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New PDT therapy for CTCL to be reviewed by FDA
based on phase 3 findings published in JAMA Dermatology.
The treatment employs an ointment formulation of synthetic hypericin (HyBryte), a photosensitizer, that is preferentially absorbed into malignant cells and activated with visible light – rather than ultraviolet light – approximately 24 hours later. Investigators saw significant clinical responses in both patch and plaque type lesions and across races during the 24-week placebo-controlled, double-blinded, phase 3, randomized clinical trial.
“Traditional phototherapy, ultraviolet B phototherapy, has a limited depth of penetration, so patients with thicker plaque lesions don’t respond as well ... and UVB phototherapy typically is less effective in penetrating pigmented skin,” Ellen J. Kim, MD, lead author of the FLASH phase 3 trial, said in an interview.
Visible light in the yellow-red spectrum (500-650 nm) “penetrates deeper into the skin” and is nonmutagenic in vitro, so “theoretically it should have a much more favorable long-term safety profile,” said Dr. Kim, a dermatologist at the University of Pennsylvania, Philadelphia.
Currently, she said, the risk of secondary malignancies inherent with UV PDT, including melanoma, is a deterrent for some patients, especially “patients with really fair skin and a history of skin cancer.”
Hypericin PDT also seems well suited for use with an at-home light unit. “In our field, it’s not about which therapy is [universally] better or best, but a matter of what works best for each patient at that moment in time, depending on the side-effect profile and other issues such as access,” Dr. Kim said. “It will be great to have another option for an incurable disease that requires chronic management.”
Mycosis fungoides (MF)/CTCL is considered an orphan disease, and the treatment has received orphan drug and fast track designations from the FDA, and orphan designation from the European Medicines Agency, according to a press release from its developer, Soligenix. The company is anticipating potential approval in the second half of 2023 and is targeting early 2024 for a U.S. launch, the statement said.
Phase 3 results
The pivotal trial involved 169 patients at 39 academic and community-based U.S. medical centers and consisted of several 6-week cycles of twice-weekly treatment punctuated by 2-week breaks. In cycle 1, patients were randomized 2:1 to receive hypericin or placebo treatment of three index lesions. Cycle 2 involved the crossover of placebo patients to active treatment of index lesions, and cycle 3 (optional) involved open-label treatment of all desired lesions (index and nonindex).
The trial defined the primary endpoint in phase 1 as 50% or greater improvement in the modified Composite Assessment of Index Lesion Severity score – a tool that’s endorsed by U.S. and international MF/CTCL specialty group consensus guidelines. For cycles 2 and 3, open-label response rates were secondary endpoints. Responses were assessed after 2-week rest periods to allow for treatment-induced skin reactions to subside.
After one cycle of treatment, topical hypericin PDT was more effective than placebo (an index lesion response rate of 16% vs. 4%; P =.04). The index lesion response rate with treatment increased to 40% after two cycles and 49% after three cycles. All were statistically significant changes.
Response rates were similar in patch and plaque-type lesions and regardless of age, sex, race, stage IA versus IB, time since diagnosis, and number of prior therapies. Adverse events were primarily mild application-site skin reactions. No serious drug-related adverse events occurred, Dr. Kim said, and “we had a low drop-out rate overall.”
Into the real world
The 24-week phase 3 trial duration is short, considering that “typically, phototherapy takes between 4 to 24 months [to achieve] full responses in CTCL,” Dr. Kim said in the interview.
So with real-world application, she said, “we’ll want to see where the overall response peaks with longer treatment, what the effects are of continuous treatment without any built-in breaks, and whether we will indeed see less skin cancer development in patients who are at higher risk of developing skin cancers from light treatment.”
Such questions will be explored as part of a new 4-year, 50-patient, open-label, multicenter study with the primary aim of investigating home-based hypericin PDT therapy in a supervised setting, said Dr. Kim, principal investigator of this study. Patients who are doing well after 6 weeks of twice-weekly therapy will be given at-home light units to continue therapy and achieve 1 year of treatment with no breaks. They will be monitored with video-based telemedicine.
“Long term, having a home unit should really improve patient access and compliance and hopefully effectiveness,” Dr. Kim said. Based on the phase 3 experience, “we think that continuous treatment will be well tolerated and that we may see greater responses.”
On Dec. 19, Soligenix announced that enrollment had begun in a phase 2a study of synthetic hypericin for treating patients with mild to moderate psoriasis.
Dr. Kim reported to JAMA Dermatology grants from Innate Pharma and Galderma; consulting/advisory fees from Almirall, Galderma, and Helsinn; and honoraria from Ology and UptoDate.
based on phase 3 findings published in JAMA Dermatology.
The treatment employs an ointment formulation of synthetic hypericin (HyBryte), a photosensitizer, that is preferentially absorbed into malignant cells and activated with visible light – rather than ultraviolet light – approximately 24 hours later. Investigators saw significant clinical responses in both patch and plaque type lesions and across races during the 24-week placebo-controlled, double-blinded, phase 3, randomized clinical trial.
“Traditional phototherapy, ultraviolet B phototherapy, has a limited depth of penetration, so patients with thicker plaque lesions don’t respond as well ... and UVB phototherapy typically is less effective in penetrating pigmented skin,” Ellen J. Kim, MD, lead author of the FLASH phase 3 trial, said in an interview.
Visible light in the yellow-red spectrum (500-650 nm) “penetrates deeper into the skin” and is nonmutagenic in vitro, so “theoretically it should have a much more favorable long-term safety profile,” said Dr. Kim, a dermatologist at the University of Pennsylvania, Philadelphia.
Currently, she said, the risk of secondary malignancies inherent with UV PDT, including melanoma, is a deterrent for some patients, especially “patients with really fair skin and a history of skin cancer.”
Hypericin PDT also seems well suited for use with an at-home light unit. “In our field, it’s not about which therapy is [universally] better or best, but a matter of what works best for each patient at that moment in time, depending on the side-effect profile and other issues such as access,” Dr. Kim said. “It will be great to have another option for an incurable disease that requires chronic management.”
Mycosis fungoides (MF)/CTCL is considered an orphan disease, and the treatment has received orphan drug and fast track designations from the FDA, and orphan designation from the European Medicines Agency, according to a press release from its developer, Soligenix. The company is anticipating potential approval in the second half of 2023 and is targeting early 2024 for a U.S. launch, the statement said.
Phase 3 results
The pivotal trial involved 169 patients at 39 academic and community-based U.S. medical centers and consisted of several 6-week cycles of twice-weekly treatment punctuated by 2-week breaks. In cycle 1, patients were randomized 2:1 to receive hypericin or placebo treatment of three index lesions. Cycle 2 involved the crossover of placebo patients to active treatment of index lesions, and cycle 3 (optional) involved open-label treatment of all desired lesions (index and nonindex).
The trial defined the primary endpoint in phase 1 as 50% or greater improvement in the modified Composite Assessment of Index Lesion Severity score – a tool that’s endorsed by U.S. and international MF/CTCL specialty group consensus guidelines. For cycles 2 and 3, open-label response rates were secondary endpoints. Responses were assessed after 2-week rest periods to allow for treatment-induced skin reactions to subside.
After one cycle of treatment, topical hypericin PDT was more effective than placebo (an index lesion response rate of 16% vs. 4%; P =.04). The index lesion response rate with treatment increased to 40% after two cycles and 49% after three cycles. All were statistically significant changes.
Response rates were similar in patch and plaque-type lesions and regardless of age, sex, race, stage IA versus IB, time since diagnosis, and number of prior therapies. Adverse events were primarily mild application-site skin reactions. No serious drug-related adverse events occurred, Dr. Kim said, and “we had a low drop-out rate overall.”
Into the real world
The 24-week phase 3 trial duration is short, considering that “typically, phototherapy takes between 4 to 24 months [to achieve] full responses in CTCL,” Dr. Kim said in the interview.
So with real-world application, she said, “we’ll want to see where the overall response peaks with longer treatment, what the effects are of continuous treatment without any built-in breaks, and whether we will indeed see less skin cancer development in patients who are at higher risk of developing skin cancers from light treatment.”
Such questions will be explored as part of a new 4-year, 50-patient, open-label, multicenter study with the primary aim of investigating home-based hypericin PDT therapy in a supervised setting, said Dr. Kim, principal investigator of this study. Patients who are doing well after 6 weeks of twice-weekly therapy will be given at-home light units to continue therapy and achieve 1 year of treatment with no breaks. They will be monitored with video-based telemedicine.
