites, we advocate use of the LUQ as an advantageous alternative site for access, but there are several other approaches described in the literature. These include right upper quadrant entry; the Lee Huang point, which is about 10 cm below the xiphoid; and uncommonly, vaginal, either posterior to the uterus into the pouch of Douglas or through the uterine fundus.2
The right upper quadrant approach is included in a recent video review in the Journal of Minimally Invasive Gynecology of safe entry techniques, along with umbilicus, LUQ, and supraumbilical entry.7
Another described entry site is the “Jain point,” located at the intersection of a vertical line drawn 2.5 cm medial to the anterior superior iliac spine, up to the level of the umbilicus, and a horizontal line at the upper margin of the umbilicus. In a retrospective study of 7,802 cases involving this method, the authors reported only one significant entry complication. Patients in the study had a wide range of BMIs and previous surgeries.8
With respect to entry techniques, we facilitate the Veress entry technique described by Frank E. Loeffler, MD, in the mid-1970s, unless there are contraindications such as second-trimester pregnancy. For umbilical entry, we first use a Kocher clamp to grasp the base of the umbilicus and then evert it. Using two towel clips, the surgeon and assistant apply countertraction by grasping the skin and fat on either side of the umbilicus. A horizontal incision is then made directly on the base of the umbilicus. The towel clips are used to elevate the anterior abdominal wall, and the Veress needle is attached to insufflation tubing, then inserted into the abdomen.
Alternatively, direct entry involves incising the skin, placing a laparoscope in a visual entry trocar, and directly visualizing each layer as the abdomen is entered. Once the trocar is intraperitoneal, insufflation is started.
In open laparoscopic/Hasson entry, the umbilical skin is incised, and the subcutaneous fat is dissected down until the rectal fascia is visualized. The fascia is then incised, the peritoneum is entered bluntly, and the Hasson trocar is placed. Insufflation is attached, and the laparoscope is inserted.
Dr. Sasaki is a partner, and Dr. McKenna is an AAGL MIGS fellow, in the private practice of Charles E. Miller, MD, & Associates in Chicago. They reported that they have no disclosures.
References
1. Vilos GA et al. J Obstet Gyneacol Can. 2021;43(3):376-89.
2. Recknagel JD and Goodman LR. J Minim Invasive Gynecol. 2021;28(3):467-74.
3. Palmer R. J Reprod Med. 1974;13:1-5.
4. Brill AI et al. Obstet Gynecol. 1995;85(2):269-72.
5. Audebert AJ and Gomel V. Fertil Steril. 2000;73(3):631-5.
6. Ahmad G et al. Cochrane Database of Systematic Reviews. 2019;1:CD006583.
7. Patzkowsky KE et al. J. Minim Invasive Gynecol. 2021;28(3):386.
8. Nutan J et al. Updates in Surgery. 2021;73(6):2321-9.
The choice of entry point for gynecologic laparoscopy is critical, considering that most laparoscopic injuries occur during initial entry into the abdomen. In addition, different abdominal access points may have differing utility and efficacy depending on the patient. (The overall rate of injuries to abdominal viscera and blood vessels at the time of entry is an estimated 1 per 1,000 cases.1)
The most conventional entry point for gynecologic laparoscopic surgeries has been the umbilicus, but there are contraindications to this choice and situations in which it may not be the best access site. It is important to have knowledge of alternate entry points and techniques that consider the patient’s current pathology, anatomy, and most importantly, surgical history to better facilitate a safe initial entry.
The left upper quadrant (LUQ) has been described as a preferred alternate site to the umbilicus, and some gynecologic surgeons even consider it as a routine mode of entry.2 In our practice, LUQ entry is a safe and commonly used technique that is chosen primarily based on a patient’s history of a midline vertical incision, the presence of abdominal mesh from a prior umbilical hernia repair, or repeated cesarean sections.
Our technique for LUQ entry is a modification of the traditional approach that employs Palmer’s point – the entry point described by Raoul Palmer, MD, in 1974 as 3-4 cm below the left subcostal margin at the midclavicular line.3 We choose to enter at the midclavicular level and directly under the last rib.
When the umbilicus is problematic
The umbilicus is a favored entry point not only for its operative access to pelvic structures but also because – in the absence of obesity – it has no or little subcutaneous fat and, therefore, provides the shortest distance from skin to peritoneum.
However, adhesive disease from a prior laparotomy involving the umbilicus is a risk factor for bowel injury during umbilical entry (direct trocar, Veress needle, or open technique). In a 1995 review of 360 women undergoing operative laparoscopy after a previous laparotomy, Brill et al. reported umbilical adhesions in 27% of those with prior horizontal suprapubic (Pfannenstiel) incisions, in 55% of those with prior incisions in the midline below the umbilicus, and 67% of those with prior midline incisions above the umbilicus.4
Of the 259 patients whose prior laparotomy was for gynecologic surgery (as opposed to obstetric or general surgery) adhesions were present in 70% of those who had midline incisions. (Direct injury to adherent omentum and bowel occurred during laparoscopic procedures in 21% of all women.)
Since the Brill paper, other studies have similarly reported significant adhesion rate, especially after midline incisions. For instance, one French study of patients undergoing laparoscopy reported umbilical adhesions in 51.7% of 89 patients who had previous laparotomy with a midline incision.5
Prior umbilical laparoscopy is not a risk factor for umbilical entry unless a hernia repair with mesh was performed at the umbilicus. Umbilical adhesions have been reported to occur in up to 15% of women who have had prior laparoscopic surgery, with more adhesions associated with larger trocar use (specifically 12-mm trocars).1 Still, the rate of those adhesions was very low.
Obesity is not necessarily a contraindication to umbilical entry; however, it can make successful entry more difficult, particularly in those with central obesity and a thicker layer of subcutaneous fat. It can be difficult in such cases to know when peritoneal access is achieved. Extra-long Veress needles or trocars may be needed, and it is important to enter the abdomen at a 90° angle to minimize risk to the great vessel vasculature.
LUQ entry is often a reliable alternative when central obesity is significant or when umbilical access proves to be difficult. Certainly, the subcutaneous fat layer is thinner at the LUQ than at the umbilicus, and in patients whose umbilicus is pulled very caudal because of a large pannus, the LUQ will also provide a better location for visualization of pelvic anatomy and for easier entry.
We still use umbilical entry in most patients with obesity, but if we are unsuccessful after two to three attempts, we proceed to the LUQ (barring any contraindications to this site).
LUQ entry: Our approach, contraindications
By entering at the midclavicular level and directly under the bottom of the rib cage, rather than 2-3 cm below the last rib as in traditional Palmer’s point LUQ entry, we benefit from the tenting up of the peritoneum by the last rib. Having space between the peritoneum and underlying omentum and stomach can facilitate an easier entry, as shown in the video.
We primarily utilize the Veress needle for entry. The needle is inserted directly perpendicular to the fascia, or at a slight angle toward the umbilicus. After the abdomen is insufflated to 15 mm Hg, we proceed with a visual peritoneal entry using a 5-mm trocar with a clear tip, which allows us to visualize both layers of fascia, and subsequently the peritoneum, as the trocar is advanced.
The fascia is not fused, so we can expect to feel three “pops” as the needle (or trocar) passes through the aponeuroses of the internal and external obliques, the aponeuroses of the internal oblique and transversus, and the peritoneum.
While successful peritoneal entry with umbilical access is generally confirmed with an intraperitoneal pressure measuring less than 7 mm Hg (which varies depending on abdominal wall thickness and adiposity), we have found that the opening pressure with LUQ entry is slightly higher. A recently published Canadian guideline for gynecologic laparoscopic entry recommends that an initial Veress intraperitoneal pressure of 10 mm Hg or below be considered an indicator of successful entry, regardless of the patient’s body habitus.1
LUQ entry can be helpful for surgeries involving large pelvic masses, for which there is little or no space to enter at the umbilicus or to optimally view the pathology. Utilizing the LUQ not only allows for an unobstructed entry and optimal viewing but also may become an extra operative port that can be used for the camera, allowing both surgeons to operate with two hands – a four-port technique. It also allows the surgeon to use a larger diameter port at the umbilicus without concern for cosmetics.
Additionally, there is a school of thought that LUQ entry is overall more successful, requiring less conversion to alternative sites and fewer attempts. This success may result from the presence of less adhesive disease in the LUQ, as well as clearer visualization of the anatomy while entering and confidence in entering the intraperitoneal space.
A prerequisite for LUQ entry is that the stomach be decompressed through placement of an oral gastric or nasogastric tube and suctioning of all gastric contents. An inability to decompress the stomach is a contraindication to LUQ entry, as is a history of splenectomy, an enlarged liver, gastric bypass surgery, or upper abdominal surgery.
Entry techniques, alternate sites
No single entry site or technique has been proven to be universally safer than another. A 2019 Cochrane review of laparoscopic entry techniques noted an advantage of direct trocar entry over Veress-needle entry for failed entry but concluded that, overall, evidence was insufficient to support the use of one entry technique over another to decrease complication rates.6
A more recently published review of randomized controlled trials, Cochrane reviews, and older descriptive accounts similarly concluded that, between the Veress needle (the oldest described technique), direct trocar insertion, and open entry (Hasson), there is no good evidence to suggest that any of these methods is universally superior.2 Surgeon comfort is, therefore, an important factor.
Regarding entry sites, we advocate use of the LUQ as an advantageous alternative site for access, but there are several other approaches described in the literature. These include right upper quadrant entry; the Lee Huang point, which is about 10 cm below the xiphoid; and uncommonly, vaginal, either posterior to the uterus into the pouch of Douglas or through the uterine fundus.2
The right upper quadrant approach is included in a recent video review in the Journal of Minimally Invasive Gynecology of safe entry techniques, along with umbilicus, LUQ, and supraumbilical entry.7
Another described entry site is the “Jain point,” located at the intersection of a vertical line drawn 2.5 cm medial to the anterior superior iliac spine, up to the level of the umbilicus, and a horizontal line at the upper margin of the umbilicus. In a retrospective study of 7,802 cases involving this method, the authors reported only one significant entry complication. Patients in the study had a wide range of BMIs and previous surgeries.8
With respect to entry techniques, we facilitate the Veress entry technique described by Frank E. Loeffler, MD, in the mid-1970s, unless there are contraindications such as second-trimester pregnancy. For umbilical entry, we first use a Kocher clamp to grasp the base of the umbilicus and then evert it. Using two towel clips, the surgeon and assistant apply countertraction by grasping the skin and fat on either side of the umbilicus. A horizontal incision is then made directly on the base of the umbilicus. The towel clips are used to elevate the anterior abdominal wall, and the Veress needle is attached to insufflation tubing, then inserted into the abdomen.
Alternatively, direct entry involves incising the skin, placing a laparoscope in a visual entry trocar, and directly visualizing each layer as the abdomen is entered. Once the trocar is intraperitoneal, insufflation is started.
In open laparoscopic/Hasson entry, the umbilical skin is incised, and the subcutaneous fat is dissected down until the rectal fascia is visualized. The fascia is then incised, the peritoneum is entered bluntly, and the Hasson trocar is placed. Insufflation is attached, and the laparoscope is inserted.
Dr. Sasaki is a partner, and Dr. McKenna is an AAGL MIGS fellow, in the private practice of Charles E. Miller, MD, & Associates in Chicago. They reported that they have no disclosures.
References
1. Vilos GA et al. J Obstet Gyneacol Can. 2021;43(3):376-89.
2. Recknagel JD and Goodman LR. J Minim Invasive Gynecol. 2021;28(3):467-74.
3. Palmer R. J Reprod Med. 1974;13:1-5.
4. Brill AI et al. Obstet Gynecol. 1995;85(2):269-72.
5. Audebert AJ and Gomel V. Fertil Steril. 2000;73(3):631-5.
6. Ahmad G et al. Cochrane Database of Systematic Reviews. 2019;1:CD006583.
7. Patzkowsky KE et al. J. Minim Invasive Gynecol. 2021;28(3):386.
8. Nutan J et al. Updates in Surgery. 2021;73(6):2321-9.
HIV Management: Insights Into ART and Weight Gain
Antiretroviral therapy (ART) regimens provide long-lasting suppression of HIV replication and have helped people with HIV live healthier lives for decades.
Today's ART regimens are associated with fewer serious and intolerable adverse effects than those used in the past, but weight gain remains a concern in clinical practice.
In this ReCAP, Dr David Wohl, from the University of North Carolina at Chapel Hill, reports on the relationship between ART and weight gain, as well as the implications of excessive weight gain in HIV management.
He shares data from multiple studies, including the ADVANCE trial, which offer insight on how different HIV therapies affect patient weight.
Dr Wohl also discusses the steps clinicians should take if weight gain does occur in people who are on HIV therapy.
--
Professor of Medicine; Medical Director, UNC COVID-19 Vaccine Clinic, COVID-19 Monoclonal Antibody Infusion Clinic, University of North Carolina at Chapel Hill
David Wohl, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Gilead; ViiV; Janssen; Merck
Serve(d) as a speaker or a member of a speakers bureau for: Gilead
Received research grant from: Gilead; Merck; ViiV
Antiretroviral therapy (ART) regimens provide long-lasting suppression of HIV replication and have helped people with HIV live healthier lives for decades.
Today's ART regimens are associated with fewer serious and intolerable adverse effects than those used in the past, but weight gain remains a concern in clinical practice.
In this ReCAP, Dr David Wohl, from the University of North Carolina at Chapel Hill, reports on the relationship between ART and weight gain, as well as the implications of excessive weight gain in HIV management.
He shares data from multiple studies, including the ADVANCE trial, which offer insight on how different HIV therapies affect patient weight.
Dr Wohl also discusses the steps clinicians should take if weight gain does occur in people who are on HIV therapy.
--
Professor of Medicine; Medical Director, UNC COVID-19 Vaccine Clinic, COVID-19 Monoclonal Antibody Infusion Clinic, University of North Carolina at Chapel Hill
David Wohl, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Gilead; ViiV; Janssen; Merck
Serve(d) as a speaker or a member of a speakers bureau for: Gilead
Received research grant from: Gilead; Merck; ViiV
Antiretroviral therapy (ART) regimens provide long-lasting suppression of HIV replication and have helped people with HIV live healthier lives for decades.
Today's ART regimens are associated with fewer serious and intolerable adverse effects than those used in the past, but weight gain remains a concern in clinical practice.
In this ReCAP, Dr David Wohl, from the University of North Carolina at Chapel Hill, reports on the relationship between ART and weight gain, as well as the implications of excessive weight gain in HIV management.
He shares data from multiple studies, including the ADVANCE trial, which offer insight on how different HIV therapies affect patient weight.
Dr Wohl also discusses the steps clinicians should take if weight gain does occur in people who are on HIV therapy.
--
Professor of Medicine; Medical Director, UNC COVID-19 Vaccine Clinic, COVID-19 Monoclonal Antibody Infusion Clinic, University of North Carolina at Chapel Hill
David Wohl, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Gilead; ViiV; Janssen; Merck
Serve(d) as a speaker or a member of a speakers bureau for: Gilead
Received research grant from: Gilead; Merck; ViiV
Psychoses: The 5 comorbidity-defined subtypes
How can we treat psychosis if we don’t know what we are treating? Over the years, attempts at defining psychosis subtypes have met with dead ends. However, recent research supports a new approach that offers a rational classification model organized according to 5 specific comorbid anxiety and depressive disorder diagnoses.
Anxiety and depressive symptoms are not just the result of psychotic despair. They are specific diagnoses, they precede psychosis onset, they help define psychotic syndromes, and they can point to much more effective treatment approaches. Most of the psychotic diagnoses in this schema are already recognized or posited. And, just as patients who do not have psychotic illness can have more than 1 anxiety or depressive disorder, patients with psychosis can present with a mixed picture that reflects more than 1 contributing comorbidity. Research further suggests that each of the 5 psychosis comorbidity diagnoses may involve some similar underlying factors that facilitate the formation of psychosis.
This article describes the basics of 5 psychosis subtypes, and provides initial guidelines to diagnosis, symptomatology, and treatment. Though clinical experience and existing research support the clinical presence and treatment value of this classification model, further verification will require considerably more controlled studies. An eventual validation of this approach could largely supplant ill-defined diagnoses of “schizophrenia” and other functional psychoses.
Recognizing the comorbidities in the context of their corresponding psychoses entails learning new interviewing skills and devoting more time to both initial and subsequent diagnosis and treatment. In our recently published book,1 we provide extensive details on the approach we describe in this article, including case examples, new interview tools to simplify the diagnostic journey, and novel treatment approaches.
Psychosis-proneness underlies functional psychoses
Functional (idiopathic) schizophrenia and psychotic disorders have long been difficult to separate, and many categorizations have been discarded. Despite clinical dissimilarities, today we too often casually lump psychoses together as schizophrenia.2,3 Eugen Bleuler first suggested the existence of a “group of schizophrenias.”4 It is possible that his group encompasses our 5 psychoses from 5 inbuilt emotional instincts,5 each corresponding to a specific anxiety or depressive subtype.