“Long term, having a home unit should really improve patient access and compliance and hopefully effectiveness,” Dr. Kim said. Based on the phase 3 experience, “we think that continuous treatment will be well tolerated and that we may see greater responses.”
On Dec. 19, Soligenix announced that enrollment had begun in a phase 2a study of synthetic hypericin for treating patients with mild to moderate psoriasis.
Dr. Kim reported to JAMA Dermatology grants from Innate Pharma and Galderma; consulting/advisory fees from Almirall, Galderma, and Helsinn; and honoraria from Ology and UptoDate.
based on phase 3 findings published in JAMA Dermatology.
The treatment employs an ointment formulation of synthetic hypericin (HyBryte), a photosensitizer, that is preferentially absorbed into malignant cells and activated with visible light – rather than ultraviolet light – approximately 24 hours later. Investigators saw significant clinical responses in both patch and plaque type lesions and across races during the 24-week placebo-controlled, double-blinded, phase 3, randomized clinical trial.
“Traditional phototherapy, ultraviolet B phototherapy, has a limited depth of penetration, so patients with thicker plaque lesions don’t respond as well ... and UVB phototherapy typically is less effective in penetrating pigmented skin,” Ellen J. Kim, MD, lead author of the FLASH phase 3 trial, said in an interview.
Visible light in the yellow-red spectrum (500-650 nm) “penetrates deeper into the skin” and is nonmutagenic in vitro, so “theoretically it should have a much more favorable long-term safety profile,” said Dr. Kim, a dermatologist at the University of Pennsylvania, Philadelphia.
Currently, she said, the risk of secondary malignancies inherent with UV PDT, including melanoma, is a deterrent for some patients, especially “patients with really fair skin and a history of skin cancer.”
Hypericin PDT also seems well suited for use with an at-home light unit. “In our field, it’s not about which therapy is [universally] better or best, but a matter of what works best for each patient at that moment in time, depending on the side-effect profile and other issues such as access,” Dr. Kim said. “It will be great to have another option for an incurable disease that requires chronic management.”
Mycosis fungoides (MF)/CTCL is considered an orphan disease, and the treatment has received orphan drug and fast track designations from the FDA, and orphan designation from the European Medicines Agency, according to a press release from its developer, Soligenix. The company is anticipating potential approval in the second half of 2023 and is targeting early 2024 for a U.S. launch, the statement said.
Phase 3 results
The pivotal trial involved 169 patients at 39 academic and community-based U.S. medical centers and consisted of several 6-week cycles of twice-weekly treatment punctuated by 2-week breaks. In cycle 1, patients were randomized 2:1 to receive hypericin or placebo treatment of three index lesions. Cycle 2 involved the crossover of placebo patients to active treatment of index lesions, and cycle 3 (optional) involved open-label treatment of all desired lesions (index and nonindex).
The trial defined the primary endpoint in phase 1 as 50% or greater improvement in the modified Composite Assessment of Index Lesion Severity score – a tool that’s endorsed by U.S. and international MF/CTCL specialty group consensus guidelines. For cycles 2 and 3, open-label response rates were secondary endpoints. Responses were assessed after 2-week rest periods to allow for treatment-induced skin reactions to subside.
After one cycle of treatment, topical hypericin PDT was more effective than placebo (an index lesion response rate of 16% vs. 4%; P =.04). The index lesion response rate with treatment increased to 40% after two cycles and 49% after three cycles. All were statistically significant changes.
Response rates were similar in patch and plaque-type lesions and regardless of age, sex, race, stage IA versus IB, time since diagnosis, and number of prior therapies. Adverse events were primarily mild application-site skin reactions. No serious drug-related adverse events occurred, Dr. Kim said, and “we had a low drop-out rate overall.”
Into the real world
The 24-week phase 3 trial duration is short, considering that “typically, phototherapy takes between 4 to 24 months [to achieve] full responses in CTCL,” Dr. Kim said in the interview.
So with real-world application, she said, “we’ll want to see where the overall response peaks with longer treatment, what the effects are of continuous treatment without any built-in breaks, and whether we will indeed see less skin cancer development in patients who are at higher risk of developing skin cancers from light treatment.”
Such questions will be explored as part of a new 4-year, 50-patient, open-label, multicenter study with the primary aim of investigating home-based hypericin PDT therapy in a supervised setting, said Dr. Kim, principal investigator of this study. Patients who are doing well after 6 weeks of twice-weekly therapy will be given at-home light units to continue therapy and achieve 1 year of treatment with no breaks. They will be monitored with video-based telemedicine.
“Long term, having a home unit should really improve patient access and compliance and hopefully effectiveness,” Dr. Kim said. Based on the phase 3 experience, “we think that continuous treatment will be well tolerated and that we may see greater responses.”
On Dec. 19, Soligenix announced that enrollment had begun in a phase 2a study of synthetic hypericin for treating patients with mild to moderate psoriasis.
Dr. Kim reported to JAMA Dermatology grants from Innate Pharma and Galderma; consulting/advisory fees from Almirall, Galderma, and Helsinn; and honoraria from Ology and UptoDate.
Dietary interventions can support IBD treatment
For Crohn’s disease, a diet low in refined carbohydrates and a symptoms-guided diet appeared to help with remission, yet reduction of refined carbohydrates or red meat didn’t reduce the risk of relapse. For ulcerative colitis, solid food diets were similar to control measures.
“The Internet has a dizzying array of diet variants touted to benefit inflammation and IBD, which has led to much confusion among patients, and even clinicians, over what is truly effective or not,” Berkeley Limketkai, MD, PhD, director of clinical research at the Center for Inflammatory Bowel Disease at the University of California, Los Angeles, said in an interview.
“Even experiences shared by well-meaning individuals might not be generalizable to others,” he said. “The lack of clarity on what is or is not effective motivated us to perform this systematic review and meta-analysis.”
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing diets
Some nutritional therapies, such as exclusive enteral nutrition, have good evidence to support their use in the treatment of IBD, Dr. Limketkai said. However, patients often find maintaining a liquid diet difficult, particularly over a long period of time, so clinicians and patients have been interested in solid food diets as a treatment for IBD.
In 2019, Dr. Limketkai and colleagues conducted a systematic review and meta-analysis of randomized controlled trials focused on solid food diets for IBD that was published with the Cochrane Collaboration. At that time, the data were considered sparse, and the certainty of evidence was very low or low. Since then, several high-quality trials have been published.
For this study, Dr. Limketkai and colleagues conducted an updated review of 36 studies and a meta-analysis of 27 studies that compared a solid food diet with a control diet in patients with Crohn’s disease or ulcerative colitis. The intervention arm had to involve a well-defined diet, not merely a “usual” diet.
Among the studies, 12 evaluated dietary interventions for inducing clinical remission in patients with active Crohn’s disease, and 639 patients were involved. Overall, a low–refined carbohydrate diet was superior to a high-carbohydrate diet or a low-fiber diet. In addition, a symptoms-guided diet, which sequentially eliminated foods that aggravated a patient’s symptoms, was superior to conventional nutrition advice. However, the studies had serious imprecisions and very low certainty of evidence.
Compared with respective controls, a highly restrictive organic diet, a low-microparticle diet, and a low-calcium diet were ineffective at inducing remission of Crohn’s disease. Studies focused on immunoglobulin G-based measures were also inconsistent.
When comparing diets touted to benefit patients with Crohn’s disease, the Specific Carbohydrate Diet was similar to the Mediterranean diet and the whole-food diet, though the certainty of evidence was low. Partial enteral nutrition was similar to exclusive enteral nutrition, though there was substantial statistical heterogeneity between studies and very low certainty of evidence.
For maintenance of Crohn’s disease remission, researchers evaluated 14 studies that included 1,211 patients with inactive disease. Partial enteral nutrition appeared to reduce the risk of relapse, although evidence certainty was very low. In contrast, reducing red meat or refined carbohydrates did not lower the risk of relapse.
“These findings seemingly contradict our belief that red meat and refined carbohydrates have proinflammatory effects, although there are other studies that appear to show inconsistent, weak, or no association between consumption of unprocessed red meat and disease,” Dr. Limketkai said. “The caveat is that our findings are based on weak evidence, which may change as more studies are performed over time.”
For induction of remission in ulcerative colitis, researchers evaluated three studies that included 124 participants with active disease. When compared with participants’ usual diet, there was no benefit from a diet that excluded symptom-provoking foods, fried foods, refined carbohydrates, additives, preservatives, most condiments, spices, and beverages other than boiled water. Other studies found no benefit from eliminating cow milk protein or gluten.
For maintenance of ulcerative colitis remission, they looked at four studies that included 101 patients with inactive disease. Overall, there was no benefit from a carrageenan-free diet, anti-inflammatory diet, or cow milk protein elimination diet.
Helping patients
Although the certainty of evidence remains very low or low for most dietary trials in IBD, the emerging data suggest that nutrition plays an important role in IBD management and should be considered in the overall treatment plan for patients, the study authors wrote.
“Patients continue to look for ways to control their IBD, particularly with diet. Providers continue to struggle with making evidence-based recommendations about dietary interventions for IBD. This systematic review is a useful tool for providers to advise their patients,” James D. Lewis, MD, associate director of the inflammatory bowel diseases program at the University of Pennsylvania, Philadelphia, said in an interview.
Dr. Lewis, who wasn’t involved with this study, has researched dietary interventions for IBD. He and his colleagues have found that reducing red meat does not lower the rate of Crohn’s disease flares and that the Mediterranean diet and Specific Carbohydrate Diet appear to be similar for inducing clinical remission.
Based on this review, partial enteral nutrition could be an option for patients with Crohn’s disease, Dr. Lewis said.
“Partial enteral nutrition is much easier than exclusive enteral nutrition for patients,” he said. “However, there remains uncertainty as to whether the solid food component of a partial enteral nutrition approach impacts outcomes.”
As more dietary studies become available, the certainty of evidence could improve and lead to better recommendations for patients, Dr. Limketkai and colleagues wrote. They are conducting several studies focused on the concept of precision nutrition.
“While certain diets may be helpful and effective for IBD, different diets work differently in different people. This concept is no different than the fact that different IBD medications work differently in different individuals,” Dr. Limketkai said. “However, given the current state of evidence for dietary interventions in IBD, we still have a long path of research ahead of us.”
The study received no funding. The study authors reported no conflicts of interest. Dr. Lewis reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
For Crohn’s disease, a diet low in refined carbohydrates and a symptoms-guided diet appeared to help with remission, yet reduction of refined carbohydrates or red meat didn’t reduce the risk of relapse. For ulcerative colitis, solid food diets were similar to control measures.
“The Internet has a dizzying array of diet variants touted to benefit inflammation and IBD, which has led to much confusion among patients, and even clinicians, over what is truly effective or not,” Berkeley Limketkai, MD, PhD, director of clinical research at the Center for Inflammatory Bowel Disease at the University of California, Los Angeles, said in an interview.
“Even experiences shared by well-meaning individuals might not be generalizable to others,” he said. “The lack of clarity on what is or is not effective motivated us to perform this systematic review and meta-analysis.”
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing diets
Some nutritional therapies, such as exclusive enteral nutrition, have good evidence to support their use in the treatment of IBD, Dr. Limketkai said. However, patients often find maintaining a liquid diet difficult, particularly over a long period of time, so clinicians and patients have been interested in solid food diets as a treatment for IBD.
In 2019, Dr. Limketkai and colleagues conducted a systematic review and meta-analysis of randomized controlled trials focused on solid food diets for IBD that was published with the Cochrane Collaboration. At that time, the data were considered sparse, and the certainty of evidence was very low or low. Since then, several high-quality trials have been published.
For this study, Dr. Limketkai and colleagues conducted an updated review of 36 studies and a meta-analysis of 27 studies that compared a solid food diet with a control diet in patients with Crohn’s disease or ulcerative colitis. The intervention arm had to involve a well-defined diet, not merely a “usual” diet.
Among the studies, 12 evaluated dietary interventions for inducing clinical remission in patients with active Crohn’s disease, and 639 patients were involved. Overall, a low–refined carbohydrate diet was superior to a high-carbohydrate diet or a low-fiber diet. In addition, a symptoms-guided diet, which sequentially eliminated foods that aggravated a patient’s symptoms, was superior to conventional nutrition advice. However, the studies had serious imprecisions and very low certainty of evidence.
Compared with respective controls, a highly restrictive organic diet, a low-microparticle diet, and a low-calcium diet were ineffective at inducing remission of Crohn’s disease. Studies focused on immunoglobulin G-based measures were also inconsistent.
When comparing diets touted to benefit patients with Crohn’s disease, the Specific Carbohydrate Diet was similar to the Mediterranean diet and the whole-food diet, though the certainty of evidence was low. Partial enteral nutrition was similar to exclusive enteral nutrition, though there was substantial statistical heterogeneity between studies and very low certainty of evidence.
For maintenance of Crohn’s disease remission, researchers evaluated 14 studies that included 1,211 patients with inactive disease. Partial enteral nutrition appeared to reduce the risk of relapse, although evidence certainty was very low. In contrast, reducing red meat or refined carbohydrates did not lower the risk of relapse.
“These findings seemingly contradict our belief that red meat and refined carbohydrates have proinflammatory effects, although there are other studies that appear to show inconsistent, weak, or no association between consumption of unprocessed red meat and disease,” Dr. Limketkai said. “The caveat is that our findings are based on weak evidence, which may change as more studies are performed over time.”
For induction of remission in ulcerative colitis, researchers evaluated three studies that included 124 participants with active disease. When compared with participants’ usual diet, there was no benefit from a diet that excluded symptom-provoking foods, fried foods, refined carbohydrates, additives, preservatives, most condiments, spices, and beverages other than boiled water. Other studies found no benefit from eliminating cow milk protein or gluten.
For maintenance of ulcerative colitis remission, they looked at four studies that included 101 patients with inactive disease. Overall, there was no benefit from a carrageenan-free diet, anti-inflammatory diet, or cow milk protein elimination diet.
Helping patients
Although the certainty of evidence remains very low or low for most dietary trials in IBD, the emerging data suggest that nutrition plays an important role in IBD management and should be considered in the overall treatment plan for patients, the study authors wrote.
“Patients continue to look for ways to control their IBD, particularly with diet. Providers continue to struggle with making evidence-based recommendations about dietary interventions for IBD. This systematic review is a useful tool for providers to advise their patients,” James D. Lewis, MD, associate director of the inflammatory bowel diseases program at the University of Pennsylvania, Philadelphia, said in an interview.
Dr. Lewis, who wasn’t involved with this study, has researched dietary interventions for IBD. He and his colleagues have found that reducing red meat does not lower the rate of Crohn’s disease flares and that the Mediterranean diet and Specific Carbohydrate Diet appear to be similar for inducing clinical remission.
Based on this review, partial enteral nutrition could be an option for patients with Crohn’s disease, Dr. Lewis said.
“Partial enteral nutrition is much easier than exclusive enteral nutrition for patients,” he said. “However, there remains uncertainty as to whether the solid food component of a partial enteral nutrition approach impacts outcomes.”
As more dietary studies become available, the certainty of evidence could improve and lead to better recommendations for patients, Dr. Limketkai and colleagues wrote. They are conducting several studies focused on the concept of precision nutrition.
“While certain diets may be helpful and effective for IBD, different diets work differently in different people. This concept is no different than the fact that different IBD medications work differently in different individuals,” Dr. Limketkai said. “However, given the current state of evidence for dietary interventions in IBD, we still have a long path of research ahead of us.”
The study received no funding. The study authors reported no conflicts of interest. Dr. Lewis reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
For Crohn’s disease, a diet low in refined carbohydrates and a symptoms-guided diet appeared to help with remission, yet reduction of refined carbohydrates or red meat didn’t reduce the risk of relapse. For ulcerative colitis, solid food diets were similar to control measures.
“The Internet has a dizzying array of diet variants touted to benefit inflammation and IBD, which has led to much confusion among patients, and even clinicians, over what is truly effective or not,” Berkeley Limketkai, MD, PhD, director of clinical research at the Center for Inflammatory Bowel Disease at the University of California, Los Angeles, said in an interview.
“Even experiences shared by well-meaning individuals might not be generalizable to others,” he said. “The lack of clarity on what is or is not effective motivated us to perform this systematic review and meta-analysis.”
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing diets
Some nutritional therapies, such as exclusive enteral nutrition, have good evidence to support their use in the treatment of IBD, Dr. Limketkai said. However, patients often find maintaining a liquid diet difficult, particularly over a long period of time, so clinicians and patients have been interested in solid food diets as a treatment for IBD.