The 5 anxiety and depressive subtypes noted in this article are common, but psychosis is not. Considerable research suggests that certain global “psychotogenic” factors create susceptibility to all psychoses.6,7 While many genetic, neuroanatomical, experiential, and other factors have been reported, the most important may be “hypofrontality” (genetically reduced frontal lobe function, size, or neuronal activity) and dopaminergic hyperfunction (genetically increased dopamine activity).5-7
An evolutionary perspective
One evolutionary theory of psychopathology starts with the subtypes of depression and anxiety. For example, major depressive disorder and generalized anxiety disorder may encompass 5 commonplace and more specific anxiety and depressive subtypes. Consideration of the emotional, cognitive, and functional aspects of those subtypes suggests that they may have once been advantageous for primeval human herds. Those primeval altruistic instincts may have helped survival, reproduction, and preservation of kin group DNA.5
More than any other species, humans can draw upon consciousness and culture to rationally overcome the influences of unconscious instincts. But those instincts can then emerge from the deep, and painfully encourage obedience to their guidance. In nonpsychotic anxiety and depressive disorders, the specific messages are experienced as specific anxiety and depressive symptoms.5 In psychotic disorders, the messages can emerge as unreasoned and frightful fears, perceptions, beliefs, and behaviors. With newer research, clinical observation, and an evolutionary perspective, a novel and counterintuitive approach may improve our ability to help patients.8
Continue to: Five affective comorbidities evolved from primeval altruistic instincts...
Five affective comorbidities evolved from primeval altruistic instincts
Melancholic depression5
Melancholic depression is often triggered by serious illness, group exclusion, pronounced loss, or purposelessness. We hear patients talk painfully about illness, guilt, and death. Indeed, some increased risk of death, especially from infectious disease, may result from hypercortisolemia (documented by the dexamethasone suppression test). Hypercortisolemic death also occurs in salmon after spawning, and in male marsupial mice after mating. The tragic passing of an individual saves scarce resources for the remainder of the herd.
Obsessive-compulsive disorder5
Factor-analytic studies suggest 4 main obsessive-compulsive disorder (OCD) subtypes: cleanliness, hoarding, intrusive thoughts, and organizing. Obsessive-compulsive traits can help maintain a safe and efficient environment in humans and other species, but OCD is dysfunctional.
Panic anxiety5
Panic anxiety is triggered by real, symbolic, or emotional separation from home and family. In toddlers, separation anxiety can reduce the odds of getting lost and hurt.
Social anxiety5
Social anxiety includes fear of self-embarrassment, exposure as a pretender to higher social rank, and thus often a reluctant avoidance of increased social rank. While consciousness and cultural encouragement can overcome that hesitation and thus lead to greater success, social anxiety activation can still cause painful anxiety. The social hierarchies of many species include comparable biological influences, and help preserve group DNA by reducing hierarchical infighting.
Atypical depression and bipolar I mania5
Atypical depression includes increased rejection sensitivity, resulting in inoffensive behavior to avoid social rejection. This reduces risk of isolation from the group, and improves group harmony. Unlike the 4 other syndromes, atypical depression and bipolar I mania may reflect 2 separate seasonal mood phases. Atypical depression (including seasonal affective disorder) often worsens with shortened winter daylight hours, akin to hibernation. Initial bipolar I mania is more common with springtime daylight, with symptoms not unlike exaggerated hibernation awakening.9
Primeval biological altruism has great evolutionary value in many species, and even somewhat in modern humans. But it is quite different from modern rational altruism. Although we sometimes override our instincts, they respond with messages experienced as emotional pain—they still tell us to follow instructions for primeval herd survival. In an earlier book, I (JPK) provide a lengthier description of the evidence for this evolutionary psychopathology theory, including interplay of the 5 instincts with psychotogenic factors.5
Continue to: Five comorbidity psychoses from 5 primeval instincts.....
Five comorbidity psychoses from 5 primeval instincts
The 5 affective comorbidities described above contribute to the presence, subtype, and treatment approaches of 5 corresponding psychoses. Ordinary panic attacks might occur when feeling trapped or separated from home, so people want to flee to safety. Nonhuman species with limited consciousness and language are unlikely to think “time to head for safety.” Instead, instincts encourage flight from danger through internally generated perceptions of threat. Likewise, people with psychosis and panic, without sufficient conscious modulation, may experience sensory perceptions of actual danger when feeling symbolically trapped.1,10
One pilot study carefully examined the prevalence of these 5 comorbidities in an unselected group of psychotic patients.10 At least 85% met criteria for ≥1 of the 5 subtypes.10 Moreover, organic psychoses related to physical illness, substances, and iatrogenesis may also predict future episodes of functional psychoses.1
Using statistical analysis of psychosis rating scales, 2 studies took a “transdiagnostic” look at psychoses, and each found 5 psychosis subtypes and a generalized psychosis susceptibility factor.11,12 Replication of that transdiagnostic approach, newly including psychosis symptoms and our 5 specific comorbidities, might well find that the 5 subtype models resemble each other.11,12
Our proposed 5 comorbidity subtypes are1:
Delusional depression (melancholic depression). Most common in geriatric patients, this psychosis can also occur at younger ages. Prodromal melancholic depression can include guilt and hopelessness, and is acute, rather than the chronic course of our other 4 syndromes. Subsequent delusional depression includes delusions of bodily decay, illness, or death, as well as overwhelming guilt, shame, and remorse. The classic vegetative symptoms of depression continue. In addition to infectious disease issues, high suicide risk makes hospitalization imperative.
Obsessive-compulsive schizophrenia. Just as OCD has an early age of onset, obsessive-compulsive schizophrenia begins earlier than other psychoses. Despite preserved cognition, some nonpsychotic patients with OCD have diminished symptom insight. OCD may be comorbid with schizophrenia in 12% of cases, typically preceding psychosis onset. Obsessive-compulsive schizophrenia symptoms may include highly exaggerated doubt or ambivalence; contamination concerns; eccentric, ritualistic, motor stereotypy, checking, disorganized, and other behaviors; and paranoia.
Schizophrenia with voices (panic anxiety). Classic paranoid schizophrenia with voices appears to be the most similar to a “panic psychosis.” Patients with nonpsychotic panic anxiety have increased paranoid ideation and ideas of reference as measured on the Symptom Checklist-90. Schizophrenia is highly comorbid with panic anxiety, estimated at 45% in the Epidemiologic Catchment Area study.13 These are likely underestimates: cognitive impairment hinders reporting, and psychotic panic is masked as auditory hallucinations. A pilot study of schizophrenia with voices using a carbon dioxide panic induction challenge found that 100% had panic anxiety.14 That study and another found that virtually all participants reported voices concurrent with panic using our Panic and Schizophrenia Interview (PaSI) (Box 1). Panic onset precedes schizophrenia onset, and panic may reappear if antipsychotic medications sufficiently control voices: “voices without the voices,” say some.
Box 1
Let’s talk for a minute about your voices.
[IDENTIFYING PAROXYSMAL MOMENTS OF VOICE ONSET]
Do you hear voices at every single moment, or are they sometimes silent? Think about those times when you are not actually hearing any voices.
Now, there may be reasons why the voices start talking when they do, but let’s leave that aside for now.
So, whenever the voices do begin speaking—and for whatever reason they do—is it all of a sudden, or do they start very softly and then very gradually get louder?
If your voices are nearly always there, then are there times when the voices suddenly come back, get louder, get more insistent, or just get more obvious to you?
[Focus patient on sudden moment of voice onset, intensification, or awareness]
Let’s talk about that sudden moment when the voices begin (or intensify, or become obvious), even if you know the reason why they start.
I’m going to ask you about some symptoms that you might have at that same sudden moment when the voices start (or intensify, or become obvious). If you have any of these symptoms at the other times, they do not count for now.
So, when I ask about each symptom, tell me whether it comes on at the same sudden moments as the voices, and also if it used to come on with the voices in the past.
For each sudden symptom, just say “YES” or “NO” or “SOMETIMES.”
[Begin each query with: “At the same sudden moment that the voices come on”]
- Sudden anxiety, fear, or panic on the inside?
- Sudden anger or rage on the inside? [ANGER QUERY]
- Sudden heart racing? Heart pounding?
- Sudden chest pain? Chest pressure?
- Sudden sweating?
- Sudden trembling or shaking?
- Sudden shortness of breath, or like you can’t catch your breath?
- Sudden choking or a lump in your throat?
- Sudden nausea or queasiness?
- Sudden dizziness, lightheadedness, or faintness?
- Sudden feeling of detachment, sort of like you are in a glass box?
- Sudden fear of losing control? Fear of going crazy?
- Sudden fear afraid of dying? Afraid of having a heart attack?
- Sudden numbness or tingling, especially in your hands or face?
- Sudden feeling of heat, or cold?
- Sudden itching in your teeth? [VALIDITY CHECK]
- Sudden fear that people want to hurt you? [EXCESS FEAR QUERY]
- Sudden voices? [VOICES QUERY]
[PAST & PRODROMAL PANIC HISTORY]
At what age did you first see a therapist or psychiatrist?
At what age were you first hospitalized for an emotional problem?
At what age did you first start hearing voices?
At what age did you first start having strong fears of other people?
Before you ever heard voices, did you ever have any of the other sudden symptoms like the ones we just talked about?
Did those episodes back then feel sort of like your voices or sudden fears do now, except that there were no voices or sudden fears of people back then?
At what age did those sudden anxiety (or panic or rage) episodes begin?
Back then, was there MORE (M) sudden anxiety, or the SAME (S) sudden anxiety, or LESS (L) sudden anxiety than with your sudden voices now?
[PAST & PRODROMAL PANIC SYMPTOMS]
Now let’s talk about some symptoms that you might have had at those same sudden anxiety moments, in the time before you ever heard any voices. So, for each sudden symptom just say “YES” or “NO” or “SOMETIMES.”
[Begin each query with: “At the same moment the sudden anxiety came on—but only during the time before you ever heard sudden voices”]
[Ask about the same 18 panic-related symptoms listed above]
[PHOBIA-RELATED PANIC AND VOICES]
Have you ever been afraid to go into a (car, bus, plane, train, subway, elevator, mall, tunnel, bridge, heights, small place, CAT scan or MRI, being alone, crowds)?
[If yes or maybe: Ask about panic symptoms in phobic situations]
Now let’s talk about some symptoms that you might have had at some of those times you were afraid. So, for each symptom just say “YES” or “NO” or “MAYBE.”
[Ask about the same 18 panic-related symptoms listed above]
At what age did you last have sudden anxiety without voices?
Has medication ever completely stopped your voices? Somewhat?
If so, did those other sudden symptoms still happen sometimes?
Thank you for your help, and for answering all of these questions!
Persecutory delusional disorder (social anxiety). Some “schizophrenia” without voices may be misdiagnosis of persecutory (paranoid) delusional disorder (PDD). Therefore, the reported population prevalence (0.02%) may be underestimated. Social anxiety is highly comorbid with “schizophrenia” (15%).16 Case reports and clinical experience suggest that PDD is commonly preceded by social anxiety.17 Some nonpsychotic social anxiety symptoms closely resemble the PDD psychotic ideas of reference (a perception that low social rank attracts critical scrutiny by authorities). Patients with PDD may remain relatively functional, with few negative symptoms, despite pronounced paranoia. Outward manifestation of paranoia may be limited, unless quite intense. The typical age of onset (40 years) is later than that of schizophrenia, and symptoms can last a long time.18
Continue to: Bipolar 1 mania with delusions...
Bipolar I mania with delusions (atypical depression). Atypical depression is the most common depression in bipolar I disorder. Often more pronounced in winter, it may intensify at any time of year. Long ago, hypersomnia, lethargy, inactivity, inoffensiveness, and craving high-calorie food may have been conducive to hibernation.
Bipolar I mania includes delusions of special accomplishments or abilities, energetically focused on a grandiose mission to help everyone. These intense symptoms may be related to reduced frontal lobe modulation. In some milder form, bipolar I mania may once have encouraged hibernation awakening. Indeed, initial bipolar I mania episodes are more common in spring, as is the spring cleaning that helps us prepare for summer.
Recognizing affective trees in a psychotic forest
Though long observed, comorbid affective symptoms have generally been considered a hodgepodge of distress caused by painful psychotic illness. But the affective symptoms precede psychosis onset, can be masked during acute psychosis, and will revert to ordinary form if psychosis abates.11-13
Rather than affective symptoms being a consequence of psychosis, it may well be the other way around. Affective disorders could be important causal and differentiating components of psychotic disorders.11-13 Research and clinical experience suggest that adjunctive treatment of the comorbidities with correct medication can greatly enhance outcome.
Diagnostic approaches
Because interviews of patients with psychosis are often complicated by confusion, irritability, paranoid evasiveness, cognitive impairment, and medication, nuanced diagnosis is difficult. Interviews should explore psychotic syndromes and subtypes that correlate with comorbidity psychoses, including pre-psychotic anxiety and depressive diagnoses that are chronic (though unlike our 4 other diagnoses, melancholic depression is not chronic).
Establishing pre-psychotic diagnosis of chronic syndromes suggests that they are still present, even if they are difficult to assess during psychosis. Re-interview after some improvement allows for a significantly better diagnosis. Just as in nonpsychotic affective disorders, multiple comorbidities are common, and can lead to a mixed psychotic diagnosis and treatment plan.1
Structured interview tools can assist diagnosis. The PaSI (Box 1,15) elicits past, present, and detailed history of DSM panic, and has been validated in a small pilot randomized controlled trial. The PaSI focuses patient attention on paroxysmal onset voices, and then evaluates the presence of concurrent DSM panic symptoms. If voices are mostly psychotic panic, they may well be a proxy for panic. Ultimately, diagnosis of 5 comorbidities and associated psychotic symptoms may allow simpler categorization into 1 (or more) of the 5 psychosis subtypes.
Continue to: Treatment by comorbidity subtype...
Treatment by comorbidity subtype
Treatment of psychosis generally begins with antipsychotics. Nominal psychotherapy (presence of a professionally detached, compassionate clinician) improves compliance and leads to supportive therapy. Cognitive-behavioral therapy and dialectical behavior therapy may help later, with limited interpersonal approaches further on for some patients.
The suggested approaches to pharmacotherapy noted here draw on research and clinical experience.1,14,19-21 All medications used to treat comorbidities noted here are approved or generally accepted for that diagnosis. Estimated doses are similar to those for comorbidities when patients are nonpsychotic, and vary among patients. Doses, dosing schedules, and titration are extremely important for full benefit. Always consider compliance issues, suicidality, possible adverse effects, and potential drug/drug interactions. Although the medications we suggest using to treat the comorbidities may appear to also benefit psychosis, only antipsychotics are approved for psychosis per se.
Delusional depression. Antipsychotic + antidepressant. Tricyclic antidepressants are possibly most effective, but increase the risk of overdose and dangerous falls among fragile patients. Electroconvulsive therapy is sometimes used.
Obsessive-compulsive schizophrenia. Antipsychotic + selective serotonin reuptake inhibitor (SSRI). Consider aripiprazole (
Schizophrenia with voices. Antipsychotic + clonazepam. Concurrent usage may stabilize psychosis more rapidly, and with a lower antipsychotic dose.23 Titrate a fixed dose of clonazepam every 12 hours (avoid as-needed doses), starting low (ie, 0.5 mg) to limit initial drowsiness (which typically diminishes in 3 to 10 days). Titrate to full voice and panic cessation (1 to 2.5 mg every 12 hours).14 Exercise caution about excessive drowsiness, as well as outpatient compliance and abuse. Besides alprazolam, other antipanic medications have little incidental benefit for psychosis.
Persecutory delusional disorder. Antipsychotic + SSRI. Aripiprazole (consider long-acting injectable for compliance) also enhances the benefits of fluoxetine for social anxiety. Long half-life fluoxetine (20 mg/d) improves compliance and near-term outcomes.
Bipolar I mania: mania with delusions. Consider olanzapine for acute phase, then add other antimanic medication (commonly lithium or valproic acid), check blood level, and then taper olanzapine some weeks later. Importantly, lamotrigine is not effective for bipolar I mania. Consider suicide risk, medical conditions, and outpatient compliance. Comorbid panic anxiety is also common in bipolar I mania, often presenting as nonthreatening voices.
Seasonality: Following research that bipolar I mania is more common in spring and summer, studies have shown beneficial clinical augmentation from dark therapy as provided by reduced light exposure, blue-blocking glasses, and exogenous melatonin (a darkness-signaling hormone).24
Bipolar I mania atypical depression (significant current or historical symptoms). SSRI + booster medication. An SSRI (ie, escitalopram, 10 mg/d) is best started several weeks after full bipolar I mania resolution, while also continuing long-term antimanic medication. Booster medications (ie, buspirone 15 mg every 12 hours; lithium 300 mg/d; or trazodone 50 mg every 12 hours) can enhance SSRI benefits. Meta-analysis suggests SSRIs may have limited risk of inducing bipolar I mania.25 Although not yet specifically tested for atypical depression, lamotrigine may be effective, and may be safer still.25 However, lamotrigine requires very gradual dose titration to prevent a potentially dangerous rash, including after periods of outpatient noncompliance.
Seasonality: Atypical depression is often worse in winter (seasonal affective disorder). Light therapy can produce some clinically helpful benefits year-round.
To illustrate this new approach to psychosis diagnosis and treatment, our book
Box 2
Ms. B, a studious 19-year-old, has been very shy since childhood, with few friends. Meeting new people always gave her gradually increasing anxiety, thinking that she would embarrass herself in their eyes. She had that same anxiety, along with sweating and tachycardia, when she couldn’t avoid speaking in front of class. Sometimes, while walking down the street she would think that strangers were casting a disdainful eye on her, though she knew that wasn’t true. Another anxiety started when she was 16. While looking for paper in a small supply closet, she suddenly felt panicky. With a racing heart and short of breath, she desperately fled the closet. These episodes continued, sometimes for no apparent reason, and nearly always unnoticed by others.