In 2019, Dr. Limketkai and colleagues conducted a systematic review and meta-analysis of randomized controlled trials focused on solid food diets for IBD that was published with the Cochrane Collaboration. At that time, the data were considered sparse, and the certainty of evidence was very low or low. Since then, several high-quality trials have been published.
For this study, Dr. Limketkai and colleagues conducted an updated review of 36 studies and a meta-analysis of 27 studies that compared a solid food diet with a control diet in patients with Crohn’s disease or ulcerative colitis. The intervention arm had to involve a well-defined diet, not merely a “usual” diet.
Among the studies, 12 evaluated dietary interventions for inducing clinical remission in patients with active Crohn’s disease, and 639 patients were involved. Overall, a low–refined carbohydrate diet was superior to a high-carbohydrate diet or a low-fiber diet. In addition, a symptoms-guided diet, which sequentially eliminated foods that aggravated a patient’s symptoms, was superior to conventional nutrition advice. However, the studies had serious imprecisions and very low certainty of evidence.
Compared with respective controls, a highly restrictive organic diet, a low-microparticle diet, and a low-calcium diet were ineffective at inducing remission of Crohn’s disease. Studies focused on immunoglobulin G-based measures were also inconsistent.
When comparing diets touted to benefit patients with Crohn’s disease, the Specific Carbohydrate Diet was similar to the Mediterranean diet and the whole-food diet, though the certainty of evidence was low. Partial enteral nutrition was similar to exclusive enteral nutrition, though there was substantial statistical heterogeneity between studies and very low certainty of evidence.
For maintenance of Crohn’s disease remission, researchers evaluated 14 studies that included 1,211 patients with inactive disease. Partial enteral nutrition appeared to reduce the risk of relapse, although evidence certainty was very low. In contrast, reducing red meat or refined carbohydrates did not lower the risk of relapse.
“These findings seemingly contradict our belief that red meat and refined carbohydrates have proinflammatory effects, although there are other studies that appear to show inconsistent, weak, or no association between consumption of unprocessed red meat and disease,” Dr. Limketkai said. “The caveat is that our findings are based on weak evidence, which may change as more studies are performed over time.”
For induction of remission in ulcerative colitis, researchers evaluated three studies that included 124 participants with active disease. When compared with participants’ usual diet, there was no benefit from a diet that excluded symptom-provoking foods, fried foods, refined carbohydrates, additives, preservatives, most condiments, spices, and beverages other than boiled water. Other studies found no benefit from eliminating cow milk protein or gluten.
For maintenance of ulcerative colitis remission, they looked at four studies that included 101 patients with inactive disease. Overall, there was no benefit from a carrageenan-free diet, anti-inflammatory diet, or cow milk protein elimination diet.
Helping patients
Although the certainty of evidence remains very low or low for most dietary trials in IBD, the emerging data suggest that nutrition plays an important role in IBD management and should be considered in the overall treatment plan for patients, the study authors wrote.
“Patients continue to look for ways to control their IBD, particularly with diet. Providers continue to struggle with making evidence-based recommendations about dietary interventions for IBD. This systematic review is a useful tool for providers to advise their patients,” James D. Lewis, MD, associate director of the inflammatory bowel diseases program at the University of Pennsylvania, Philadelphia, said in an interview.
Dr. Lewis, who wasn’t involved with this study, has researched dietary interventions for IBD. He and his colleagues have found that reducing red meat does not lower the rate of Crohn’s disease flares and that the Mediterranean diet and Specific Carbohydrate Diet appear to be similar for inducing clinical remission.
Based on this review, partial enteral nutrition could be an option for patients with Crohn’s disease, Dr. Lewis said.
“Partial enteral nutrition is much easier than exclusive enteral nutrition for patients,” he said. “However, there remains uncertainty as to whether the solid food component of a partial enteral nutrition approach impacts outcomes.”
As more dietary studies become available, the certainty of evidence could improve and lead to better recommendations for patients, Dr. Limketkai and colleagues wrote. They are conducting several studies focused on the concept of precision nutrition.
“While certain diets may be helpful and effective for IBD, different diets work differently in different people. This concept is no different than the fact that different IBD medications work differently in different individuals,” Dr. Limketkai said. “However, given the current state of evidence for dietary interventions in IBD, we still have a long path of research ahead of us.”
The study received no funding. The study authors reported no conflicts of interest. Dr. Lewis reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
All the National Health Service wants for Christmas is tea and biscuits
Three cups of tea, two biscuit packs, and a Christmas study from the BMJ
Warning: The following content may contain excessive Britishness. Continue at your own risk.
It’s no secret that the world economy is in an … interesting spot right now. Belt tightening is occurring around the world despite the holiday season, and hospitals across the pond in Great Britain are no exception.
It was a simple sign that prompted the study, published in the Christmas edition of the BMJ: “Please do not take excessive quantities of these refreshments.” And if we all know one thing, you do not get between Brits and their tea and biscuits. So the researchers behind the study drafted a survey and sent it around to nearly 2,000 British health care workers and asked what they considered to be excessive consumption of work-provided hot drinks and biscuits.
In the hot drinks department (tea and coffee, though we appreciate the two people who voiced a preference for free hot whiskey, if it was available) the survey participants decreed that 3.32 drinks was the maximum before consumption became excessive. That’s pretty close to the actual number of hot drinks respondents drank daily (3.04), so it’s pretty fair to say that British health care workers do a good job of self-limiting.
It’s much the same story with biscuits: Health care workers reported that consuming 2.25 packets of free biscuits would be excessive. Notably, doctors would take more than nondoctors (2.35 vs. 2.14 – typical doctor behavior), and those who had been in their role for less than 2 years would consume nearly 3 packets a day before calling it quits.
The study did not include an official cost analysis, but calculations conducted on a biscuit wrapper (that’s not a joke, by the way) estimated that the combined cost for providing every National Health Service employee with three free drinks and two free biscuit packages a day would be about 160 million pounds a year. Now, that’s a lot of money for tea and biscuits, but, they added, it’s a meager 0.1% of the NHS annual budget. They also noted that most employees consider free hot drinks a more valuable workplace perk than free support for mental health.
In conclusion, the authors wrote, “As a target for cost-saving initiatives, limiting free refreshment consumption is really scraping the biscuit barrel (although some limits on hot whiskey availability may be necessary), and implementing, or continuing, perks that improve staff morale seems justifiable. … Healthcare employers should allow biscuits and hot drinks to be freely available to staff, and they should leave these grateful recipients to judge for themselves what constitutes reasonable consumption.”
Now there’s a Christmas sentiment we can all get behind.
We come not to bury sugar, but to improve it
When we think about sugar, healthy isn’t the first thing that comes to mind. Research also shows that artificial sweeteners, as well as processed foods in general, are bad for your body and brain. People, however, love the stuff. That’s why one of the leading brands in processed foods, Kraft Heinz, partnered with the Wyss Institute for Biologically Inspired Engineering at Harvard to find a way to reduce consumers’ sugar consumption.
The question that Kraft Heinz presented to Wyss was this: How could it reduce the fructose in its products without losing the functionality of regular sugar.
The Wyss team’s approach seems pretty simple: Use a naturally occurring enzyme to convert sugar to fiber. The trick was to add the enzymes into the food so they could convert the sugar to fiber after being consumed. The enzymes also needed to be able to be added to existing food products without changing their existing recipes, Kraft Heinz insisted.
How does it work? The crafted enzyme is encapsulated to remain dormant in the food until exposed to an increased pH level, as is found in the GI tract between the stomach and the intestine. It reduces the amount of sugar absorbed in the bloodstream and creates a healthy prebiotic fiber, the institute explained.
This opens a whole new window for consumers. People with diabetes can enjoy their favorite cookies from time to time, while parents can feel less guilty about their children bathing their chicken nuggets in unholy amounts of ketchup.
New genes, or not new genes? That is the question
… and the police report that no capybaras were harmed in the incident. What a relief. Now Action News 8 brings you Carol Espinosa’s exclusive interview with legendary scientist and zombie, Charles Darwin.
Carol: Thanks, Daryl. Tell us, Prof. Darwin, what have you been up to lately?
Prof. Darwin: Please, Carol, call me Chuck. As always, I’ve got my hands full with the whole evolution thing. The big news right now is a study published in Cell Reports that offers evidence of the continuing evolution of humans. Can I eat your brain now?
Carol: No, Chuck, you may not. So people are still evolving? It sure seems like we’ve reverted to survival of the dumbest.
Chuck Darwin: Good one, Carol, but evolution hasn’t stopped. The investigators used a previously published dataset of functionally relevant new genes to create an ancestral tree comparing humans with other vertebrate species. By tracking the genes across evolution, they found 155 from regions of unique DNA that arose from scratch and not from duplication events in the existing genome. That’s a big deal.
Carol: Anything made from scratch is always better. Everyone knows that. What else can you tell us, Chuck?
Chuck Darwin: So these 155 genes didn’t exist when humans separated from chimpanzees nearly 7 million years ago. Turns out that 44 of them are associated with growth defects in cell cultures and three “have disease-associated DNA markers that point to connections with ailments such as muscular dystrophy, retinitis pigmentosa, and Alazami syndrome.” At least that’s what the investigators said in a written statement. I must say, Carol, that your brain is looking particularly delicious tonight.
Carol: Ironic. For years I’ve been hoping a man would appreciate me for my brain, and now I get this. Back to you, Daryl.
Three cups of tea, two biscuit packs, and a Christmas study from the BMJ
Warning: The following content may contain excessive Britishness. Continue at your own risk.
It’s no secret that the world economy is in an … interesting spot right now. Belt tightening is occurring around the world despite the holiday season, and hospitals across the pond in Great Britain are no exception.
It was a simple sign that prompted the study, published in the Christmas edition of the BMJ: “Please do not take excessive quantities of these refreshments.” And if we all know one thing, you do not get between Brits and their tea and biscuits. So the researchers behind the study drafted a survey and sent it around to nearly 2,000 British health care workers and asked what they considered to be excessive consumption of work-provided hot drinks and biscuits.
In the hot drinks department (tea and coffee, though we appreciate the two people who voiced a preference for free hot whiskey, if it was available) the survey participants decreed that 3.32 drinks was the maximum before consumption became excessive. That’s pretty close to the actual number of hot drinks respondents drank daily (3.04), so it’s pretty fair to say that British health care workers do a good job of self-limiting.
It’s much the same story with biscuits: Health care workers reported that consuming 2.25 packets of free biscuits would be excessive. Notably, doctors would take more than nondoctors (2.35 vs. 2.14 – typical doctor behavior), and those who had been in their role for less than 2 years would consume nearly 3 packets a day before calling it quits.
The study did not include an official cost analysis, but calculations conducted on a biscuit wrapper (that’s not a joke, by the way) estimated that the combined cost for providing every National Health Service employee with three free drinks and two free biscuit packages a day would be about 160 million pounds a year. Now, that’s a lot of money for tea and biscuits, but, they added, it’s a meager 0.1% of the NHS annual budget. They also noted that most employees consider free hot drinks a more valuable workplace perk than free support for mental health.
In conclusion, the authors wrote, “As a target for cost-saving initiatives, limiting free refreshment consumption is really scraping the biscuit barrel (although some limits on hot whiskey availability may be necessary), and implementing, or continuing, perks that improve staff morale seems justifiable. … Healthcare employers should allow biscuits and hot drinks to be freely available to staff, and they should leave these grateful recipients to judge for themselves what constitutes reasonable consumption.”
Now there’s a Christmas sentiment we can all get behind.
We come not to bury sugar, but to improve it
When we think about sugar, healthy isn’t the first thing that comes to mind. Research also shows that artificial sweeteners, as well as processed foods in general, are bad for your body and brain. People, however, love the stuff. That’s why one of the leading brands in processed foods, Kraft Heinz, partnered with the Wyss Institute for Biologically Inspired Engineering at Harvard to find a way to reduce consumers’ sugar consumption.
The question that Kraft Heinz presented to Wyss was this: How could it reduce the fructose in its products without losing the functionality of regular sugar.
The Wyss team’s approach seems pretty simple: Use a naturally occurring enzyme to convert sugar to fiber. The trick was to add the enzymes into the food so they could convert the sugar to fiber after being consumed. The enzymes also needed to be able to be added to existing food products without changing their existing recipes, Kraft Heinz insisted.
How does it work? The crafted enzyme is encapsulated to remain dormant in the food until exposed to an increased pH level, as is found in the GI tract between the stomach and the intestine. It reduces the amount of sugar absorbed in the bloodstream and creates a healthy prebiotic fiber, the institute explained.
This opens a whole new window for consumers. People with diabetes can enjoy their favorite cookies from time to time, while parents can feel less guilty about their children bathing their chicken nuggets in unholy amounts of ketchup.
New genes, or not new genes? That is the question
… and the police report that no capybaras were harmed in the incident. What a relief. Now Action News 8 brings you Carol Espinosa’s exclusive interview with legendary scientist and zombie, Charles Darwin.
Carol: Thanks, Daryl. Tell us, Prof. Darwin, what have you been up to lately?
Prof. Darwin: Please, Carol, call me Chuck. As always, I’ve got my hands full with the whole evolution thing. The big news right now is a study published in Cell Reports that offers evidence of the continuing evolution of humans. Can I eat your brain now?
Carol: No, Chuck, you may not. So people are still evolving? It sure seems like we’ve reverted to survival of the dumbest.
Chuck Darwin: Good one, Carol, but evolution hasn’t stopped. The investigators used a previously published dataset of functionally relevant new genes to create an ancestral tree comparing humans with other vertebrate species. By tracking the genes across evolution, they found 155 from regions of unique DNA that arose from scratch and not from duplication events in the existing genome. That’s a big deal.
Carol: Anything made from scratch is always better. Everyone knows that. What else can you tell us, Chuck?
Chuck Darwin: So these 155 genes didn’t exist when humans separated from chimpanzees nearly 7 million years ago. Turns out that 44 of them are associated with growth defects in cell cultures and three “have disease-associated DNA markers that point to connections with ailments such as muscular dystrophy, retinitis pigmentosa, and Alazami syndrome.” At least that’s what the investigators said in a written statement. I must say, Carol, that your brain is looking particularly delicious tonight.
Carol: Ironic. For years I’ve been hoping a man would appreciate me for my brain, and now I get this. Back to you, Daryl.
Three cups of tea, two biscuit packs, and a Christmas study from the BMJ
Warning: The following content may contain excessive Britishness. Continue at your own risk.
It’s no secret that the world economy is in an … interesting spot right now. Belt tightening is occurring around the world despite the holiday season, and hospitals across the pond in Great Britain are no exception.
It was a simple sign that prompted the study, published in the Christmas edition of the BMJ: “Please do not take excessive quantities of these refreshments.” And if we all know one thing, you do not get between Brits and their tea and biscuits. So the researchers behind the study drafted a survey and sent it around to nearly 2,000 British health care workers and asked what they considered to be excessive consumption of work-provided hot drinks and biscuits.
In the hot drinks department (tea and coffee, though we appreciate the two people who voiced a preference for free hot whiskey, if it was available) the survey participants decreed that 3.32 drinks was the maximum before consumption became excessive. That’s pretty close to the actual number of hot drinks respondents drank daily (3.04), so it’s pretty fair to say that British health care workers do a good job of self-limiting.
It’s much the same story with biscuits: Health care workers reported that consuming 2.25 packets of free biscuits would be excessive. Notably, doctors would take more than nondoctors (2.35 vs. 2.14 – typical doctor behavior), and those who had been in their role for less than 2 years would consume nearly 3 packets a day before calling it quits.
The study did not include an official cost analysis, but calculations conducted on a biscuit wrapper (that’s not a joke, by the way) estimated that the combined cost for providing every National Health Service employee with three free drinks and two free biscuit packages a day would be about 160 million pounds a year. Now, that’s a lot of money for tea and biscuits, but, they added, it’s a meager 0.1% of the NHS annual budget. They also noted that most employees consider free hot drinks a more valuable workplace perk than free support for mental health.
In conclusion, the authors wrote, “As a target for cost-saving initiatives, limiting free refreshment consumption is really scraping the biscuit barrel (although some limits on hot whiskey availability may be necessary), and implementing, or continuing, perks that improve staff morale seems justifiable. … Healthcare employers should allow biscuits and hot drinks to be freely available to staff, and they should leave these grateful recipients to judge for themselves what constitutes reasonable consumption.”
Now there’s a Christmas sentiment we can all get behind.
We come not to bury sugar, but to improve it
When we think about sugar, healthy isn’t the first thing that comes to mind. Research also shows that artificial sweeteners, as well as processed foods in general, are bad for your body and brain. People, however, love the stuff. That’s why one of the leading brands in processed foods, Kraft Heinz, partnered with the Wyss Institute for Biologically Inspired Engineering at Harvard to find a way to reduce consumers’ sugar consumption.