At age 17, she began to believe that those strangers on the street were looking down on her with evil intent, and even following her around. She became afraid to walk around town. A few months later, she also started to hear angry and critical voices at sudden moments. Although the paroxysmal voices always coincided with her panicky symptoms, the threatening voices now felt more important to her than the panic itself. Nonpsychotic panics had stopped. Mostly a recluse, she saw less of her family, left her job, and stopped going to the movies.
After a family dinner, she was detached, scared, and quieter than usual. She sought help from her primary care physician, who referred her to a psychiatrist. A thorough history from Ms. B and her family revealed her disturbing fears, as well as her history of social anxiety. Interviewing for panic was prompted by her mother’s recollection of the supply closet story.
In view of Ms. B’s cooperativeness and supportive family, outpatient treatment of her recent-onset psychosis began with aripiprazole, 10 mg/d, and clonazepam, 0.5 mg every 12 hours. Clonazepam was gradually increased until voices (and panic) ceased. She was then able to describe how earlier panics had felt just like voices, but without the voices. The fears of strangers continued. Escitalopram, 20 mg/d, was added for social anxiety (aripiprazole enhances the benefits of selective serotonin reuptake inhibitors).
One month later, her fears of strangers diminished, and she felt more comfortable around people than ever before. On the same medications, and in psychotherapy over the next year, she began to increase her social network while making plans to start college.
Larger studies are needed
Current research supports the concept of a 5-diagnosis classification of psychoses, which may correlate with our comorbid anxiety and depression model. Larger diagnostic and treatment studies would invaluably examine existing research and clinical experience, and potentially encourage more clinically useful diagnoses, specific treatments, and improved outcomes.
Bottom Line
New insights from evolutionary psychopathology, clinical research and observation, psychotogenesis, genetics, and epidemiology suggest that most functional psychoses may fall into 1 of 5 comorbidity-defined subtypes, for which specific treatments can lead to much improved outcomes.
1. Veras AB, Kahn JP, eds. Psychotic Disorders: Comorbidity Detection Promotes Improved Diagnosis and Treatment. Elsevier; 2021.
2. Gaebel W, Zielasek J. Focus on psychosis. Dialogues Clin Neuroscience. 2015;17(1):9-18.
3. Guloksuz S, Van Os J. The slow death of the concept of schizophrenia and the painful birth of the psychosis spectrum. Psychological Medicine. 2018;48(2):229-244.
4. Bleuler E. Dementia Praecox or the Group of Schizophrenias. International Universities Press; 1950.
5. Kahn JP. Angst: Origins of Depression and Anxiety. Oxford University Press; 2013.
6. Howes OD, McCutcheon R, Owen MJ, et al. The role of genes, stress, and dopamine in the development of schizophrenia. Biol Psychiatry. 2017;81(1):9-20.
7. Mubarik A, Tohid H. Frontal lobe alterations in schizophrenia: a review. Trends Psychiatry Psychother. 2016;38(4):198-206.
8. Murray RM, Bhavsar V, Tripoli G, et al. 30 Years on: How the neurodevelopmental hypothesis of schizophrenia morphed into the developmental risk factor model of psychosis. Schizophr Bull. 2017;43(6):1190-1196.
9. Bauer M, Glenn T, Alda M, et al. Solar insolation in springtime influences age of onset of bipolar I disorder. Acta Psychiatr Scand. 2017;136(6):571-582.
10. Kahn JP, Bombassaro T, Veras AB. Comorbid schizophrenia and panic anxiety: panic psychosis revisited. Psychiatr Ann. 2018;48(12):561-565.
11. Bebbington P, Freeman D. Transdiagnostic extension of delusions: schizophrenia and beyond. Schizophr Bull. 2017;43(2):273-282.
12. Catalan A, Simons CJP, Bustamante S, et al. Data gathering bias: trait vulnerability to psychotic symptoms? PLoS One. 2015;10(7):e0132442. doi:10.1371/journal.pone.0132442
13. Goodwin R, Lyons JS, McNally RJ. Panic attacks in schizophrenia. Schizophr Res. 2002;58(2-3):213-220.
14. Kahn JP, Puertollano MA, Schane MD, et al. Adjunctive alprazolam for schizophrenia with panic anxiety: clinical observation and pathogenetic implications. Am J Psychiatry. 1988;145(6):742-744.
15. Kahn JP. Chapter 4: Paranoid schizophrenia with voices and panic anxiety. In: Veras AB, Kahn JP, eds. Psychotic Disorders: Comorbidity Detection Promotes Improved Diagnosis and Treatment. Elsevier; 2021.
16. Achim AM, Maziade M, Raymond E, et al. How prevalent are anxiety disorders in schizophrenia? A meta-analysis and critical review on a significant association. Schizophr Bull. 2011;37(4):811-821.
17. Veras AB, Souza TG, Ricci TG, et al. Paranoid delusional disorder follows social anxiety disorder in a long-term case series: evolutionary perspective. J Nerv Ment Dis. 2015;203(6):477-479.
18. McIntyre JC, Wickham S, Barr B, et al. Social identity and psychosis: associations and psychological mechanisms. Schizophr Bull. 2018;44(3):681-690.
19. Barbee JG, Mancuso DM, Freed CR. Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia. Am J Psychiatry. 1992;149(4):506-510.
20. Nardi AE, Machado S, Almada LF. Clonazepam for the treatment of panic disorder. Curr Drug Targets. 2013;14(3):353-364.
21. Poyurovsky M. Schizo-Obsessive Disorder. Cambridge University Press; 2013.
22. Reznik I, Sirota P. Obsessive and compulsive symptoms in schizophrenia: a randomized controlled trial with fluvoxamine and neuroleptics. J Clin Psychopharmacol. 2000;20(4):410-416.
23. Bodkin JA. Emerging uses for high-potency benzodiazepines in psychotic disorders. J Clin Psychiatry. 1990;51 Suppl:41-53.
24. Gottlieb JF, Benedetti F, Geoffroy PA, et al. The chronotherapeutic treatment of bipolar disorders: a systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology. Bipolar Disord. 2019;21(8):741-773.
25. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249-1262.
How can we treat psychosis if we don’t know what we are treating? Over the years, attempts at defining psychosis subtypes have met with dead ends. However, recent research supports a new approach that offers a rational classification model organized according to 5 specific comorbid anxiety and depressive disorder diagnoses.
Anxiety and depressive symptoms are not just the result of psychotic despair. They are specific diagnoses, they precede psychosis onset, they help define psychotic syndromes, and they can point to much more effective treatment approaches. Most of the psychotic diagnoses in this schema are already recognized or posited. And, just as patients who do not have psychotic illness can have more than 1 anxiety or depressive disorder, patients with psychosis can present with a mixed picture that reflects more than 1 contributing comorbidity. Research further suggests that each of the 5 psychosis comorbidity diagnoses may involve some similar underlying factors that facilitate the formation of psychosis.
This article describes the basics of 5 psychosis subtypes, and provides initial guidelines to diagnosis, symptomatology, and treatment. Though clinical experience and existing research support the clinical presence and treatment value of this classification model, further verification will require considerably more controlled studies. An eventual validation of this approach could largely supplant ill-defined diagnoses of “schizophrenia” and other functional psychoses.
Recognizing the comorbidities in the context of their corresponding psychoses entails learning new interviewing skills and devoting more time to both initial and subsequent diagnosis and treatment. In our recently published book,1 we provide extensive details on the approach we describe in this article, including case examples, new interview tools to simplify the diagnostic journey, and novel treatment approaches.
Psychosis-proneness underlies functional psychoses
Functional (idiopathic) schizophrenia and psychotic disorders have long been difficult to separate, and many categorizations have been discarded. Despite clinical dissimilarities, today we too often casually lump psychoses together as schizophrenia.2,3 Eugen Bleuler first suggested the existence of a “group of schizophrenias.”4 It is possible that his group encompasses our 5 psychoses from 5 inbuilt emotional instincts,5 each corresponding to a specific anxiety or depressive subtype.
The 5 anxiety and depressive subtypes noted in this article are common, but psychosis is not. Considerable research suggests that certain global “psychotogenic” factors create susceptibility to all psychoses.6,7 While many genetic, neuroanatomical, experiential, and other factors have been reported, the most important may be “hypofrontality” (genetically reduced frontal lobe function, size, or neuronal activity) and dopaminergic hyperfunction (genetically increased dopamine activity).5-7
An evolutionary perspective
One evolutionary theory of psychopathology starts with the subtypes of depression and anxiety. For example, major depressive disorder and generalized anxiety disorder may encompass 5 commonplace and more specific anxiety and depressive subtypes. Consideration of the emotional, cognitive, and functional aspects of those subtypes suggests that they may have once been advantageous for primeval human herds. Those primeval altruistic instincts may have helped survival, reproduction, and preservation of kin group DNA.5
More than any other species, humans can draw upon consciousness and culture to rationally overcome the influences of unconscious instincts. But those instincts can then emerge from the deep, and painfully encourage obedience to their guidance. In nonpsychotic anxiety and depressive disorders, the specific messages are experienced as specific anxiety and depressive symptoms.5 In psychotic disorders, the messages can emerge as unreasoned and frightful fears, perceptions, beliefs, and behaviors. With newer research, clinical observation, and an evolutionary perspective, a novel and counterintuitive approach may improve our ability to help patients.8
Continue to: Five affective comorbidities evolved from primeval altruistic instincts...
Five affective comorbidities evolved from primeval altruistic instincts
Melancholic depression5
Melancholic depression is often triggered by serious illness, group exclusion, pronounced loss, or purposelessness. We hear patients talk painfully about illness, guilt, and death. Indeed, some increased risk of death, especially from infectious disease, may result from hypercortisolemia (documented by the dexamethasone suppression test). Hypercortisolemic death also occurs in salmon after spawning, and in male marsupial mice after mating. The tragic passing of an individual saves scarce resources for the remainder of the herd.
Obsessive-compulsive disorder5
Factor-analytic studies suggest 4 main obsessive-compulsive disorder (OCD) subtypes: cleanliness, hoarding, intrusive thoughts, and organizing. Obsessive-compulsive traits can help maintain a safe and efficient environment in humans and other species, but OCD is dysfunctional.
Panic anxiety5
Panic anxiety is triggered by real, symbolic, or emotional separation from home and family. In toddlers, separation anxiety can reduce the odds of getting lost and hurt.
Social anxiety5
Social anxiety includes fear of self-embarrassment, exposure as a pretender to higher social rank, and thus often a reluctant avoidance of increased social rank. While consciousness and cultural encouragement can overcome that hesitation and thus lead to greater success, social anxiety activation can still cause painful anxiety. The social hierarchies of many species include comparable biological influences, and help preserve group DNA by reducing hierarchical infighting.
Atypical depression and bipolar I mania5
Atypical depression includes increased rejection sensitivity, resulting in inoffensive behavior to avoid social rejection. This reduces risk of isolation from the group, and improves group harmony. Unlike the 4 other syndromes, atypical depression and bipolar I mania may reflect 2 separate seasonal mood phases. Atypical depression (including seasonal affective disorder) often worsens with shortened winter daylight hours, akin to hibernation. Initial bipolar I mania is more common with springtime daylight, with symptoms not unlike exaggerated hibernation awakening.9
Primeval biological altruism has great evolutionary value in many species, and even somewhat in modern humans. But it is quite different from modern rational altruism. Although we sometimes override our instincts, they respond with messages experienced as emotional pain—they still tell us to follow instructions for primeval herd survival. In an earlier book, I (JPK) provide a lengthier description of the evidence for this evolutionary psychopathology theory, including interplay of the 5 instincts with psychotogenic factors.5
Continue to: Five comorbidity psychoses from 5 primeval instincts.....
Five comorbidity psychoses from 5 primeval instincts
The 5 affective comorbidities described above contribute to the presence, subtype, and treatment approaches of 5 corresponding psychoses. Ordinary panic attacks might occur when feeling trapped or separated from home, so people want to flee to safety. Nonhuman species with limited consciousness and language are unlikely to think “time to head for safety.” Instead, instincts encourage flight from danger through internally generated perceptions of threat. Likewise, people with psychosis and panic, without sufficient conscious modulation, may experience sensory perceptions of actual danger when feeling symbolically trapped.1,10
One pilot study carefully examined the prevalence of these 5 comorbidities in an unselected group of psychotic patients.10 At least 85% met criteria for ≥1 of the 5 subtypes.10 Moreover, organic psychoses related to physical illness, substances, and iatrogenesis may also predict future episodes of functional psychoses.1
Using statistical analysis of psychosis rating scales, 2 studies took a “transdiagnostic” look at psychoses, and each found 5 psychosis subtypes and a generalized psychosis susceptibility factor.11,12 Replication of that transdiagnostic approach, newly including psychosis symptoms and our 5 specific comorbidities, might well find that the 5 subtype models resemble each other.11,12
Our proposed 5 comorbidity subtypes are1:
Delusional depression (melancholic depression). Most common in geriatric patients, this psychosis can also occur at younger ages. Prodromal melancholic depression can include guilt and hopelessness, and is acute, rather than the chronic course of our other 4 syndromes. Subsequent delusional depression includes delusions of bodily decay, illness, or death, as well as overwhelming guilt, shame, and remorse. The classic vegetative symptoms of depression continue. In addition to infectious disease issues, high suicide risk makes hospitalization imperative.
Obsessive-compulsive schizophrenia. Just as OCD has an early age of onset, obsessive-compulsive schizophrenia begins earlier than other psychoses. Despite preserved cognition, some nonpsychotic patients with OCD have diminished symptom insight. OCD may be comorbid with schizophrenia in 12% of cases, typically preceding psychosis onset. Obsessive-compulsive schizophrenia symptoms may include highly exaggerated doubt or ambivalence; contamination concerns; eccentric, ritualistic, motor stereotypy, checking, disorganized, and other behaviors; and paranoia.
Schizophrenia with voices (panic anxiety). Classic paranoid schizophrenia with voices appears to be the most similar to a “panic psychosis.” Patients with nonpsychotic panic anxiety have increased paranoid ideation and ideas of reference as measured on the Symptom Checklist-90. Schizophrenia is highly comorbid with panic anxiety, estimated at 45% in the Epidemiologic Catchment Area study.13 These are likely underestimates: cognitive impairment hinders reporting, and psychotic panic is masked as auditory hallucinations. A pilot study of schizophrenia with voices using a carbon dioxide panic induction challenge found that 100% had panic anxiety.14 That study and another found that virtually all participants reported voices concurrent with panic using our Panic and Schizophrenia Interview (PaSI) (Box 1). Panic onset precedes schizophrenia onset, and panic may reappear if antipsychotic medications sufficiently control voices: “voices without the voices,” say some.
Box 1
Let’s talk for a minute about your voices.
[IDENTIFYING PAROXYSMAL MOMENTS OF VOICE ONSET]
Do you hear voices at every single moment, or are they sometimes silent? Think about those times when you are not actually hearing any voices.
Now, there may be reasons why the voices start talking when they do, but let’s leave that aside for now.
So, whenever the voices do begin speaking—and for whatever reason they do—is it all of a sudden, or do they start very softly and then very gradually get louder?
If your voices are nearly always there, then are there times when the voices suddenly come back, get louder, get more insistent, or just get more obvious to you?
[Focus patient on sudden moment of voice onset, intensification, or awareness]
Let’s talk about that sudden moment when the voices begin (or intensify, or become obvious), even if you know the reason why they start.
I’m going to ask you about some symptoms that you might have at that same sudden moment when the voices start (or intensify, or become obvious). If you have any of these symptoms at the other times, they do not count for now.
So, when I ask about each symptom, tell me whether it comes on at the same sudden moments as the voices, and also if it used to come on with the voices in the past.
For each sudden symptom, just say “YES” or “NO” or “SOMETIMES.”
[Begin each query with: “At the same sudden moment that the voices come on”]
- Sudden anxiety, fear, or panic on the inside?
- Sudden anger or rage on the inside? [ANGER QUERY]
- Sudden heart racing? Heart pounding?
- Sudden chest pain? Chest pressure?
- Sudden sweating?
- Sudden trembling or shaking?
- Sudden shortness of breath, or like you can’t catch your breath?
- Sudden choking or a lump in your throat?
- Sudden nausea or queasiness?
- Sudden dizziness, lightheadedness, or faintness?
- Sudden feeling of detachment, sort of like you are in a glass box?
- Sudden fear of losing control? Fear of going crazy?
- Sudden fear afraid of dying? Afraid of having a heart attack?
- Sudden numbness or tingling, especially in your hands or face?
- Sudden feeling of heat, or cold?
- Sudden itching in your teeth? [VALIDITY CHECK]
- Sudden fear that people want to hurt you? [EXCESS FEAR QUERY]
- Sudden voices? [VOICES QUERY]
[PAST & PRODROMAL PANIC HISTORY]
At what age did you first see a therapist or psychiatrist?
At what age were you first hospitalized for an emotional problem?
At what age did you first start hearing voices?
At what age did you first start having strong fears of other people?
Before you ever heard voices, did you ever have any of the other sudden symptoms like the ones we just talked about?
Did those episodes back then feel sort of like your voices or sudden fears do now, except that there were no voices or sudden fears of people back then?
At what age did those sudden anxiety (or panic or rage) episodes begin?
Back then, was there MORE (M) sudden anxiety, or the SAME (S) sudden anxiety, or LESS (L) sudden anxiety than with your sudden voices now?
[PAST & PRODROMAL PANIC SYMPTOMS]
Now let’s talk about some symptoms that you might have had at those same sudden anxiety moments, in the time before you ever heard any voices. So, for each sudden symptom just say “YES” or “NO” or “SOMETIMES.”