The question that Kraft Heinz presented to Wyss was this: How could it reduce the fructose in its products without losing the functionality of regular sugar.
The Wyss team’s approach seems pretty simple: Use a naturally occurring enzyme to convert sugar to fiber. The trick was to add the enzymes into the food so they could convert the sugar to fiber after being consumed. The enzymes also needed to be able to be added to existing food products without changing their existing recipes, Kraft Heinz insisted.
How does it work? The crafted enzyme is encapsulated to remain dormant in the food until exposed to an increased pH level, as is found in the GI tract between the stomach and the intestine. It reduces the amount of sugar absorbed in the bloodstream and creates a healthy prebiotic fiber, the institute explained.
This opens a whole new window for consumers. People with diabetes can enjoy their favorite cookies from time to time, while parents can feel less guilty about their children bathing their chicken nuggets in unholy amounts of ketchup.
New genes, or not new genes? That is the question
… and the police report that no capybaras were harmed in the incident. What a relief. Now Action News 8 brings you Carol Espinosa’s exclusive interview with legendary scientist and zombie, Charles Darwin.
Carol: Thanks, Daryl. Tell us, Prof. Darwin, what have you been up to lately?
Prof. Darwin: Please, Carol, call me Chuck. As always, I’ve got my hands full with the whole evolution thing. The big news right now is a study published in Cell Reports that offers evidence of the continuing evolution of humans. Can I eat your brain now?
Carol: No, Chuck, you may not. So people are still evolving? It sure seems like we’ve reverted to survival of the dumbest.
Chuck Darwin: Good one, Carol, but evolution hasn’t stopped. The investigators used a previously published dataset of functionally relevant new genes to create an ancestral tree comparing humans with other vertebrate species. By tracking the genes across evolution, they found 155 from regions of unique DNA that arose from scratch and not from duplication events in the existing genome. That’s a big deal.
Carol: Anything made from scratch is always better. Everyone knows that. What else can you tell us, Chuck?
Chuck Darwin: So these 155 genes didn’t exist when humans separated from chimpanzees nearly 7 million years ago. Turns out that 44 of them are associated with growth defects in cell cultures and three “have disease-associated DNA markers that point to connections with ailments such as muscular dystrophy, retinitis pigmentosa, and Alazami syndrome.” At least that’s what the investigators said in a written statement. I must say, Carol, that your brain is looking particularly delicious tonight.
Carol: Ironic. For years I’ve been hoping a man would appreciate me for my brain, and now I get this. Back to you, Daryl.
GLP-1 agonists for weight loss: What you need to know
Obesity and overweight, with or without metabolic dysregulation, pose vexing problems for many patients with mood, anxiety, or psychotic disorders. More than one-half of individuals with severe mental illnesses are obese or overweight,1 resulting from multiple factors that may include psychiatric symptoms (eg, anergia and hyperphagia), poor dietary choices, sedentary lifestyle, underlying inflammatory processes, medical comorbidities, and iatrogenic consequences of certain medications. Unfortunately, numerous psychotropic medications can increase weight and appetite due to a variety of mechanisms, including antihistaminergic effects, direct appetite-stimulating effects, and proclivities to cause insulin resistance. While individual agents can vary, a recent review identified an overall 2-fold increased risk for rapid, significant weight gain during treatment with antipsychotics as a class.2 In addition to lifestyle modifications (diet and exercise), many pharmacologic strategies have been proposed to counter iatrogenic weight gain, including appetite suppressants (eg, pro-dopaminergic agents such as phentermine, stimulants, and amantadine), pro-anorectant anticonvulsants (eg, topiramate or zonisamide), opioid receptor antagonists (eg, olanzapine/samidorphan or naltrexone) and oral hypoglycemics such as metformin. However, the magnitude of impact for most of these agents to reverse iatrogenic weight gain tends to be modest, particularly once significant weight gain (ie, ≥7% of initial body weight) has already occurred.
Pharmacologic strategies to modulate or enhance the effects of insulin hold particular importance for combatting psychotropic-associated weight gain. Insulin transports glucose from the intravascular space to end organs for fuel consumption; to varying degrees, second-generation antipsychotics (SGAs) and some other psychotropic medications can cause insulin resistance. This in turn leads to excessive storage of underutilized glucose in the liver (glycogenesis), the potential for developing fatty liver (ie, nonalcoholic steatohepatitis), and conversion of excess carbohydrates to fatty acids and triglycerides, with subsequent storage in adipose tissue. Medications that can enhance the activity of insulin (so-called incretin mimetics) can help to overcome insulin resistance caused by SGAs (and potentially by other psychotropic medications) and essentially lead to weight loss through enhanced “fuel efficiency.”
Metformin, typically dosed up to 1,000 mg twice daily with meals, has increasingly become recognized as a first-line strategy to attenuate weight gain and glycemic dysregulation from SGAs via its ability to reduce insulin resistance. Yet meta-analyses have shown that although results are significantly better than placebo, overall long-term weight loss from metformin alone tends to be rather modest (<4 kg) and associated with a reduction in body mass index (BMI) of only approximately 1 point.3 Psychiatrists (and other clinicians who prescribe psychotropic medications that can cause weight gain or metabolic dysregulation) therefore need to become familiar with alternative or adjunctive weight loss options. The use of a relatively new class of incretin mimetics called glucagon-like peptide 1 (GLP-1) agonists (Table) has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation.
What are GLP-1 agonists?
GLP-1 is a hormone secreted by L cells in the intestinal mucosa in response to food. GLP-1 agonists reduce blood sugar by increasing insulin secretion, decreasing glucagon release (thus downregulating further increases in blood sugar), and reducing insulin resistance. GLP-1 agonists also reduce appetite by directly stimulating the satiety center and slowing gastric emptying and GI motility. In addition to GLP-1 agonism, some medications in this family (notably tirzepatide) also agonize a second hormone, glucose-dependent insulinotropic polypeptide, which can further induce insulin secretion as well as decrease stomach acid secretion, potentially delivering an even more substantial reduction in appetite and weight.
Routes of administration and FDA indications
Due to limited bioavailability, most GLP-1 agonists require subcutaneous (SC) injections (the sole exception is the Rybelsus brand of semaglutide, which comes in a daily pill form). Most are FDA-approved not specifically for weight loss but for patients with type 2 diabetes (defined as a hemoglobin A1C ≥6.5% or a fasting blood glucose level ≥126 mg/dL). Weight loss represents a secondary outcome for GLP-1 agonists FDA-approved for glycemic control in patients with type 2 diabetes. The 2 current exceptions to this classification are the Wegovy brand of semaglutide (ie, dosing of 2.4 mg) and the Saxenda brand of liraglutide, both of which carry FDA indications for chronic weight management alone (when paired with dietary and lifestyle modification) in individuals who are obese (BMI >30 kg/m2) regardless of the presence or absence of diabetes, or for persons who are overweight (BMI >27 kg/m2) and have ≥1 weight-related comorbid condition (eg, hypertension, type 2 diabetes, or dyslipidemia). Although patients at risk for diabetes (ie, prediabetes, defined as a hemoglobin A1C 5.7% to 6.4% or a fasting blood glucose level 100 to 125 mg/dL) were included in FDA registration trials of Saxenda or Wegovy, prediabetes is not an FDA indication for any GLP-1 agonist.
Data in weight loss
Most of the existing empirical data on weight loss with GLP-1 agonists come from studies of individuals who are overweight or obese, with or without type 2 diabetes, rather than from studies using these agents to counteract iatrogenic weight gain. In a retrospective cohort study of patients with type 2 diabetes, coadministration with serotonergic antidepressants (eg, citalopram/escitalopram) was associated with attenuation of the weight loss effects of GLP-1 agonists.4
Liraglutide currently is the sole GLP-1 agonist studied for treating SGA-associated weight gain. A 16-week randomized trial compared once-daily SC injected liraglutide vs placebo in patients with schizophrenia who incurred weight gain and prediabetes after taking olanzapine or clozapine.5 Significantly more patients taking liraglutide than placebo developed normal glucose tolerance (64% vs 16%), and body weight decreased by a mean of 5.3 kg.
Continue to: In studies of semaglutide...