[Begin each query with: “At the same moment the sudden anxiety came on—but only during the time before you ever heard sudden voices”]
[Ask about the same 18 panic-related symptoms listed above]
[PHOBIA-RELATED PANIC AND VOICES]
Have you ever been afraid to go into a (car, bus, plane, train, subway, elevator, mall, tunnel, bridge, heights, small place, CAT scan or MRI, being alone, crowds)?
[If yes or maybe: Ask about panic symptoms in phobic situations]
Now let’s talk about some symptoms that you might have had at some of those times you were afraid. So, for each symptom just say “YES” or “NO” or “MAYBE.”
[Ask about the same 18 panic-related symptoms listed above]
At what age did you last have sudden anxiety without voices?
Has medication ever completely stopped your voices? Somewhat?
If so, did those other sudden symptoms still happen sometimes?
Thank you for your help, and for answering all of these questions!
Persecutory delusional disorder (social anxiety). Some “schizophrenia” without voices may be misdiagnosis of persecutory (paranoid) delusional disorder (PDD). Therefore, the reported population prevalence (0.02%) may be underestimated. Social anxiety is highly comorbid with “schizophrenia” (15%).16 Case reports and clinical experience suggest that PDD is commonly preceded by social anxiety.17 Some nonpsychotic social anxiety symptoms closely resemble the PDD psychotic ideas of reference (a perception that low social rank attracts critical scrutiny by authorities). Patients with PDD may remain relatively functional, with few negative symptoms, despite pronounced paranoia. Outward manifestation of paranoia may be limited, unless quite intense. The typical age of onset (40 years) is later than that of schizophrenia, and symptoms can last a long time.18
Continue to: Bipolar 1 mania with delusions...
Bipolar I mania with delusions (atypical depression). Atypical depression is the most common depression in bipolar I disorder. Often more pronounced in winter, it may intensify at any time of year. Long ago, hypersomnia, lethargy, inactivity, inoffensiveness, and craving high-calorie food may have been conducive to hibernation.
Bipolar I mania includes delusions of special accomplishments or abilities, energetically focused on a grandiose mission to help everyone. These intense symptoms may be related to reduced frontal lobe modulation. In some milder form, bipolar I mania may once have encouraged hibernation awakening. Indeed, initial bipolar I mania episodes are more common in spring, as is the spring cleaning that helps us prepare for summer.
Recognizing affective trees in a psychotic forest
Though long observed, comorbid affective symptoms have generally been considered a hodgepodge of distress caused by painful psychotic illness. But the affective symptoms precede psychosis onset, can be masked during acute psychosis, and will revert to ordinary form if psychosis abates.11-13
Rather than affective symptoms being a consequence of psychosis, it may well be the other way around. Affective disorders could be important causal and differentiating components of psychotic disorders.11-13 Research and clinical experience suggest that adjunctive treatment of the comorbidities with correct medication can greatly enhance outcome.
Diagnostic approaches
Because interviews of patients with psychosis are often complicated by confusion, irritability, paranoid evasiveness, cognitive impairment, and medication, nuanced diagnosis is difficult. Interviews should explore psychotic syndromes and subtypes that correlate with comorbidity psychoses, including pre-psychotic anxiety and depressive diagnoses that are chronic (though unlike our 4 other diagnoses, melancholic depression is not chronic).
Establishing pre-psychotic diagnosis of chronic syndromes suggests that they are still present, even if they are difficult to assess during psychosis. Re-interview after some improvement allows for a significantly better diagnosis. Just as in nonpsychotic affective disorders, multiple comorbidities are common, and can lead to a mixed psychotic diagnosis and treatment plan.1
Structured interview tools can assist diagnosis. The PaSI (Box 1,15) elicits past, present, and detailed history of DSM panic, and has been validated in a small pilot randomized controlled trial. The PaSI focuses patient attention on paroxysmal onset voices, and then evaluates the presence of concurrent DSM panic symptoms. If voices are mostly psychotic panic, they may well be a proxy for panic. Ultimately, diagnosis of 5 comorbidities and associated psychotic symptoms may allow simpler categorization into 1 (or more) of the 5 psychosis subtypes.
Continue to: Treatment by comorbidity subtype...
Treatment by comorbidity subtype
Treatment of psychosis generally begins with antipsychotics. Nominal psychotherapy (presence of a professionally detached, compassionate clinician) improves compliance and leads to supportive therapy. Cognitive-behavioral therapy and dialectical behavior therapy may help later, with limited interpersonal approaches further on for some patients.
The suggested approaches to pharmacotherapy noted here draw on research and clinical experience.1,14,19-21 All medications used to treat comorbidities noted here are approved or generally accepted for that diagnosis. Estimated doses are similar to those for comorbidities when patients are nonpsychotic, and vary among patients. Doses, dosing schedules, and titration are extremely important for full benefit. Always consider compliance issues, suicidality, possible adverse effects, and potential drug/drug interactions. Although the medications we suggest using to treat the comorbidities may appear to also benefit psychosis, only antipsychotics are approved for psychosis per se.
Delusional depression. Antipsychotic + antidepressant. Tricyclic antidepressants are possibly most effective, but increase the risk of overdose and dangerous falls among fragile patients. Electroconvulsive therapy is sometimes used.
Obsessive-compulsive schizophrenia. Antipsychotic + selective serotonin reuptake inhibitor (SSRI). Consider aripiprazole (
Schizophrenia with voices. Antipsychotic + clonazepam. Concurrent usage may stabilize psychosis more rapidly, and with a lower antipsychotic dose.23 Titrate a fixed dose of clonazepam every 12 hours (avoid as-needed doses), starting low (ie, 0.5 mg) to limit initial drowsiness (which typically diminishes in 3 to 10 days). Titrate to full voice and panic cessation (1 to 2.5 mg every 12 hours).14 Exercise caution about excessive drowsiness, as well as outpatient compliance and abuse. Besides alprazolam, other antipanic medications have little incidental benefit for psychosis.
Persecutory delusional disorder. Antipsychotic + SSRI. Aripiprazole (consider long-acting injectable for compliance) also enhances the benefits of fluoxetine for social anxiety. Long half-life fluoxetine (20 mg/d) improves compliance and near-term outcomes.
Bipolar I mania: mania with delusions. Consider olanzapine for acute phase, then add other antimanic medication (commonly lithium or valproic acid), check blood level, and then taper olanzapine some weeks later. Importantly, lamotrigine is not effective for bipolar I mania. Consider suicide risk, medical conditions, and outpatient compliance. Comorbid panic anxiety is also common in bipolar I mania, often presenting as nonthreatening voices.
Seasonality: Following research that bipolar I mania is more common in spring and summer, studies have shown beneficial clinical augmentation from dark therapy as provided by reduced light exposure, blue-blocking glasses, and exogenous melatonin (a darkness-signaling hormone).24
Bipolar I mania atypical depression (significant current or historical symptoms). SSRI + booster medication. An SSRI (ie, escitalopram, 10 mg/d) is best started several weeks after full bipolar I mania resolution, while also continuing long-term antimanic medication. Booster medications (ie, buspirone 15 mg every 12 hours; lithium 300 mg/d; or trazodone 50 mg every 12 hours) can enhance SSRI benefits. Meta-analysis suggests SSRIs may have limited risk of inducing bipolar I mania.25 Although not yet specifically tested for atypical depression, lamotrigine may be effective, and may be safer still.25 However, lamotrigine requires very gradual dose titration to prevent a potentially dangerous rash, including after periods of outpatient noncompliance.
Seasonality: Atypical depression is often worse in winter (seasonal affective disorder). Light therapy can produce some clinically helpful benefits year-round.
To illustrate this new approach to psychosis diagnosis and treatment, our book
Box 2
Ms. B, a studious 19-year-old, has been very shy since childhood, with few friends. Meeting new people always gave her gradually increasing anxiety, thinking that she would embarrass herself in their eyes. She had that same anxiety, along with sweating and tachycardia, when she couldn’t avoid speaking in front of class. Sometimes, while walking down the street she would think that strangers were casting a disdainful eye on her, though she knew that wasn’t true. Another anxiety started when she was 16. While looking for paper in a small supply closet, she suddenly felt panicky. With a racing heart and short of breath, she desperately fled the closet. These episodes continued, sometimes for no apparent reason, and nearly always unnoticed by others.
At age 17, she began to believe that those strangers on the street were looking down on her with evil intent, and even following her around. She became afraid to walk around town. A few months later, she also started to hear angry and critical voices at sudden moments. Although the paroxysmal voices always coincided with her panicky symptoms, the threatening voices now felt more important to her than the panic itself. Nonpsychotic panics had stopped. Mostly a recluse, she saw less of her family, left her job, and stopped going to the movies.
After a family dinner, she was detached, scared, and quieter than usual. She sought help from her primary care physician, who referred her to a psychiatrist. A thorough history from Ms. B and her family revealed her disturbing fears, as well as her history of social anxiety. Interviewing for panic was prompted by her mother’s recollection of the supply closet story.
In view of Ms. B’s cooperativeness and supportive family, outpatient treatment of her recent-onset psychosis began with aripiprazole, 10 mg/d, and clonazepam, 0.5 mg every 12 hours. Clonazepam was gradually increased until voices (and panic) ceased. She was then able to describe how earlier panics had felt just like voices, but without the voices. The fears of strangers continued. Escitalopram, 20 mg/d, was added for social anxiety (aripiprazole enhances the benefits of selective serotonin reuptake inhibitors).
One month later, her fears of strangers diminished, and she felt more comfortable around people than ever before. On the same medications, and in psychotherapy over the next year, she began to increase her social network while making plans to start college.
Larger studies are needed
Current research supports the concept of a 5-diagnosis classification of psychoses, which may correlate with our comorbid anxiety and depression model. Larger diagnostic and treatment studies would invaluably examine existing research and clinical experience, and potentially encourage more clinically useful diagnoses, specific treatments, and improved outcomes.
Bottom Line
New insights from evolutionary psychopathology, clinical research and observation, psychotogenesis, genetics, and epidemiology suggest that most functional psychoses may fall into 1 of 5 comorbidity-defined subtypes, for which specific treatments can lead to much improved outcomes.
How can we treat psychosis if we don’t know what we are treating? Over the years, attempts at defining psychosis subtypes have met with dead ends. However, recent research supports a new approach that offers a rational classification model organized according to 5 specific comorbid anxiety and depressive disorder diagnoses.
Anxiety and depressive symptoms are not just the result of psychotic despair. They are specific diagnoses, they precede psychosis onset, they help define psychotic syndromes, and they can point to much more effective treatment approaches. Most of the psychotic diagnoses in this schema are already recognized or posited. And, just as patients who do not have psychotic illness can have more than 1 anxiety or depressive disorder, patients with psychosis can present with a mixed picture that reflects more than 1 contributing comorbidity. Research further suggests that each of the 5 psychosis comorbidity diagnoses may involve some similar underlying factors that facilitate the formation of psychosis.
This article describes the basics of 5 psychosis subtypes, and provides initial guidelines to diagnosis, symptomatology, and treatment. Though clinical experience and existing research support the clinical presence and treatment value of this classification model, further verification will require considerably more controlled studies. An eventual validation of this approach could largely supplant ill-defined diagnoses of “schizophrenia” and other functional psychoses.
Recognizing the comorbidities in the context of their corresponding psychoses entails learning new interviewing skills and devoting more time to both initial and subsequent diagnosis and treatment. In our recently published book,1 we provide extensive details on the approach we describe in this article, including case examples, new interview tools to simplify the diagnostic journey, and novel treatment approaches.
Psychosis-proneness underlies functional psychoses
Functional (idiopathic) schizophrenia and psychotic disorders have long been difficult to separate, and many categorizations have been discarded. Despite clinical dissimilarities, today we too often casually lump psychoses together as schizophrenia.2,3 Eugen Bleuler first suggested the existence of a “group of schizophrenias.”4 It is possible that his group encompasses our 5 psychoses from 5 inbuilt emotional instincts,5 each corresponding to a specific anxiety or depressive subtype.
The 5 anxiety and depressive subtypes noted in this article are common, but psychosis is not. Considerable research suggests that certain global “psychotogenic” factors create susceptibility to all psychoses.6,7 While many genetic, neuroanatomical, experiential, and other factors have been reported, the most important may be “hypofrontality” (genetically reduced frontal lobe function, size, or neuronal activity) and dopaminergic hyperfunction (genetically increased dopamine activity).5-7
An evolutionary perspective
One evolutionary theory of psychopathology starts with the subtypes of depression and anxiety. For example, major depressive disorder and generalized anxiety disorder may encompass 5 commonplace and more specific anxiety and depressive subtypes. Consideration of the emotional, cognitive, and functional aspects of those subtypes suggests that they may have once been advantageous for primeval human herds. Those primeval altruistic instincts may have helped survival, reproduction, and preservation of kin group DNA.5
More than any other species, humans can draw upon consciousness and culture to rationally overcome the influences of unconscious instincts. But those instincts can then emerge from the deep, and painfully encourage obedience to their guidance. In nonpsychotic anxiety and depressive disorders, the specific messages are experienced as specific anxiety and depressive symptoms.5 In psychotic disorders, the messages can emerge as unreasoned and frightful fears, perceptions, beliefs, and behaviors. With newer research, clinical observation, and an evolutionary perspective, a novel and counterintuitive approach may improve our ability to help patients.8
Continue to: Five affective comorbidities evolved from primeval altruistic instincts...
Five affective comorbidities evolved from primeval altruistic instincts
Melancholic depression5
Melancholic depression is often triggered by serious illness, group exclusion, pronounced loss, or purposelessness. We hear patients talk painfully about illness, guilt, and death. Indeed, some increased risk of death, especially from infectious disease, may result from hypercortisolemia (documented by the dexamethasone suppression test). Hypercortisolemic death also occurs in salmon after spawning, and in male marsupial mice after mating. The tragic passing of an individual saves scarce resources for the remainder of the herd.
Obsessive-compulsive disorder5
Factor-analytic studies suggest 4 main obsessive-compulsive disorder (OCD) subtypes: cleanliness, hoarding, intrusive thoughts, and organizing. Obsessive-compulsive traits can help maintain a safe and efficient environment in humans and other species, but OCD is dysfunctional.
Panic anxiety5
Panic anxiety is triggered by real, symbolic, or emotional separation from home and family. In toddlers, separation anxiety can reduce the odds of getting lost and hurt.
Social anxiety5
Social anxiety includes fear of self-embarrassment, exposure as a pretender to higher social rank, and thus often a reluctant avoidance of increased social rank. While consciousness and cultural encouragement can overcome that hesitation and thus lead to greater success, social anxiety activation can still cause painful anxiety. The social hierarchies of many species include comparable biological influences, and help preserve group DNA by reducing hierarchical infighting.
Atypical depression and bipolar I mania5
Atypical depression includes increased rejection sensitivity, resulting in inoffensive behavior to avoid social rejection. This reduces risk of isolation from the group, and improves group harmony. Unlike the 4 other syndromes, atypical depression and bipolar I mania may reflect 2 separate seasonal mood phases. Atypical depression (including seasonal affective disorder) often worsens with shortened winter daylight hours, akin to hibernation. Initial bipolar I mania is more common with springtime daylight, with symptoms not unlike exaggerated hibernation awakening.9
Primeval biological altruism has great evolutionary value in many species, and even somewhat in modern humans. But it is quite different from modern rational altruism. Although we sometimes override our instincts, they respond with messages experienced as emotional pain—they still tell us to follow instructions for primeval herd survival. In an earlier book, I (JPK) provide a lengthier description of the evidence for this evolutionary psychopathology theory, including interplay of the 5 instincts with psychotogenic factors.5
Continue to: Five comorbidity psychoses from 5 primeval instincts.....
Five comorbidity psychoses from 5 primeval instincts
The 5 affective comorbidities described above contribute to the presence, subtype, and treatment approaches of 5 corresponding psychoses. Ordinary panic attacks might occur when feeling trapped or separated from home, so people want to flee to safety. Nonhuman species with limited consciousness and language are unlikely to think “time to head for safety.” Instead, instincts encourage flight from danger through internally generated perceptions of threat. Likewise, people with psychosis and panic, without sufficient conscious modulation, may experience sensory perceptions of actual danger when feeling symbolically trapped.1,10
One pilot study carefully examined the prevalence of these 5 comorbidities in an unselected group of psychotic patients.10 At least 85% met criteria for ≥1 of the 5 subtypes.10 Moreover, organic psychoses related to physical illness, substances, and iatrogenesis may also predict future episodes of functional psychoses.1
Using statistical analysis of psychosis rating scales, 2 studies took a “transdiagnostic” look at psychoses, and each found 5 psychosis subtypes and a generalized psychosis susceptibility factor.11,12 Replication of that transdiagnostic approach, newly including psychosis symptoms and our 5 specific comorbidities, might well find that the 5 subtype models resemble each other.11,12
Our proposed 5 comorbidity subtypes are1:
Delusional depression (melancholic depression). Most common in geriatric patients, this psychosis can also occur at younger ages. Prodromal melancholic depression can include guilt and hopelessness, and is acute, rather than the chronic course of our other 4 syndromes. Subsequent delusional depression includes delusions of bodily decay, illness, or death, as well as overwhelming guilt, shame, and remorse. The classic vegetative symptoms of depression continue. In addition to infectious disease issues, high suicide risk makes hospitalization imperative.
Obsessive-compulsive schizophrenia. Just as OCD has an early age of onset, obsessive-compulsive schizophrenia begins earlier than other psychoses. Despite preserved cognition, some nonpsychotic patients with OCD have diminished symptom insight. OCD may be comorbid with schizophrenia in 12% of cases, typically preceding psychosis onset. Obsessive-compulsive schizophrenia symptoms may include highly exaggerated doubt or ambivalence; contamination concerns; eccentric, ritualistic, motor stereotypy, checking, disorganized, and other behaviors; and paranoia.
Schizophrenia with voices (panic anxiety). Classic paranoid schizophrenia with voices appears to be the most similar to a “panic psychosis.” Patients with nonpsychotic panic anxiety have increased paranoid ideation and ideas of reference as measured on the Symptom Checklist-90. Schizophrenia is highly comorbid with panic anxiety, estimated at 45% in the Epidemiologic Catchment Area study.13 These are likely underestimates: cognitive impairment hinders reporting, and psychotic panic is masked as auditory hallucinations. A pilot study of schizophrenia with voices using a carbon dioxide panic induction challenge found that 100% had panic anxiety.14 That study and another found that virtually all participants reported voices concurrent with panic using our Panic and Schizophrenia Interview (PaSI) (Box 1). Panic onset precedes schizophrenia onset, and panic may reappear if antipsychotic medications sufficiently control voices: “voices without the voices,” say some.
Box 1
Let’s talk for a minute about your voices.
[IDENTIFYING PAROXYSMAL MOMENTS OF VOICE ONSET]
Do you hear voices at every single moment, or are they sometimes silent? Think about those times when you are not actually hearing any voices.
Now, there may be reasons why the voices start talking when they do, but let’s leave that aside for now.
So, whenever the voices do begin speaking—and for whatever reason they do—is it all of a sudden, or do they start very softly and then very gradually get louder?
If your voices are nearly always there, then are there times when the voices suddenly come back, get louder, get more insistent, or just get more obvious to you?
[Focus patient on sudden moment of voice onset, intensification, or awareness]
Let’s talk about that sudden moment when the voices begin (or intensify, or become obvious), even if you know the reason why they start.
I’m going to ask you about some symptoms that you might have at that same sudden moment when the voices start (or intensify, or become obvious). If you have any of these symptoms at the other times, they do not count for now.
So, when I ask about each symptom, tell me whether it comes on at the same sudden moments as the voices, and also if it used to come on with the voices in the past.
For each sudden symptom, just say “YES” or “NO” or “SOMETIMES.”
[Begin each query with: “At the same sudden moment that the voices come on”]
- Sudden anxiety, fear, or panic on the inside?
- Sudden anger or rage on the inside? [ANGER QUERY]
- Sudden heart racing? Heart pounding?
- Sudden chest pain? Chest pressure?
- Sudden sweating?
- Sudden trembling or shaking?
- Sudden shortness of breath, or like you can’t catch your breath?
- Sudden choking or a lump in your throat?
- Sudden nausea or queasiness?
- Sudden dizziness, lightheadedness, or faintness?
- Sudden feeling of detachment, sort of like you are in a glass box?
- Sudden fear of losing control? Fear of going crazy?
- Sudden fear afraid of dying? Afraid of having a heart attack?
- Sudden numbness or tingling, especially in your hands or face?
- Sudden feeling of heat, or cold?
- Sudden itching in your teeth? [VALIDITY CHECK]
- Sudden fear that people want to hurt you? [EXCESS FEAR QUERY]
- Sudden voices? [VOICES QUERY]
[PAST & PRODROMAL PANIC HISTORY]
At what age did you first see a therapist or psychiatrist?
At what age were you first hospitalized for an emotional problem?
At what age did you first start hearing voices?
At what age did you first start having strong fears of other people?
Before you ever heard voices, did you ever have any of the other sudden symptoms like the ones we just talked about?
Did those episodes back then feel sort of like your voices or sudden fears do now, except that there were no voices or sudden fears of people back then?
At what age did those sudden anxiety (or panic or rage) episodes begin?
Back then, was there MORE (M) sudden anxiety, or the SAME (S) sudden anxiety, or LESS (L) sudden anxiety than with your sudden voices now?
[PAST & PRODROMAL PANIC SYMPTOMS]
Now let’s talk about some symptoms that you might have had at those same sudden anxiety moments, in the time before you ever heard any voices. So, for each sudden symptom just say “YES” or “NO” or “SOMETIMES.”
[Begin each query with: “At the same moment the sudden anxiety came on—but only during the time before you ever heard sudden voices”]
[Ask about the same 18 panic-related symptoms listed above]
[PHOBIA-RELATED PANIC AND VOICES]
Have you ever been afraid to go into a (car, bus, plane, train, subway, elevator, mall, tunnel, bridge, heights, small place, CAT scan or MRI, being alone, crowds)?
[If yes or maybe: Ask about panic symptoms in phobic situations]
Now let’s talk about some symptoms that you might have had at some of those times you were afraid. So, for each symptom just say “YES” or “NO” or “MAYBE.”
[Ask about the same 18 panic-related symptoms listed above]
At what age did you last have sudden anxiety without voices?
Has medication ever completely stopped your voices? Somewhat?
If so, did those other sudden symptoms still happen sometimes?
Thank you for your help, and for answering all of these questions!
Persecutory delusional disorder (social anxiety). Some “schizophrenia” without voices may be misdiagnosis of persecutory (paranoid) delusional disorder (PDD). Therefore, the reported population prevalence (0.02%) may be underestimated. Social anxiety is highly comorbid with “schizophrenia” (15%).16 Case reports and clinical experience suggest that PDD is commonly preceded by social anxiety.17 Some nonpsychotic social anxiety symptoms closely resemble the PDD psychotic ideas of reference (a perception that low social rank attracts critical scrutiny by authorities). Patients with PDD may remain relatively functional, with few negative symptoms, despite pronounced paranoia. Outward manifestation of paranoia may be limited, unless quite intense. The typical age of onset (40 years) is later than that of schizophrenia, and symptoms can last a long time.18
Continue to: Bipolar 1 mania with delusions...
Bipolar I mania with delusions (atypical depression). Atypical depression is the most common depression in bipolar I disorder. Often more pronounced in winter, it may intensify at any time of year. Long ago, hypersomnia, lethargy, inactivity, inoffensiveness, and craving high-calorie food may have been conducive to hibernation.
Bipolar I mania includes delusions of special accomplishments or abilities, energetically focused on a grandiose mission to help everyone. These intense symptoms may be related to reduced frontal lobe modulation. In some milder form, bipolar I mania may once have encouraged hibernation awakening. Indeed, initial bipolar I mania episodes are more common in spring, as is the spring cleaning that helps us prepare for summer.
Recognizing affective trees in a psychotic forest
Though long observed, comorbid affective symptoms have generally been considered a hodgepodge of distress caused by painful psychotic illness. But the affective symptoms precede psychosis onset, can be masked during acute psychosis, and will revert to ordinary form if psychosis abates.11-13
Rather than affective symptoms being a consequence of psychosis, it may well be the other way around. Affective disorders could be important causal and differentiating components of psychotic disorders.11-13 Research and clinical experience suggest that adjunctive treatment of the comorbidities with correct medication can greatly enhance outcome.
Diagnostic approaches
Because interviews of patients with psychosis are often complicated by confusion, irritability, paranoid evasiveness, cognitive impairment, and medication, nuanced diagnosis is difficult. Interviews should explore psychotic syndromes and subtypes that correlate with comorbidity psychoses, including pre-psychotic anxiety and depressive diagnoses that are chronic (though unlike our 4 other diagnoses, melancholic depression is not chronic).
Establishing pre-psychotic diagnosis of chronic syndromes suggests that they are still present, even if they are difficult to assess during psychosis. Re-interview after some improvement allows for a significantly better diagnosis. Just as in nonpsychotic affective disorders, multiple comorbidities are common, and can lead to a mixed psychotic diagnosis and treatment plan.1
Structured interview tools can assist diagnosis. The PaSI (Box 1,15) elicits past, present, and detailed history of DSM panic, and has been validated in a small pilot randomized controlled trial. The PaSI focuses patient attention on paroxysmal onset voices, and then evaluates the presence of concurrent DSM panic symptoms. If voices are mostly psychotic panic, they may well be a proxy for panic. Ultimately, diagnosis of 5 comorbidities and associated psychotic symptoms may allow simpler categorization into 1 (or more) of the 5 psychosis subtypes.
Continue to: Treatment by comorbidity subtype...
Treatment by comorbidity subtype
Treatment of psychosis generally begins with antipsychotics. Nominal psychotherapy (presence of a professionally detached, compassionate clinician) improves compliance and leads to supportive therapy. Cognitive-behavioral therapy and dialectical behavior therapy may help later, with limited interpersonal approaches further on for some patients.
The suggested approaches to pharmacotherapy noted here draw on research and clinical experience.1,14,19-21 All medications used to treat comorbidities noted here are approved or generally accepted for that diagnosis. Estimated doses are similar to those for comorbidities when patients are nonpsychotic, and vary among patients. Doses, dosing schedules, and titration are extremely important for full benefit. Always consider compliance issues, suicidality, possible adverse effects, and potential drug/drug interactions. Although the medications we suggest using to treat the comorbidities may appear to also benefit psychosis, only antipsychotics are approved for psychosis per se.
Delusional depression. Antipsychotic + antidepressant. Tricyclic antidepressants are possibly most effective, but increase the risk of overdose and dangerous falls among fragile patients. Electroconvulsive therapy is sometimes used.
Obsessive-compulsive schizophrenia. Antipsychotic + selective serotonin reuptake inhibitor (SSRI). Consider aripiprazole (
Schizophrenia with voices. Antipsychotic + clonazepam. Concurrent usage may stabilize psychosis more rapidly, and with a lower antipsychotic dose.23 Titrate a fixed dose of clonazepam every 12 hours (avoid as-needed doses), starting low (ie, 0.5 mg) to limit initial drowsiness (which typically diminishes in 3 to 10 days). Titrate to full voice and panic cessation (1 to 2.5 mg every 12 hours).14 Exercise caution about excessive drowsiness, as well as outpatient compliance and abuse. Besides alprazolam, other antipanic medications have little incidental benefit for psychosis.
Persecutory delusional disorder. Antipsychotic + SSRI. Aripiprazole (consider long-acting injectable for compliance) also enhances the benefits of fluoxetine for social anxiety. Long half-life fluoxetine (20 mg/d) improves compliance and near-term outcomes.
Bipolar I mania: mania with delusions. Consider olanzapine for acute phase, then add other antimanic medication (commonly lithium or valproic acid), check blood level, and then taper olanzapine some weeks later. Importantly, lamotrigine is not effective for bipolar I mania. Consider suicide risk, medical conditions, and outpatient compliance. Comorbid panic anxiety is also common in bipolar I mania, often presenting as nonthreatening voices.
Seasonality: Following research that bipolar I mania is more common in spring and summer, studies have shown beneficial clinical augmentation from dark therapy as provided by reduced light exposure, blue-blocking glasses, and exogenous melatonin (a darkness-signaling hormone).24
Bipolar I mania atypical depression (significant current or historical symptoms). SSRI + booster medication. An SSRI (ie, escitalopram, 10 mg/d) is best started several weeks after full bipolar I mania resolution, while also continuing long-term antimanic medication. Booster medications (ie, buspirone 15 mg every 12 hours; lithium 300 mg/d; or trazodone 50 mg every 12 hours) can enhance SSRI benefits. Meta-analysis suggests SSRIs may have limited risk of inducing bipolar I mania.25 Although not yet specifically tested for atypical depression, lamotrigine may be effective, and may be safer still.25 However, lamotrigine requires very gradual dose titration to prevent a potentially dangerous rash, including after periods of outpatient noncompliance.
Seasonality: Atypical depression is often worse in winter (seasonal affective disorder). Light therapy can produce some clinically helpful benefits year-round.
To illustrate this new approach to psychosis diagnosis and treatment, our book
Box 2
Ms. B, a studious 19-year-old, has been very shy since childhood, with few friends. Meeting new people always gave her gradually increasing anxiety, thinking that she would embarrass herself in their eyes. She had that same anxiety, along with sweating and tachycardia, when she couldn’t avoid speaking in front of class. Sometimes, while walking down the street she would think that strangers were casting a disdainful eye on her, though she knew that wasn’t true. Another anxiety started when she was 16. While looking for paper in a small supply closet, she suddenly felt panicky. With a racing heart and short of breath, she desperately fled the closet. These episodes continued, sometimes for no apparent reason, and nearly always unnoticed by others.
At age 17, she began to believe that those strangers on the street were looking down on her with evil intent, and even following her around. She became afraid to walk around town. A few months later, she also started to hear angry and critical voices at sudden moments. Although the paroxysmal voices always coincided with her panicky symptoms, the threatening voices now felt more important to her than the panic itself. Nonpsychotic panics had stopped. Mostly a recluse, she saw less of her family, left her job, and stopped going to the movies.
After a family dinner, she was detached, scared, and quieter than usual. She sought help from her primary care physician, who referred her to a psychiatrist. A thorough history from Ms. B and her family revealed her disturbing fears, as well as her history of social anxiety. Interviewing for panic was prompted by her mother’s recollection of the supply closet story.
In view of Ms. B’s cooperativeness and supportive family, outpatient treatment of her recent-onset psychosis began with aripiprazole, 10 mg/d, and clonazepam, 0.5 mg every 12 hours. Clonazepam was gradually increased until voices (and panic) ceased. She was then able to describe how earlier panics had felt just like voices, but without the voices. The fears of strangers continued. Escitalopram, 20 mg/d, was added for social anxiety (aripiprazole enhances the benefits of selective serotonin reuptake inhibitors).
One month later, her fears of strangers diminished, and she felt more comfortable around people than ever before. On the same medications, and in psychotherapy over the next year, she began to increase her social network while making plans to start college.
Larger studies are needed
Current research supports the concept of a 5-diagnosis classification of psychoses, which may correlate with our comorbid anxiety and depression model. Larger diagnostic and treatment studies would invaluably examine existing research and clinical experience, and potentially encourage more clinically useful diagnoses, specific treatments, and improved outcomes.
Bottom Line
New insights from evolutionary psychopathology, clinical research and observation, psychotogenesis, genetics, and epidemiology suggest that most functional psychoses may fall into 1 of 5 comorbidity-defined subtypes, for which specific treatments can lead to much improved outcomes.
1. Veras AB, Kahn JP, eds. Psychotic Disorders: Comorbidity Detection Promotes Improved Diagnosis and Treatment. Elsevier; 2021.
2. Gaebel W, Zielasek J. Focus on psychosis. Dialogues Clin Neuroscience. 2015;17(1):9-18.
3. Guloksuz S, Van Os J. The slow death of the concept of schizophrenia and the painful birth of the psychosis spectrum. Psychological Medicine. 2018;48(2):229-244.
4. Bleuler E. Dementia Praecox or the Group of Schizophrenias. International Universities Press; 1950.
5. Kahn JP. Angst: Origins of Depression and Anxiety. Oxford University Press; 2013.
6. Howes OD, McCutcheon R, Owen MJ, et al. The role of genes, stress, and dopamine in the development of schizophrenia. Biol Psychiatry. 2017;81(1):9-20.
7. Mubarik A, Tohid H. Frontal lobe alterations in schizophrenia: a review. Trends Psychiatry Psychother. 2016;38(4):198-206.
8. Murray RM, Bhavsar V, Tripoli G, et al. 30 Years on: How the neurodevelopmental hypothesis of schizophrenia morphed into the developmental risk factor model of psychosis. Schizophr Bull. 2017;43(6):1190-1196.
9. Bauer M, Glenn T, Alda M, et al. Solar insolation in springtime influences age of onset of bipolar I disorder. Acta Psychiatr Scand. 2017;136(6):571-582.
10. Kahn JP, Bombassaro T, Veras AB. Comorbid schizophrenia and panic anxiety: panic psychosis revisited. Psychiatr Ann. 2018;48(12):561-565.
11. Bebbington P, Freeman D. Transdiagnostic extension of delusions: schizophrenia and beyond. Schizophr Bull. 2017;43(2):273-282.
12. Catalan A, Simons CJP, Bustamante S, et al. Data gathering bias: trait vulnerability to psychotic symptoms? PLoS One. 2015;10(7):e0132442. doi:10.1371/journal.pone.0132442
13. Goodwin R, Lyons JS, McNally RJ. Panic attacks in schizophrenia. Schizophr Res. 2002;58(2-3):213-220.
14. Kahn JP, Puertollano MA, Schane MD, et al. Adjunctive alprazolam for schizophrenia with panic anxiety: clinical observation and pathogenetic implications. Am J Psychiatry. 1988;145(6):742-744.
15. Kahn JP. Chapter 4: Paranoid schizophrenia with voices and panic anxiety. In: Veras AB, Kahn JP, eds. Psychotic Disorders: Comorbidity Detection Promotes Improved Diagnosis and Treatment. Elsevier; 2021.
16. Achim AM, Maziade M, Raymond E, et al. How prevalent are anxiety disorders in schizophrenia? A meta-analysis and critical review on a significant association. Schizophr Bull. 2011;37(4):811-821.
17. Veras AB, Souza TG, Ricci TG, et al. Paranoid delusional disorder follows social anxiety disorder in a long-term case series: evolutionary perspective. J Nerv Ment Dis. 2015;203(6):477-479.
18. McIntyre JC, Wickham S, Barr B, et al. Social identity and psychosis: associations and psychological mechanisms. Schizophr Bull. 2018;44(3):681-690.
19. Barbee JG, Mancuso DM, Freed CR. Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia. Am J Psychiatry. 1992;149(4):506-510.
20. Nardi AE, Machado S, Almada LF. Clonazepam for the treatment of panic disorder. Curr Drug Targets. 2013;14(3):353-364.