In studies of semaglutide for overweight/obese patients with type 2 diabetes or prediabetes, clinical trials of oral semaglutide (Rybelsus) found a mean weight loss over 26 weeks of -1.0 kg with dosing at 7 mg/d and -2.6 kg with dosing at 14 mg/d.6 A 68-week placebo-controlled trial of semaglutide (dosed at 2.4 mg SC weekly) for overweight/obese adults who did not have diabetes yielded a -15.3 kg weight loss (vs -2.6 kg with placebo); one-half of those who received semaglutide lost 15% of their initial body weight (Figure 1A and Figure 1B).7 Similar findings with semaglutide 2.4 mg SC weekly (Wegovy) were observed in overweight/obese adolescents, with 73% of participants losing ≥5% of their baseline weight.8 A comparative randomized trial in patients with type 2 diabetes also found modestly but significantly greater weight loss with oral semaglutide than with SC liraglutide.9
In a 72-week study of tirzepatide specifically for weight loss in nondiabetic patients who were overweight or obese, findings were especially dramatic (Figure 2A and Figure 2B).10 An overall 15% decrease in body weight was observed with 5 mg/week dosing alongside a 19.5% decrease in body weight with 10 mg/week dosing and a 20.9% weight reduction with 15 mg/week dosing.10 As noted in Figure 2B, the observed pattern of weight loss occurred along an exponential decay curve. Notably, a comparative study of tirzepatide vs once-weekly semaglutide (1 mg) in patients with type 2 diabetes11 found significantly greater dose-dependent weight loss with tirzepatide than semaglutide (-1.9 kg at 5 mg, -3.6 kg at 10 mg, and -5.5 kg at 15 mg)—although the somewhat low dosing of semaglutide may have limited its optimal possible weight loss benefit.
Tolerability
Adverse effects with GLP-1 agonists are mainly gastrointestinal (eg, nausea, vomiting, abdominal pain, diarrhea, or constipation)5-11 and generally transient. SC administration is performed in fatty tissue of the abdomen, thigh, or upper arm; site rotation is recommended to minimize injection site pain. All GLP-1 agonists carry manufacturers’ warning and precaution statements identifying the rare potential for acute pancreatitis, acute gall bladder disease, acute kidney injury, and hypoglycemia. Animal studies also have suggested an increased, dose-dependent risk for thyroid C-cell tumors with GLP-1 agonists; this has not been observed in human trials, although postmarketing pharmacovigilance reports have identified cases of medullary thyroid carcinoma in patients who took liraglutide. A manufacturer’s boxed warning indicates that a personal or family history of medullary carcinoma of the thyroid poses a contraindication for taking semaglutide, liraglutide, or tirzepatide.
Initial evidence prompts additional questions
GLP-1 agonists represent an emerging class of novel agents that can modulate glycemic dysregulation and overweight/obesity, often with dramatic results whose magnitude rivals the efficacy of bariatric surgery. Once-weekly formulations of semaglutide (Wegovy) and daily liraglutide (Saxenda) are FDA-approved for weight loss in patients who are overweight or obese while other existing formulations are approved solely for patients with type 2 diabetes, although it is likely that broader indications for weight loss (regardless of glycemic status) are forthcoming. Targeted use of GLP-1 agonists to counteract SGA-associated weight gain is supported by a handful of preliminary reports, with additional studies likely to come. Unanswered questions include:
- When should GLP-1 agonists be considered within a treatment algorithm for iatrogenic weight gain relative to other antidote strategies such as metformin or appetite-suppressing anticonvulsants?
- How effective might GLP-1 agonists be for iatrogenic weight gain from non-SGA psychotropic medications, such as serotonergic antidepressants?
- When and how can GLP-1 agonists be safely coprescribed with other nonincretin mimetic weight loss medications?
- When should psychiatrists prescribe GLP-1 agonists, or do so collaboratively with primary care physicians or endocrinologists, particularly in patients with metabolic syndrome?
Followers of the rapidly emerging literature in this area will likely find themselves best positioned to address these and other questions about optimal management of psychotropic-induced weight gain for the patients they treat.
Bottom Line
The use of glucagon-like peptide 1 (GLP-1) agonists, a relatively new class of incretin mimetics, has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation. Preliminary reports support the potential targeted use of GLP-1 agonists to counteract weight gain associated with second-generation antipsychotics.
Related Resources
- Singh F, Allen A, Ianni A. Managing metabolic syndrome in patients with schizophrenia. Current Psychiatry. 2020;19(12):20-24,26. doi:10.12788/cp.0064
- Ard J, Fitch A, Fruh S, et al. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv Ther. 2021;38(6):2821- 2839. doi:10.1007/s12325-021-01710-0
Drug Brand Names
Amantadine • Gocovri
Citalopram • Celexa
Clozapine • Clozaril
Escitalopram • Lexapro
Liraglutide • Victoza, Saxenda
Metformin • Glucophage
Naltrexone • ReVia
Olanzapine • Zyprexa
Olanzapine/samidorphan • Lybalvi
Phentermine • Ionamin
Semaglutide • Rybelsus, Ozempic, Wegovy
Tirzepatide • Mounjaro
Topiramate • Topamax
Zonisamide • Zonegran
1. Afzal M, Siddiqi N, Ahmad B, et al. Prevalence of overweight and obesity in people with severe mental illness: systematic review and meta-analysis. Front Endocrinol (Lausanne). 2021;25;12:769309.
2. Barton BB, Segger F, Fischer K, et al. Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis. Expert Opin Drug Safety. 2020;19(3):295-314.
3. de Silva AV, Suraweera C, Ratnatunga SS, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.
4. Durell N, Franks R, Coon S, et al. Effects of antidepressants on glucagon-like peptide-1 receptor agonist-related weight loss. J Pharm Technol. 2022;38(5):283-288.
5. Larsen JR, Vedtofte L, Jakobsen MSL, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry. 2017;74(7):719-728.
6. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care. 2019;42(9):1724-1732.
7. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002.
8. Weghuber D, Barrett T, Barrientos-Pérez M, et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med. Published online November 2, 2022. doi:10.1056/NEJMoa2208601.
9. Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomized, double-blind, phase 3a trial. Lancet. 2019;394(10192):39-50.
10. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216.
11. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-515.
Obesity and overweight, with or without metabolic dysregulation, pose vexing problems for many patients with mood, anxiety, or psychotic disorders. More than one-half of individuals with severe mental illnesses are obese or overweight,1 resulting from multiple factors that may include psychiatric symptoms (eg, anergia and hyperphagia), poor dietary choices, sedentary lifestyle, underlying inflammatory processes, medical comorbidities, and iatrogenic consequences of certain medications. Unfortunately, numerous psychotropic medications can increase weight and appetite due to a variety of mechanisms, including antihistaminergic effects, direct appetite-stimulating effects, and proclivities to cause insulin resistance. While individual agents can vary, a recent review identified an overall 2-fold increased risk for rapid, significant weight gain during treatment with antipsychotics as a class.2 In addition to lifestyle modifications (diet and exercise), many pharmacologic strategies have been proposed to counter iatrogenic weight gain, including appetite suppressants (eg, pro-dopaminergic agents such as phentermine, stimulants, and amantadine), pro-anorectant anticonvulsants (eg, topiramate or zonisamide), opioid receptor antagonists (eg, olanzapine/samidorphan or naltrexone) and oral hypoglycemics such as metformin. However, the magnitude of impact for most of these agents to reverse iatrogenic weight gain tends to be modest, particularly once significant weight gain (ie, ≥7% of initial body weight) has already occurred.
Pharmacologic strategies to modulate or enhance the effects of insulin hold particular importance for combatting psychotropic-associated weight gain. Insulin transports glucose from the intravascular space to end organs for fuel consumption; to varying degrees, second-generation antipsychotics (SGAs) and some other psychotropic medications can cause insulin resistance. This in turn leads to excessive storage of underutilized glucose in the liver (glycogenesis), the potential for developing fatty liver (ie, nonalcoholic steatohepatitis), and conversion of excess carbohydrates to fatty acids and triglycerides, with subsequent storage in adipose tissue. Medications that can enhance the activity of insulin (so-called incretin mimetics) can help to overcome insulin resistance caused by SGAs (and potentially by other psychotropic medications) and essentially lead to weight loss through enhanced “fuel efficiency.”
Metformin, typically dosed up to 1,000 mg twice daily with meals, has increasingly become recognized as a first-line strategy to attenuate weight gain and glycemic dysregulation from SGAs via its ability to reduce insulin resistance. Yet meta-analyses have shown that although results are significantly better than placebo, overall long-term weight loss from metformin alone tends to be rather modest (<4 kg) and associated with a reduction in body mass index (BMI) of only approximately 1 point.3 Psychiatrists (and other clinicians who prescribe psychotropic medications that can cause weight gain or metabolic dysregulation) therefore need to become familiar with alternative or adjunctive weight loss options. The use of a relatively new class of incretin mimetics called glucagon-like peptide 1 (GLP-1) agonists (Table) has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation.