21. Poyurovsky M. Schizo-Obsessive Disorder. Cambridge University Press; 2013.
22. Reznik I, Sirota P. Obsessive and compulsive symptoms in schizophrenia: a randomized controlled trial with fluvoxamine and neuroleptics. J Clin Psychopharmacol. 2000;20(4):410-416.
23. Bodkin JA. Emerging uses for high-potency benzodiazepines in psychotic disorders. J Clin Psychiatry. 1990;51 Suppl:41-53.
24. Gottlieb JF, Benedetti F, Geoffroy PA, et al. The chronotherapeutic treatment of bipolar disorders: a systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology. Bipolar Disord. 2019;21(8):741-773.
25. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249-1262.
1. Veras AB, Kahn JP, eds. Psychotic Disorders: Comorbidity Detection Promotes Improved Diagnosis and Treatment. Elsevier; 2021.
2. Gaebel W, Zielasek J. Focus on psychosis. Dialogues Clin Neuroscience. 2015;17(1):9-18.
3. Guloksuz S, Van Os J. The slow death of the concept of schizophrenia and the painful birth of the psychosis spectrum. Psychological Medicine. 2018;48(2):229-244.
4. Bleuler E. Dementia Praecox or the Group of Schizophrenias. International Universities Press; 1950.
5. Kahn JP. Angst: Origins of Depression and Anxiety. Oxford University Press; 2013.
6. Howes OD, McCutcheon R, Owen MJ, et al. The role of genes, stress, and dopamine in the development of schizophrenia. Biol Psychiatry. 2017;81(1):9-20.
7. Mubarik A, Tohid H. Frontal lobe alterations in schizophrenia: a review. Trends Psychiatry Psychother. 2016;38(4):198-206.
8. Murray RM, Bhavsar V, Tripoli G, et al. 30 Years on: How the neurodevelopmental hypothesis of schizophrenia morphed into the developmental risk factor model of psychosis. Schizophr Bull. 2017;43(6):1190-1196.
9. Bauer M, Glenn T, Alda M, et al. Solar insolation in springtime influences age of onset of bipolar I disorder. Acta Psychiatr Scand. 2017;136(6):571-582.
10. Kahn JP, Bombassaro T, Veras AB. Comorbid schizophrenia and panic anxiety: panic psychosis revisited. Psychiatr Ann. 2018;48(12):561-565.
11. Bebbington P, Freeman D. Transdiagnostic extension of delusions: schizophrenia and beyond. Schizophr Bull. 2017;43(2):273-282.
12. Catalan A, Simons CJP, Bustamante S, et al. Data gathering bias: trait vulnerability to psychotic symptoms? PLoS One. 2015;10(7):e0132442. doi:10.1371/journal.pone.0132442
13. Goodwin R, Lyons JS, McNally RJ. Panic attacks in schizophrenia. Schizophr Res. 2002;58(2-3):213-220.
14. Kahn JP, Puertollano MA, Schane MD, et al. Adjunctive alprazolam for schizophrenia with panic anxiety: clinical observation and pathogenetic implications. Am J Psychiatry. 1988;145(6):742-744.
15. Kahn JP. Chapter 4: Paranoid schizophrenia with voices and panic anxiety. In: Veras AB, Kahn JP, eds. Psychotic Disorders: Comorbidity Detection Promotes Improved Diagnosis and Treatment. Elsevier; 2021.
16. Achim AM, Maziade M, Raymond E, et al. How prevalent are anxiety disorders in schizophrenia? A meta-analysis and critical review on a significant association. Schizophr Bull. 2011;37(4):811-821.
17. Veras AB, Souza TG, Ricci TG, et al. Paranoid delusional disorder follows social anxiety disorder in a long-term case series: evolutionary perspective. J Nerv Ment Dis. 2015;203(6):477-479.
18. McIntyre JC, Wickham S, Barr B, et al. Social identity and psychosis: associations and psychological mechanisms. Schizophr Bull. 2018;44(3):681-690.
19. Barbee JG, Mancuso DM, Freed CR. Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia. Am J Psychiatry. 1992;149(4):506-510.
20. Nardi AE, Machado S, Almada LF. Clonazepam for the treatment of panic disorder. Curr Drug Targets. 2013;14(3):353-364.
21. Poyurovsky M. Schizo-Obsessive Disorder. Cambridge University Press; 2013.
22. Reznik I, Sirota P. Obsessive and compulsive symptoms in schizophrenia: a randomized controlled trial with fluvoxamine and neuroleptics. J Clin Psychopharmacol. 2000;20(4):410-416.
23. Bodkin JA. Emerging uses for high-potency benzodiazepines in psychotic disorders. J Clin Psychiatry. 1990;51 Suppl:41-53.
24. Gottlieb JF, Benedetti F, Geoffroy PA, et al. The chronotherapeutic treatment of bipolar disorders: a systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology. Bipolar Disord. 2019;21(8):741-773.
25. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249-1262.
Autism spectrum disorder: Keys to early detection and accurate diagnosis
FIRST OF 2 PARTS
Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.6,10-14 In recent years, the prevalence of ASD has been increasing.3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,10 which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.
This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.
Benefits of early detection
Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.2,3,5,6,9,13,14,16-22 Earlier age of intervention correlates with greater developmental gain and symptom reduction.21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.1 This necessitates early recognition of ASD,9,17 and the need for further research to find novel ways to detect ASD earlier.
In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.18 Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.1,17,19 Problems with sleeping and eating may be evident in early childhood.19 Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.6,24
In a prospective study, Anderson et al25 found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.6 Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.25
Continue to: Characteristics of ASD...
Characteristics of ASD
Table 16,8,10,13,15,26-29 outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.
Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.30 More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.13 The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.13 Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.13 Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.13,30
Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.2 Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.27
Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.32 These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.32
A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.33 It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.
Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box1-3,7-9,12,13,30,35-39).
Box
Compared with individuals who do not have autism spectrum disorder (ASD), individuals with ASD exhibit anatomical differences in the brain that can be seen on MRI.9,35 Brain regions affected in ASD include the frontal gyrus, temporal gyrus, cingulate gyrus, postcentral gyrus, precuneus, caudate, and hippocampus.9 Some studies have found anomalous structural neural characteristics in infants, such as in the uncinate fasciculus, that correlated with later joint attention challenges, while others have found aberrations in the corpus callosum(responsible for transfer of procedural learning between the hemispheres, and oculomotor response)and internal capsule (responsible for sensorimotor function, as well as other functions) in children with ASD.12
Widespread white matter anomalies have been noted in ASD.12,35,36 In a 2-year longitudinal study that used diffusion tensor imaging, Li et al35 found that preschool children with ASD experience overgrowth of the uncinate fasciculus, which is one of the brain regions implicated in socioemotional processing, and concluded that this overgrowth correlated with ASD severity.35 Andrews et al37 used diffusion-weighted MRI to examine white matter in 127 preschool children. They found that compared with typically developing children, children with ASD exhibited altered white matter microstructure.37
Research suggests that developing representations of the reward value of social stimuli may be challenging for children with ASD.2 Abrams et al30 used resting-state functional brain MRI to evaluate children with typical development and children with highfunctioning, “verbally fluent” ASD. They found that the children with ASD exhibited lower functional connectivity between voice-specific left hemisphere posterior superior temporal sulcus and areas representing the reward circuitry.30 This study also found that children with ASD had underconnectivity between the right hemisphere posterior superior temporal sulcus (which deals with speech prosody) and areas known for emotion-linked associative learning, the orbitofrontal cortex and amygdala.30 These findings are thought to align with the social motivation theory of ASD.13,30,38
The extent of underconnectivity between these systems was found to determine the severity of communication challenges in high-functioning children with ASD.30 One MRI study observed lower gray matter volume in the voice-selective bilateral superior temporal sulcus in children age approximately 9 to 11 years with ASD.39
Neural systems responsible for facial recognition (particularly the right fusiform gyrus and other brain areas) have been shown to exist or begin “very early in life,” which suggests that impaired face recognition may be an early marker of ASD.2 In addition to problems with visual scanning, preferential attention to (and visual sensitivity to) biological motion is a forerunner for the development of social interactions in infants, specifically in regard to being able to detect and recognize emotion, which is considered vital for attachment.7,8 Impaired biological motion perception has been found in very young children with ASD.7,8 This presents an important avenue/potential biomarker for further research to better understand neurobiologic processes underlying atypical development at an earlier age.3,8
Early neural biomarkers for ASD
Nonlinear EEG values may serve as an early neurobiomarker for detecting ASD in young children.1 Because it is relatively inexpensive and convenient, EEG may be highly useful for detecting ASD.1 A study that compared EEG results of 99 infants who had siblings with ASD and 89 low-risk controls from age 3 months to 36 months found that nonlinear EEG measurements predicted with high accuracy later diagnosis of ASD, and were strongly correlated with later Autism Diagnostic Observation Schedule scores.1
Continue to: A complex differential diagnosis...
A complex differential diagnosis
The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.
Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.28 Still, ASD is often overdiagnosed in children with ID.28 Research suggests phenotypic and genetic overlap between ID and ASD.28 Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.28 In approximately 30% of cases, ASD and ID are comorbid.6 This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.28 When ID is present in ASD, there is a greater degree of social-communication deficits.6 It may be difficult to assess for ASD symptoms in children with severe ID.28 Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.28 It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.28
Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,3 Rett syndrome6), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.18 ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.41 In a systematic review, Moss and Howlin42 recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.6,43 McDuffie et al43 used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.43
Milder manifestations of ASD may be more challenging to diagnose,1 particularly in children age <3 and those with above-average cognition.6 Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.17
ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.6 In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.44
Table 26,10,15,17,31,43 highlights some of the features that can be used to distinguish ASD from other conditions.
Continue to: Screening and diagnosis...
Screening and diagnosis
A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.17 Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.6 A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.6
The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.5,6 Research has shown that this survey has <50% specificity.5A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.6,19
Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al45 used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.5,6,45
Definitive diagnosis of ASD is ideally done by a multidisciplinary team46 using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.47 Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,6 in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.6
ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.47 Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.47 However, in combination, these 2 tools are generally efficacious.47 Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.
A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.48,49
Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.
1. Bosl WJ, Tager-Flusberg H, Nelson CA. EEG analytics for early detection of autism spectrum disorder: a data-driven approach. Sci Rep. 2018;8(1):6828. doi:10.1038/s41598-018-24318-x
2. Dawson G, Carver L, Meltzoff AN, et al. Neural correlates of face and object recognition in young children with autism spectrum disorder, developmental delay, and typical development. Child Dev. 2002;73(3):700-717. doi:10.1111/1467-8624.00433
3. Frye RE, Vassall S, Kaur G, et al. Emerging biomarkers in autism spectrum disorder: a systematic review. Ann Transl Med. 2019;7(23):792. doi:10.21037/atm.2019.11.5
4. Gordon I, Vander Wyk BC, Bennett RH, et al. Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci U S A. 2013;110(52):20953-20958. doi:10.1073/pnas.1312857110
5. Hicks SD, Carpenter RL, Wagner KE, et al. Saliva microRNA differentiates children with autism from peers with typical and atypical development. J Am Acad Child Adolesc Psychiatry. 2020;59(2):296-308.
6. Hyman SL, Levy SE, Myers SM, et al; Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics. 2020;145(1):e20193447. doi:10.1542/peds.2019-3447
7. Kaiser MD, Hudac CM, Shultz S, et al. Neural signatures of autism. Proc Natl Acad Sci U S A. 2010;107(49):21223-1228. doi:10.1073/pnas.1010412107
8. Klin A, Lin DJ, Gorrindo P, et al. Two-year-olds with autism orient to non-social contingencies rather than biological motion. Nature. 2009;459(7244):257-261. doi:10.1038/nature07868
9. Chen T, Chen Y, Yuan M, et al. Towards developing a practical artificial intelligence tool for diagnosing and evaluating autism spectrum disorder: a study using multicenter ABIDE II datasets. JMIR Med Inform. 2020;8(5):e15767. doi:10.2196/15767
10. Maglione MA, Gans D, Das L, et al; Technical Expert Panel, & HRSA Autism Intervention Research – Behavioral (AIR‐B) Network. Nonmedical interventions for children with ASD: recommended guidelines and further research needs. Pediatrics. 2012;30(Suppl 2), S169-S178.
11. Monz BU, Houghton R, Law K, et al. Treatment patterns in children with autism in the United States. Autism Res. 2019;12(3):5170-526. doi:10.1002/aur.2070
12. Shukla DK, Keehn B, Lincoln AJ, et al. White matter compromise of callosal and subcortical fiber tracts in children with autism spectrum disorder: a diffusion tensor imaging study. J Am Acad Child Adolesc Psychiatry. 2010;49(12):1269-1278.e12782. doi:10.1016/j.jaac.2010.08.018
13. Sperdin HF, Schaer M. Aberrant development of speech processing in young children with autism: new insights from neuroimaging biomarkers. Front Neurosci. 2016;10:393. doi: 10.3389/fnins.2016.00393
14. Zwaigenbaum L, Brian JA, Ip A. Early detection for autism spectrum disorder in young children. Paediatr Child Health. 2019;24(7):424-443. doi:10.1093/pch/pxz119
15. Simms MD, Jin XM. Autism, language disorder, and social (pragmatic) communication disorder: DSM-V and differential diagnoses. Pediatr Rev. 2015;36(8):355-363. doi:10.1542/pir.36-8-355
16. Su Maw S, Haga C. Effectiveness of cognitive, developmental, and behavioural interventions for autism spectrum disorder in preschool-aged children: a systematic review and meta-analysis. Heliyon. 2018;4(9):e00763. doi:10.1016/j.heliyon.2018.e00763
17. Volkmar F, Siegel M, Woodbury-Smith M, et al. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry, 2014;53(2):237-257.
18. Landa RJ. Efficacy of early interventions for infants and young children with, and at risk for, autism spectrum disorders. Int Rev Psychiatry. 2018;30(1):25-39. doi:10.1080/09540261.2018.1432574
19. Lipkin PH, Macias MM; Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Promoting optimal development: identifying infants and young children with developmental disorders through developmental surveillance and screening. Pediatrics. 2020;145(1)e20193449. doi:10.1542/peds.2019-3449
20. Pickles A, Le Couteur A, Leadbitter K, et al. Parent-mediated social communication therapy for young children with autism (PACT): long-term follow-up of a randomised controlled trial. Lancet. 2016;388:2501-2509.
21. Rogers SJ, Estes A, Lord C, et al. Effects of a brief early start Denver model (ESDM)-based parent intervention on toddlers at risk for autism spectrum disorders: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2012;51(10):1052-1065. doi:10.1016/j.jaac.2012.08.003
22. Schreibman L, Dawson G, Stahmer AC, et al. Naturalistic developmental behavioral interventions: empirically validated treatments for autism spectrum disorder. J Autism Dev Disord. 2015;45(8):2411-2428. doi:10.1007/s10803-015-2407-8
23. Mundy P. A review of joint attention and social-cognitive brain systems in typical development and autism spectrum disorder. Eur J Neurosci. 2018;47(6):497-514.
24. Zwaigenbaum L, Bryson SE, Brian J, et al. Stability of diagnostic assessment for autism spectrum disorder between 18 and 36 months in a high-risk cohort. Autism Res. 2016;9(7):790-800. doi:10.1002/aur.1585
25. Anderson DK, Liang JW, Lord C. Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. J Child Psychol Psychiatry. 2014;55(5):485-494. doi:10.1111/jcpp.12178
26. Jones W, Carr K, Klin A. Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder. Arch Gen Psychiatry. 2008;65(8):946-954. doi:10.1001/archpsyc.65.8.946
27. Van der Donck S, Dzhelyova M, Vettori S, et al. Rapid neural categorization of angry and fearful faces is specifically impaired in boys with autism spectrum disorder. J Child Psychol Psychiatry. 2020;61(9):1019-1029. doi:10.1111/jcpp.13201
28. Thurm A, Farmer C, Salzman E, et al. State of the field: differentiating intellectual disability from autism spectrum disorder. Front Psychiatry. 2019;10:526. doi:10.3389/fpsyt.2019.00526
29. Kuno-Fujita A, Iwabuchi T, Wakusawa K, et al. Sensory processing patterns and fusiform activity during face processing in autism spectrum disorder. Autism Res. 2020;13(5):741-750. doi: 10.1002/aur.2283
30. Abrams DA, Lynch CJ, Cheng KM, et al. Underconnectivity between voice-selective cortex and reward circuitry in children with autism. Proc Natl Acad Sci U S A. 2013;110(29):12060-12065. doi:10.1073/pnas.1302982110
31. Osterling J, Dawson G. Early recognition of children with autism: a study of first birthday home videotapes. J Autism Dev Disord. 1994;24(3):247-257.
32. Zampella CJ, Csumitta KD, Simon E, et al. Interactional synchrony and its association with social and communication ability in children with and without autism spectrum disorder. J Autism Dev Disord. 2020;50(9):3195-3206. doi:10.1007/s10803-020-04412-8
33. McFayden T, Jarrett MA, White SW, et al. Sluggish cognitive tempo in autism spectrum disorder, ADHD, and their comorbidity: implications for impairment. J Clin Child Adolesc Psychol. 2020:1-8. doi:10.1080/15374416.2020.1716365
34. Baribeau DA, Vigod S, Pullenayegum E, et al. Repetitive behavior severity as an early indicator of risk for elevated anxiety symptoms in autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2020;59(7):890-899.e3. doi:10.1016/j.jaac.2019.08.478
35. Li Y, Zhou Z, Chang C, et al. Anomalies in uncinate fasciculus development and social defects in preschoolers with autism spectrum disorder. BMC Psychiatry. 2019;19(1):399. doi:10.1186/s12888-019-2391-1
36. Payabvash S, Palacios EM, Owen JP, et al. White matter connectome edge density in children with autism spectrum disorders: potential imaging biomarkers using machine-learning models. Brain Connect. 2019;9(2):209-220. doi:10.1089/brain.2018.0658
37. Andrews DS, Lee JK, Solomon M, et al. A diffusion-weighted imaging tract-based spatial statistics study of autism spectrum disorder in preschool-aged children. J Neurodev Disord. 2019;11(1):32. doi:10.1186/s11689-019-9291-z
38. Chevallier C, Kohls G, Troiani V, et al. The social motivation theory of autism. Trends Cogn Sci. 2012;16(4):231-239. doi:10.1016/j.tics.2012.02.007
39. Boddaert N, Chabane N, Gervais H, et al. Superior temporal sulcus anatomical abnormalities in childhood autism: a voxel-based morphometry MRI study. Neuroimage. 2004;23(1):364-369. doi:10.1016/j.neuroimage.2004.06.016
40. Lord C, Petkova E, Hus V, et al. A multisite study of the clinical diagnosis of different autism spectrum disorders. Arch Gen Psychiatry. 2012;69(3):306-313. doi:10.1001/archgenpsychiatry.2011.148
41. Trillingsgaard A, ØStergaard JR. Autism in Angelman syndrome: an exploration of comorbidity. Autism. 2004;8(2):163-174.
42. Moss J, Howlin P. Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population. J Intellect Disabil Res. 2009;53(10):852-873. doi:10.1111/j.1365-2788.2009.01197.x
43. McDuffie A, Thurman AJ, Hagerman RJ, et al. Symptoms of autism in males with Fragile X syndrome: a comparison to nonsyndromic ASD using current ADI-R scores. J Autism Dev Disord. 2015;45(7):1925-1937. doi:10.1007/s10803-013-2013-6
44. Ashwood KL, Tye C, Azadi B, et al. Brief report: adaptive functioning in children with ASD, ADHD and ASD + ADHD. J Autism Dev Disord. 2015;45(7):2235-4222. doi:10.1007/s10803-014-2352-y
45. Guthrie W, Wallis K, Bennett A, et al. Accuracy of autism screening in a large pediatric network. Pediatrics. 2019;144(4): e20183963. doi:10.1542/peds.2018-3963
46. Brian JA, Zwaigenbaum L, Ip A. Standards of diagnostic assessment for autism spectrum disorder. Paediatr Child Health. 2019;24(7):444-460. doi:10.1093/pch/pxz117
47. Frigaux A, Evrard R, Lighezzolo-Alnot J. ADI-R and ADOS and the differential diagnosis of autism spectrum disorders: interests, limits and openings. Encephale. 2019;45(5):441-448. doi:10.1016/j.encep.2019.07.002
48. Sacrey LR, Zwaigenbaum L, Bryson S, et al. Screening for behavioral signs of autism spectrum disorder in 9-month-old infant siblings. J Autism Dev Disord. 2021;51(3):839-848. doi:10.1007/s10803-020-04371-0
49. Sacrey LR, Bryson S, Zwaigenbaum L, et al. The autism parent screen for infants: predicting risk of autism spectrum disorder based on parent-reported behavior observed at 6-24 months of age. Autism. 2018;22(3):322-334
FIRST OF 2 PARTS
Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.6,10-14 In recent years, the prevalence of ASD has been increasing.3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,10 which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.
This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.
Benefits of early detection
Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.2,3,5,6,9,13,14,16-22 Earlier age of intervention correlates with greater developmental gain and symptom reduction.21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.1 This necessitates early recognition of ASD,9,17 and the need for further research to find novel ways to detect ASD earlier.
In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.18 Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.1,17,19 Problems with sleeping and eating may be evident in early childhood.19 Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.6,24
In a prospective study, Anderson et al25 found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.6 Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.25
Continue to: Characteristics of ASD...
Characteristics of ASD
Table 16,8,10,13,15,26-29 outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.
Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.30 More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.13 The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.13 Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.13 Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.13,30
Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.2 Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.27
Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.32 These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.32
A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.33 It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.
Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box1-3,7-9,12,13,30,35-39).
Box
Compared with individuals who do not have autism spectrum disorder (ASD), individuals with ASD exhibit anatomical differences in the brain that can be seen on MRI.9,35 Brain regions affected in ASD include the frontal gyrus, temporal gyrus, cingulate gyrus, postcentral gyrus, precuneus, caudate, and hippocampus.9 Some studies have found anomalous structural neural characteristics in infants, such as in the uncinate fasciculus, that correlated with later joint attention challenges, while others have found aberrations in the corpus callosum(responsible for transfer of procedural learning between the hemispheres, and oculomotor response)and internal capsule (responsible for sensorimotor function, as well as other functions) in children with ASD.12
Widespread white matter anomalies have been noted in ASD.12,35,36 In a 2-year longitudinal study that used diffusion tensor imaging, Li et al35 found that preschool children with ASD experience overgrowth of the uncinate fasciculus, which is one of the brain regions implicated in socioemotional processing, and concluded that this overgrowth correlated with ASD severity.35 Andrews et al37 used diffusion-weighted MRI to examine white matter in 127 preschool children. They found that compared with typically developing children, children with ASD exhibited altered white matter microstructure.37
Research suggests that developing representations of the reward value of social stimuli may be challenging for children with ASD.2 Abrams et al30 used resting-state functional brain MRI to evaluate children with typical development and children with highfunctioning, “verbally fluent” ASD. They found that the children with ASD exhibited lower functional connectivity between voice-specific left hemisphere posterior superior temporal sulcus and areas representing the reward circuitry.30 This study also found that children with ASD had underconnectivity between the right hemisphere posterior superior temporal sulcus (which deals with speech prosody) and areas known for emotion-linked associative learning, the orbitofrontal cortex and amygdala.30 These findings are thought to align with the social motivation theory of ASD.13,30,38
The extent of underconnectivity between these systems was found to determine the severity of communication challenges in high-functioning children with ASD.30 One MRI study observed lower gray matter volume in the voice-selective bilateral superior temporal sulcus in children age approximately 9 to 11 years with ASD.39
Neural systems responsible for facial recognition (particularly the right fusiform gyrus and other brain areas) have been shown to exist or begin “very early in life,” which suggests that impaired face recognition may be an early marker of ASD.2 In addition to problems with visual scanning, preferential attention to (and visual sensitivity to) biological motion is a forerunner for the development of social interactions in infants, specifically in regard to being able to detect and recognize emotion, which is considered vital for attachment.7,8 Impaired biological motion perception has been found in very young children with ASD.7,8 This presents an important avenue/potential biomarker for further research to better understand neurobiologic processes underlying atypical development at an earlier age.3,8
Early neural biomarkers for ASD
Nonlinear EEG values may serve as an early neurobiomarker for detecting ASD in young children.1 Because it is relatively inexpensive and convenient, EEG may be highly useful for detecting ASD.1 A study that compared EEG results of 99 infants who had siblings with ASD and 89 low-risk controls from age 3 months to 36 months found that nonlinear EEG measurements predicted with high accuracy later diagnosis of ASD, and were strongly correlated with later Autism Diagnostic Observation Schedule scores.1
Continue to: A complex differential diagnosis...
A complex differential diagnosis
The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.
Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.28 Still, ASD is often overdiagnosed in children with ID.28 Research suggests phenotypic and genetic overlap between ID and ASD.28 Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.28 In approximately 30% of cases, ASD and ID are comorbid.6 This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.28 When ID is present in ASD, there is a greater degree of social-communication deficits.6 It may be difficult to assess for ASD symptoms in children with severe ID.28 Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.28 It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.28
Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,3 Rett syndrome6), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.18 ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.41 In a systematic review, Moss and Howlin42 recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.6,43 McDuffie et al43 used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.43
Milder manifestations of ASD may be more challenging to diagnose,1 particularly in children age <3 and those with above-average cognition.6 Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.17
ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.6 In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.44
Table 26,10,15,17,31,43 highlights some of the features that can be used to distinguish ASD from other conditions.
Continue to: Screening and diagnosis...
Screening and diagnosis
A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.17 Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.6 A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.6
The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.5,6 Research has shown that this survey has <50% specificity.5A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.6,19
Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al45 used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.5,6,45
Definitive diagnosis of ASD is ideally done by a multidisciplinary team46 using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.47 Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,6 in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.6
ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.47 Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.47 However, in combination, these 2 tools are generally efficacious.47 Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.
A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.48,49
Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.
FIRST OF 2 PARTS
Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.6,10-14 In recent years, the prevalence of ASD has been increasing.3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,10 which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.
This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.
Benefits of early detection
Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.2,3,5,6,9,13,14,16-22 Earlier age of intervention correlates with greater developmental gain and symptom reduction.21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.1 This necessitates early recognition of ASD,9,17 and the need for further research to find novel ways to detect ASD earlier.
In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.18 Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.1,17,19 Problems with sleeping and eating may be evident in early childhood.19 Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.6,24
In a prospective study, Anderson et al25 found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.6 Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.25
Continue to: Characteristics of ASD...
Characteristics of ASD
Table 16,8,10,13,15,26-29 outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.
Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.30 More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.13 The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.13 Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.13 Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.13,30
Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.2 Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.27
Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.32 These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.32
A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.33 It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.
Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box1-3,7-9,12,13,30,35-39).
Box
Compared with individuals who do not have autism spectrum disorder (ASD), individuals with ASD exhibit anatomical differences in the brain that can be seen on MRI.9,35 Brain regions affected in ASD include the frontal gyrus, temporal gyrus, cingulate gyrus, postcentral gyrus, precuneus, caudate, and hippocampus.9 Some studies have found anomalous structural neural characteristics in infants, such as in the uncinate fasciculus, that correlated with later joint attention challenges, while others have found aberrations in the corpus callosum(responsible for transfer of procedural learning between the hemispheres, and oculomotor response)and internal capsule (responsible for sensorimotor function, as well as other functions) in children with ASD.12
Widespread white matter anomalies have been noted in ASD.12,35,36 In a 2-year longitudinal study that used diffusion tensor imaging, Li et al35 found that preschool children with ASD experience overgrowth of the uncinate fasciculus, which is one of the brain regions implicated in socioemotional processing, and concluded that this overgrowth correlated with ASD severity.35 Andrews et al37 used diffusion-weighted MRI to examine white matter in 127 preschool children. They found that compared with typically developing children, children with ASD exhibited altered white matter microstructure.37
Research suggests that developing representations of the reward value of social stimuli may be challenging for children with ASD.2 Abrams et al30 used resting-state functional brain MRI to evaluate children with typical development and children with highfunctioning, “verbally fluent” ASD. They found that the children with ASD exhibited lower functional connectivity between voice-specific left hemisphere posterior superior temporal sulcus and areas representing the reward circuitry.30 This study also found that children with ASD had underconnectivity between the right hemisphere posterior superior temporal sulcus (which deals with speech prosody) and areas known for emotion-linked associative learning, the orbitofrontal cortex and amygdala.30 These findings are thought to align with the social motivation theory of ASD.13,30,38
The extent of underconnectivity between these systems was found to determine the severity of communication challenges in high-functioning children with ASD.30 One MRI study observed lower gray matter volume in the voice-selective bilateral superior temporal sulcus in children age approximately 9 to 11 years with ASD.39
Neural systems responsible for facial recognition (particularly the right fusiform gyrus and other brain areas) have been shown to exist or begin “very early in life,” which suggests that impaired face recognition may be an early marker of ASD.2 In addition to problems with visual scanning, preferential attention to (and visual sensitivity to) biological motion is a forerunner for the development of social interactions in infants, specifically in regard to being able to detect and recognize emotion, which is considered vital for attachment.7,8 Impaired biological motion perception has been found in very young children with ASD.7,8 This presents an important avenue/potential biomarker for further research to better understand neurobiologic processes underlying atypical development at an earlier age.3,8
Early neural biomarkers for ASD
Nonlinear EEG values may serve as an early neurobiomarker for detecting ASD in young children.1 Because it is relatively inexpensive and convenient, EEG may be highly useful for detecting ASD.1 A study that compared EEG results of 99 infants who had siblings with ASD and 89 low-risk controls from age 3 months to 36 months found that nonlinear EEG measurements predicted with high accuracy later diagnosis of ASD, and were strongly correlated with later Autism Diagnostic Observation Schedule scores.1
Continue to: A complex differential diagnosis...
A complex differential diagnosis
The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.
Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.28 Still, ASD is often overdiagnosed in children with ID.28 Research suggests phenotypic and genetic overlap between ID and ASD.28 Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.28 In approximately 30% of cases, ASD and ID are comorbid.6 This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.28 When ID is present in ASD, there is a greater degree of social-communication deficits.6 It may be difficult to assess for ASD symptoms in children with severe ID.28 Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.28 It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.28
Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,3 Rett syndrome6), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.18 ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.41 In a systematic review, Moss and Howlin42 recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.6,43 McDuffie et al43 used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.43
Milder manifestations of ASD may be more challenging to diagnose,1 particularly in children age <3 and those with above-average cognition.6 Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.17
ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.6 In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.44
Table 26,10,15,17,31,43 highlights some of the features that can be used to distinguish ASD from other conditions.
Continue to: Screening and diagnosis...
Screening and diagnosis
A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.17 Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.6 A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.6
The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.5,6 Research has shown that this survey has <50% specificity.5A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.6,19
Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al45 used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.5,6,45
Definitive diagnosis of ASD is ideally done by a multidisciplinary team46 using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.47 Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,6 in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.6
ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.47 Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.47 However, in combination, these 2 tools are generally efficacious.47 Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.
A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.48,49
Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.
1. Bosl WJ, Tager-Flusberg H, Nelson CA. EEG analytics for early detection of autism spectrum disorder: a data-driven approach. Sci Rep. 2018;8(1):6828. doi:10.1038/s41598-018-24318-x
2. Dawson G, Carver L, Meltzoff AN, et al. Neural correlates of face and object recognition in young children with autism spectrum disorder, developmental delay, and typical development. Child Dev. 2002;73(3):700-717. doi:10.1111/1467-8624.00433
3. Frye RE, Vassall S, Kaur G, et al. Emerging biomarkers in autism spectrum disorder: a systematic review. Ann Transl Med. 2019;7(23):792. doi:10.21037/atm.2019.11.5
4. Gordon I, Vander Wyk BC, Bennett RH, et al. Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci U S A. 2013;110(52):20953-20958. doi:10.1073/pnas.1312857110
5. Hicks SD, Carpenter RL, Wagner KE, et al. Saliva microRNA differentiates children with autism from peers with typical and atypical development. J Am Acad Child Adolesc Psychiatry. 2020;59(2):296-308.
6. Hyman SL, Levy SE, Myers SM, et al; Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics. 2020;145(1):e20193447. doi:10.1542/peds.2019-3447
7. Kaiser MD, Hudac CM, Shultz S, et al. Neural signatures of autism. Proc Natl Acad Sci U S A. 2010;107(49):21223-1228. doi:10.1073/pnas.1010412107
8. Klin A, Lin DJ, Gorrindo P, et al. Two-year-olds with autism orient to non-social contingencies rather than biological motion. Nature. 2009;459(7244):257-261. doi:10.1038/nature07868
9. Chen T, Chen Y, Yuan M, et al. Towards developing a practical artificial intelligence tool for diagnosing and evaluating autism spectrum disorder: a study using multicenter ABIDE II datasets. JMIR Med Inform. 2020;8(5):e15767. doi:10.2196/15767
10. Maglione MA, Gans D, Das L, et al; Technical Expert Panel, & HRSA Autism Intervention Research – Behavioral (AIR‐B) Network. Nonmedical interventions for children with ASD: recommended guidelines and further research needs. Pediatrics. 2012;30(Suppl 2), S169-S178.
11. Monz BU, Houghton R, Law K, et al. Treatment patterns in children with autism in the United States. Autism Res. 2019;12(3):5170-526. doi:10.1002/aur.2070
12. Shukla DK, Keehn B, Lincoln AJ, et al. White matter compromise of callosal and subcortical fiber tracts in children with autism spectrum disorder: a diffusion tensor imaging study. J Am Acad Child Adolesc Psychiatry. 2010;49(12):1269-1278.e12782. doi:10.1016/j.jaac.2010.08.018
13. Sperdin HF, Schaer M. Aberrant development of speech processing in young children with autism: new insights from neuroimaging biomarkers. Front Neurosci. 2016;10:393. doi: 10.3389/fnins.2016.00393
14. Zwaigenbaum L, Brian JA, Ip A. Early detection for autism spectrum disorder in young children. Paediatr Child Health. 2019;24(7):424-443. doi:10.1093/pch/pxz119
15. Simms MD, Jin XM. Autism, language disorder, and social (pragmatic) communication disorder: DSM-V and differential diagnoses. Pediatr Rev. 2015;36(8):355-363. doi:10.1542/pir.36-8-355
16. Su Maw S, Haga C. Effectiveness of cognitive, developmental, and behavioural interventions for autism spectrum disorder in preschool-aged children: a systematic review and meta-analysis. Heliyon. 2018;4(9):e00763. doi:10.1016/j.heliyon.2018.e00763
17. Volkmar F, Siegel M, Woodbury-Smith M, et al. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry, 2014;53(2):237-257.
18. Landa RJ. Efficacy of early interventions for infants and young children with, and at risk for, autism spectrum disorders. Int Rev Psychiatry. 2018;30(1):25-39. doi:10.1080/09540261.2018.1432574
19. Lipkin PH, Macias MM; Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Promoting optimal development: identifying infants and young children with developmental disorders through developmental surveillance and screening. Pediatrics. 2020;145(1)e20193449. doi:10.1542/peds.2019-3449
20. Pickles A, Le Couteur A, Leadbitter K, et al. Parent-mediated social communication therapy for young children with autism (PACT): long-term follow-up of a randomised controlled trial. Lancet. 2016;388:2501-2509.
21. Rogers SJ, Estes A, Lord C, et al. Effects of a brief early start Denver model (ESDM)-based parent intervention on toddlers at risk for autism spectrum disorders: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2012;51(10):1052-1065. doi:10.1016/j.jaac.2012.08.003
22. Schreibman L, Dawson G, Stahmer AC, et al. Naturalistic developmental behavioral interventions: empirically validated treatments for autism spectrum disorder. J Autism Dev Disord. 2015;45(8):2411-2428. doi:10.1007/s10803-015-2407-8
23. Mundy P. A review of joint attention and social-cognitive brain systems in typical development and autism spectrum disorder. Eur J Neurosci. 2018;47(6):497-514.
24. Zwaigenbaum L, Bryson SE, Brian J, et al. Stability of diagnostic assessment for autism spectrum disorder between 18 and 36 months in a high-risk cohort. Autism Res. 2016;9(7):790-800. doi:10.1002/aur.1585
25. Anderson DK, Liang JW, Lord C. Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. J Child Psychol Psychiatry. 2014;55(5):485-494. doi:10.1111/jcpp.12178
26. Jones W, Carr K, Klin A. Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder. Arch Gen Psychiatry. 2008;65(8):946-954. doi:10.1001/archpsyc.65.8.946
27. Van der Donck S, Dzhelyova M, Vettori S, et al. Rapid neural categorization of angry and fearful faces is specifically impaired in boys with autism spectrum disorder. J Child Psychol Psychiatry. 2020;61(9):1019-1029. doi:10.1111/jcpp.13201
28. Thurm A, Farmer C, Salzman E, et al. State of the field: differentiating intellectual disability from autism spectrum disorder. Front Psychiatry. 2019;10:526. doi:10.3389/fpsyt.2019.00526
29. Kuno-Fujita A, Iwabuchi T, Wakusawa K, et al. Sensory processing patterns and fusiform activity during face processing in autism spectrum disorder. Autism Res. 2020;13(5):741-750. doi: 10.1002/aur.2283
30. Abrams DA, Lynch CJ, Cheng KM, et al. Underconnectivity between voice-selective cortex and reward circuitry in children with autism. Proc Natl Acad Sci U S A. 2013;110(29):12060-12065. doi:10.1073/pnas.1302982110
31. Osterling J, Dawson G. Early recognition of children with autism: a study of first birthday home videotapes. J Autism Dev Disord. 1994;24(3):247-257.
32. Zampella CJ, Csumitta KD, Simon E, et al. Interactional synchrony and its association with social and communication ability in children with and without autism spectrum disorder. J Autism Dev Disord. 2020;50(9):3195-3206. doi:10.1007/s10803-020-04412-8
33. McFayden T, Jarrett MA, White SW, et al. Sluggish cognitive tempo in autism spectrum disorder, ADHD, and their comorbidity: implications for impairment. J Clin Child Adolesc Psychol. 2020:1-8. doi:10.1080/15374416.2020.1716365
34. Baribeau DA, Vigod S, Pullenayegum E, et al. Repetitive behavior severity as an early indicator of risk for elevated anxiety symptoms in autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2020;59(7):890-899.e3. doi:10.1016/j.jaac.2019.08.478
35. Li Y, Zhou Z, Chang C, et al. Anomalies in uncinate fasciculus development and social defects in preschoolers with autism spectrum disorder. BMC Psychiatry. 2019;19(1):399. doi:10.1186/s12888-019-2391-1
36. Payabvash S, Palacios EM, Owen JP, et al. White matter connectome edge density in children with autism spectrum disorders: potential imaging biomarkers using machine-learning models. Brain Connect. 2019;9(2):209-220. doi:10.1089/brain.2018.0658
37. Andrews DS, Lee JK, Solomon M, et al. A diffusion-weighted imaging tract-based spatial statistics study of autism spectrum disorder in preschool-aged children. J Neurodev Disord. 2019;11(1):32. doi:10.1186/s11689-019-9291-z
38. Chevallier C, Kohls G, Troiani V, et al. The social motivation theory of autism. Trends Cogn Sci. 2012;16(4):231-239. doi:10.1016/j.tics.2012.02.007
39. Boddaert N, Chabane N, Gervais H, et al. Superior temporal sulcus anatomical abnormalities in childhood autism: a voxel-based morphometry MRI study. Neuroimage. 2004;23(1):364-369. doi:10.1016/j.neuroimage.2004.06.016
40. Lord C, Petkova E, Hus V, et al. A multisite study of the clinical diagnosis of different autism spectrum disorders. Arch Gen Psychiatry. 2012;69(3):306-313. doi:10.1001/archgenpsychiatry.2011.148
41. Trillingsgaard A, ØStergaard JR. Autism in Angelman syndrome: an exploration of comorbidity. Autism. 2004;8(2):163-174.
42. Moss J, Howlin P. Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population. J Intellect Disabil Res. 2009;53(10):852-873. doi:10.1111/j.1365-2788.2009.01197.x
43. McDuffie A, Thurman AJ, Hagerman RJ, et al. Symptoms of autism in males with Fragile X syndrome: a comparison to nonsyndromic ASD using current ADI-R scores. J Autism Dev Disord. 2015;45(7):1925-1937. doi:10.1007/s10803-013-2013-6
44. Ashwood KL, Tye C, Azadi B, et al. Brief report: adaptive functioning in children with ASD, ADHD and ASD + ADHD. J Autism Dev Disord. 2015;45(7):2235-4222. doi:10.1007/s10803-014-2352-y
45. Guthrie W, Wallis K, Bennett A, et al. Accuracy of autism screening in a large pediatric network. Pediatrics. 2019;144(4): e20183963. doi:10.1542/peds.2018-3963
46. Brian JA, Zwaigenbaum L, Ip A. Standards of diagnostic assessment for autism spectrum disorder. Paediatr Child Health. 2019;24(7):444-460. doi:10.1093/pch/pxz117
47. Frigaux A, Evrard R, Lighezzolo-Alnot J. ADI-R and ADOS and the differential diagnosis of autism spectrum disorders: interests, limits and openings. Encephale. 2019;45(5):441-448. doi:10.1016/j.encep.2019.07.002
48. Sacrey LR, Zwaigenbaum L, Bryson S, et al. Screening for behavioral signs of autism spectrum disorder in 9-month-old infant siblings. J Autism Dev Disord. 2021;51(3):839-848. doi:10.1007/s10803-020-04371-0
49. Sacrey LR, Bryson S, Zwaigenbaum L, et al. The autism parent screen for infants: predicting risk of autism spectrum disorder based on parent-reported behavior observed at 6-24 months of age. Autism. 2018;22(3):322-334
1. Bosl WJ, Tager-Flusberg H, Nelson CA. EEG analytics for early detection of autism spectrum disorder: a data-driven approach. Sci Rep. 2018;8(1):6828. doi:10.1038/s41598-018-24318-x
2. Dawson G, Carver L, Meltzoff AN, et al. Neural correlates of face and object recognition in young children with autism spectrum disorder, developmental delay, and typical development. Child Dev. 2002;73(3):700-717. doi:10.1111/1467-8624.00433
3. Frye RE, Vassall S, Kaur G, et al. Emerging biomarkers in autism spectrum disorder: a systematic review. Ann Transl Med. 2019;7(23):792. doi:10.21037/atm.2019.11.5
4. Gordon I, Vander Wyk BC, Bennett RH, et al. Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci U S A. 2013;110(52):20953-20958. doi:10.1073/pnas.1312857110
5. Hicks SD, Carpenter RL, Wagner KE, et al. Saliva microRNA differentiates children with autism from peers with typical and atypical development. J Am Acad Child Adolesc Psychiatry. 2020;59(2):296-308.
6. Hyman SL, Levy SE, Myers SM, et al; Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics. 2020;145(1):e20193447. doi:10.1542/peds.2019-3447
7. Kaiser MD, Hudac CM, Shultz S, et al. Neural signatures of autism. Proc Natl Acad Sci U S A. 2010;107(49):21223-1228. doi:10.1073/pnas.1010412107
8. Klin A, Lin DJ, Gorrindo P, et al. Two-year-olds with autism orient to non-social contingencies rather than biological motion. Nature. 2009;459(7244):257-261. doi:10.1038/nature07868
9. Chen T, Chen Y, Yuan M, et al. Towards developing a practical artificial intelligence tool for diagnosing and evaluating autism spectrum disorder: a study using multicenter ABIDE II datasets. JMIR Med Inform. 2020;8(5):e15767. doi:10.2196/15767
10. Maglione MA, Gans D, Das L, et al; Technical Expert Panel, & HRSA Autism Intervention Research – Behavioral (AIR‐B) Network. Nonmedical interventions for children with ASD: recommended guidelines and further research needs. Pediatrics. 2012;30(Suppl 2), S169-S178.
11. Monz BU, Houghton R, Law K, et al. Treatment patterns in children with autism in the United States. Autism Res. 2019;12(3):5170-526. doi:10.1002/aur.2070
12. Shukla DK, Keehn B, Lincoln AJ, et al. White matter compromise of callosal and subcortical fiber tracts in children with autism spectrum disorder: a diffusion tensor imaging study. J Am Acad Child Adolesc Psychiatry. 2010;49(12):1269-1278.e12782. doi:10.1016/j.jaac.2010.08.018
13. Sperdin HF, Schaer M. Aberrant development of speech processing in young children with autism: new insights from neuroimaging biomarkers. Front Neurosci. 2016;10:393. doi: 10.3389/fnins.2016.00393
14. Zwaigenbaum L, Brian JA, Ip A. Early detection for autism spectrum disorder in young children. Paediatr Child Health. 2019;24(7):424-443. doi:10.1093/pch/pxz119
15. Simms MD, Jin XM. Autism, language disorder, and social (pragmatic) communication disorder: DSM-V and differential diagnoses. Pediatr Rev. 2015;36(8):355-363. doi:10.1542/pir.36-8-355
16. Su Maw S, Haga C. Effectiveness of cognitive, developmental, and behavioural interventions for autism spectrum disorder in preschool-aged children: a systematic review and meta-analysis. Heliyon. 2018;4(9):e00763. doi:10.1016/j.heliyon.2018.e00763
17. Volkmar F, Siegel M, Woodbury-Smith M, et al. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry, 2014;53(2):237-257.
18. Landa RJ. Efficacy of early interventions for infants and young children with, and at risk for, autism spectrum disorders. Int Rev Psychiatry. 2018;30(1):25-39. doi:10.1080/09540261.2018.1432574
19. Lipkin PH, Macias MM; Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Promoting optimal development: identifying infants and young children with developmental disorders through developmental surveillance and screening. Pediatrics. 2020;145(1)e20193449. doi:10.1542/peds.2019-3449
20. Pickles A, Le Couteur A, Leadbitter K, et al. Parent-mediated social communication therapy for young children with autism (PACT): long-term follow-up of a randomised controlled trial. Lancet. 2016;388:2501-2509.
21. Rogers SJ, Estes A, Lord C, et al. Effects of a brief early start Denver model (ESDM)-based parent intervention on toddlers at risk for autism spectrum disorders: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2012;51(10):1052-1065. doi:10.1016/j.jaac.2012.08.003
22. Schreibman L, Dawson G, Stahmer AC, et al. Naturalistic developmental behavioral interventions: empirically validated treatments for autism spectrum disorder. J Autism Dev Disord. 2015;45(8):2411-2428. doi:10.1007/s10803-015-2407-8
23. Mundy P. A review of joint attention and social-cognitive brain systems in typical development and autism spectrum disorder. Eur J Neurosci. 2018;47(6):497-514.
24. Zwaigenbaum L, Bryson SE, Brian J, et al. Stability of diagnostic assessment for autism spectrum disorder between 18 and 36 months in a high-risk cohort. Autism Res. 2016;9(7):790-800. doi:10.1002/aur.1585
25. Anderson DK, Liang JW, Lord C. Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. J Child Psychol Psychiatry. 2014;55(5):485-494. doi:10.1111/jcpp.12178
26. Jones W, Carr K, Klin A. Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder. Arch Gen Psychiatry. 2008;65(8):946-954. doi:10.1001/archpsyc.65.8.946
27. Van der Donck S, Dzhelyova M, Vettori S, et al. Rapid neural categorization of angry and fearful faces is specifically impaired in boys with autism spectrum disorder. J Child Psychol Psychiatry. 2020;61(9):1019-1029. doi:10.1111/jcpp.13201
28. Thurm A, Farmer C, Salzman E, et al. State of the field: differentiating intellectual disability from autism spectrum disorder. Front Psychiatry. 2019;10:526. doi:10.3389/fpsyt.2019.00526
29. Kuno-Fujita A, Iwabuchi T, Wakusawa K, et al. Sensory processing patterns and fusiform activity during face processing in autism spectrum disorder. Autism Res. 2020;13(5):741-750. doi: 10.1002/aur.2283
30. Abrams DA, Lynch CJ, Cheng KM, et al. Underconnectivity between voice-selective cortex and reward circuitry in children with autism. Proc Natl Acad Sci U S A. 2013;110(29):12060-12065. doi:10.1073/pnas.1302982110
31. Osterling J, Dawson G. Early recognition of children with autism: a study of first birthday home videotapes. J Autism Dev Disord. 1994;24(3):247-257.
32. Zampella CJ, Csumitta KD, Simon E, et al. Interactional synchrony and its association with social and communication ability in children with and without autism spectrum disorder. J Autism Dev Disord. 2020;50(9):3195-3206. doi:10.1007/s10803-020-04412-8
33. McFayden T, Jarrett MA, White SW, et al. Sluggish cognitive tempo in autism spectrum disorder, ADHD, and their comorbidity: implications for impairment. J Clin Child Adolesc Psychol. 2020:1-8. doi:10.1080/15374416.2020.1716365
34. Baribeau DA, Vigod S, Pullenayegum E, et al. Repetitive behavior severity as an early indicator of risk for elevated anxiety symptoms in autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2020;59(7):890-899.e3. doi:10.1016/j.jaac.2019.08.478
35. Li Y, Zhou Z, Chang C, et al. Anomalies in uncinate fasciculus development and social defects in preschoolers with autism spectrum disorder. BMC Psychiatry. 2019;19(1):399. doi:10.1186/s12888-019-2391-1
36. Payabvash S, Palacios EM, Owen JP, et al. White matter connectome edge density in children with autism spectrum disorders: potential imaging biomarkers using machine-learning models. Brain Connect. 2019;9(2):209-220. doi:10.1089/brain.2018.0658
37. Andrews DS, Lee JK, Solomon M, et al. A diffusion-weighted imaging tract-based spatial statistics study of autism spectrum disorder in preschool-aged children. J Neurodev Disord. 2019;11(1):32. doi:10.1186/s11689-019-9291-z
38. Chevallier C, Kohls G, Troiani V, et al. The social motivation theory of autism. Trends Cogn Sci. 2012;16(4):231-239. doi:10.1016/j.tics.2012.02.007
39. Boddaert N, Chabane N, Gervais H, et al. Superior temporal sulcus anatomical abnormalities in childhood autism: a voxel-based morphometry MRI study. Neuroimage. 2004;23(1):364-369. doi:10.1016/j.neuroimage.2004.06.016
40. Lord C, Petkova E, Hus V, et al. A multisite study of the clinical diagnosis of different autism spectrum disorders. Arch Gen Psychiatry. 2012;69(3):306-313. doi:10.1001/archgenpsychiatry.2011.148
41. Trillingsgaard A, ØStergaard JR. Autism in Angelman syndrome: an exploration of comorbidity. Autism. 2004;8(2):163-174.
42. Moss J, Howlin P. Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population. J Intellect Disabil Res. 2009;53(10):852-873. doi:10.1111/j.1365-2788.2009.01197.x
43. McDuffie A, Thurman AJ, Hagerman RJ, et al. Symptoms of autism in males with Fragile X syndrome: a comparison to nonsyndromic ASD using current ADI-R scores. J Autism Dev Disord. 2015;45(7):1925-1937. doi:10.1007/s10803-013-2013-6
44. Ashwood KL, Tye C, Azadi B, et al. Brief report: adaptive functioning in children with ASD, ADHD and ASD + ADHD. J Autism Dev Disord. 2015;45(7):2235-4222. doi:10.1007/s10803-014-2352-y
45. Guthrie W, Wallis K, Bennett A, et al. Accuracy of autism screening in a large pediatric network. Pediatrics. 2019;144(4): e20183963. doi:10.1542/peds.2018-3963
46. Brian JA, Zwaigenbaum L, Ip A. Standards of diagnostic assessment for autism spectrum disorder. Paediatr Child Health. 2019;24(7):444-460. doi:10.1093/pch/pxz117
47. Frigaux A, Evrard R, Lighezzolo-Alnot J. ADI-R and ADOS and the differential diagnosis of autism spectrum disorders: interests, limits and openings. Encephale. 2019;45(5):441-448. doi:10.1016/j.encep.2019.07.002
48. Sacrey LR, Zwaigenbaum L, Bryson S, et al. Screening for behavioral signs of autism spectrum disorder in 9-month-old infant siblings. J Autism Dev Disord. 2021;51(3):839-848. doi:10.1007/s10803-020-04371-0
49. Sacrey LR, Bryson S, Zwaigenbaum L, et al. The autism parent screen for infants: predicting risk of autism spectrum disorder based on parent-reported behavior observed at 6-24 months of age. Autism. 2018;22(3):322-334