What are GLP-1 agonists?
GLP-1 is a hormone secreted by L cells in the intestinal mucosa in response to food. GLP-1 agonists reduce blood sugar by increasing insulin secretion, decreasing glucagon release (thus downregulating further increases in blood sugar), and reducing insulin resistance. GLP-1 agonists also reduce appetite by directly stimulating the satiety center and slowing gastric emptying and GI motility. In addition to GLP-1 agonism, some medications in this family (notably tirzepatide) also agonize a second hormone, glucose-dependent insulinotropic polypeptide, which can further induce insulin secretion as well as decrease stomach acid secretion, potentially delivering an even more substantial reduction in appetite and weight.
Routes of administration and FDA indications
Due to limited bioavailability, most GLP-1 agonists require subcutaneous (SC) injections (the sole exception is the Rybelsus brand of semaglutide, which comes in a daily pill form). Most are FDA-approved not specifically for weight loss but for patients with type 2 diabetes (defined as a hemoglobin A1C ≥6.5% or a fasting blood glucose level ≥126 mg/dL). Weight loss represents a secondary outcome for GLP-1 agonists FDA-approved for glycemic control in patients with type 2 diabetes. The 2 current exceptions to this classification are the Wegovy brand of semaglutide (ie, dosing of 2.4 mg) and the Saxenda brand of liraglutide, both of which carry FDA indications for chronic weight management alone (when paired with dietary and lifestyle modification) in individuals who are obese (BMI >30 kg/m2) regardless of the presence or absence of diabetes, or for persons who are overweight (BMI >27 kg/m2) and have ≥1 weight-related comorbid condition (eg, hypertension, type 2 diabetes, or dyslipidemia). Although patients at risk for diabetes (ie, prediabetes, defined as a hemoglobin A1C 5.7% to 6.4% or a fasting blood glucose level 100 to 125 mg/dL) were included in FDA registration trials of Saxenda or Wegovy, prediabetes is not an FDA indication for any GLP-1 agonist.
Data in weight loss
Most of the existing empirical data on weight loss with GLP-1 agonists come from studies of individuals who are overweight or obese, with or without type 2 diabetes, rather than from studies using these agents to counteract iatrogenic weight gain. In a retrospective cohort study of patients with type 2 diabetes, coadministration with serotonergic antidepressants (eg, citalopram/escitalopram) was associated with attenuation of the weight loss effects of GLP-1 agonists.4
Liraglutide currently is the sole GLP-1 agonist studied for treating SGA-associated weight gain. A 16-week randomized trial compared once-daily SC injected liraglutide vs placebo in patients with schizophrenia who incurred weight gain and prediabetes after taking olanzapine or clozapine.5 Significantly more patients taking liraglutide than placebo developed normal glucose tolerance (64% vs 16%), and body weight decreased by a mean of 5.3 kg.
Continue to: In studies of semaglutide...
In studies of semaglutide for overweight/obese patients with type 2 diabetes or prediabetes, clinical trials of oral semaglutide (Rybelsus) found a mean weight loss over 26 weeks of -1.0 kg with dosing at 7 mg/d and -2.6 kg with dosing at 14 mg/d.6 A 68-week placebo-controlled trial of semaglutide (dosed at 2.4 mg SC weekly) for overweight/obese adults who did not have diabetes yielded a -15.3 kg weight loss (vs -2.6 kg with placebo); one-half of those who received semaglutide lost 15% of their initial body weight (Figure 1A and Figure 1B).7 Similar findings with semaglutide 2.4 mg SC weekly (Wegovy) were observed in overweight/obese adolescents, with 73% of participants losing ≥5% of their baseline weight.8 A comparative randomized trial in patients with type 2 diabetes also found modestly but significantly greater weight loss with oral semaglutide than with SC liraglutide.9
In a 72-week study of tirzepatide specifically for weight loss in nondiabetic patients who were overweight or obese, findings were especially dramatic (Figure 2A and Figure 2B).10 An overall 15% decrease in body weight was observed with 5 mg/week dosing alongside a 19.5% decrease in body weight with 10 mg/week dosing and a 20.9% weight reduction with 15 mg/week dosing.10 As noted in Figure 2B, the observed pattern of weight loss occurred along an exponential decay curve. Notably, a comparative study of tirzepatide vs once-weekly semaglutide (1 mg) in patients with type 2 diabetes11 found significantly greater dose-dependent weight loss with tirzepatide than semaglutide (-1.9 kg at 5 mg, -3.6 kg at 10 mg, and -5.5 kg at 15 mg)—although the somewhat low dosing of semaglutide may have limited its optimal possible weight loss benefit.
Tolerability
Adverse effects with GLP-1 agonists are mainly gastrointestinal (eg, nausea, vomiting, abdominal pain, diarrhea, or constipation)5-11 and generally transient. SC administration is performed in fatty tissue of the abdomen, thigh, or upper arm; site rotation is recommended to minimize injection site pain. All GLP-1 agonists carry manufacturers’ warning and precaution statements identifying the rare potential for acute pancreatitis, acute gall bladder disease, acute kidney injury, and hypoglycemia. Animal studies also have suggested an increased, dose-dependent risk for thyroid C-cell tumors with GLP-1 agonists; this has not been observed in human trials, although postmarketing pharmacovigilance reports have identified cases of medullary thyroid carcinoma in patients who took liraglutide. A manufacturer’s boxed warning indicates that a personal or family history of medullary carcinoma of the thyroid poses a contraindication for taking semaglutide, liraglutide, or tirzepatide.
Initial evidence prompts additional questions
GLP-1 agonists represent an emerging class of novel agents that can modulate glycemic dysregulation and overweight/obesity, often with dramatic results whose magnitude rivals the efficacy of bariatric surgery. Once-weekly formulations of semaglutide (Wegovy) and daily liraglutide (Saxenda) are FDA-approved for weight loss in patients who are overweight or obese while other existing formulations are approved solely for patients with type 2 diabetes, although it is likely that broader indications for weight loss (regardless of glycemic status) are forthcoming. Targeted use of GLP-1 agonists to counteract SGA-associated weight gain is supported by a handful of preliminary reports, with additional studies likely to come. Unanswered questions include:
- When should GLP-1 agonists be considered within a treatment algorithm for iatrogenic weight gain relative to other antidote strategies such as metformin or appetite-suppressing anticonvulsants?
- How effective might GLP-1 agonists be for iatrogenic weight gain from non-SGA psychotropic medications, such as serotonergic antidepressants?
- When and how can GLP-1 agonists be safely coprescribed with other nonincretin mimetic weight loss medications?
- When should psychiatrists prescribe GLP-1 agonists, or do so collaboratively with primary care physicians or endocrinologists, particularly in patients with metabolic syndrome?
Followers of the rapidly emerging literature in this area will likely find themselves best positioned to address these and other questions about optimal management of psychotropic-induced weight gain for the patients they treat.
Bottom Line
The use of glucagon-like peptide 1 (GLP-1) agonists, a relatively new class of incretin mimetics, has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation. Preliminary reports support the potential targeted use of GLP-1 agonists to counteract weight gain associated with second-generation antipsychotics.
Related Resources
- Singh F, Allen A, Ianni A. Managing metabolic syndrome in patients with schizophrenia. Current Psychiatry. 2020;19(12):20-24,26. doi:10.12788/cp.0064
- Ard J, Fitch A, Fruh S, et al. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv Ther. 2021;38(6):2821- 2839. doi:10.1007/s12325-021-01710-0
Drug Brand Names
Amantadine • Gocovri
Citalopram • Celexa
Clozapine • Clozaril
Escitalopram • Lexapro
Liraglutide • Victoza, Saxenda
Metformin • Glucophage
Naltrexone • ReVia
Olanzapine • Zyprexa
Olanzapine/samidorphan • Lybalvi
Phentermine • Ionamin
Semaglutide • Rybelsus, Ozempic, Wegovy
Tirzepatide • Mounjaro
Topiramate • Topamax
Zonisamide • Zonegran
Obesity and overweight, with or without metabolic dysregulation, pose vexing problems for many patients with mood, anxiety, or psychotic disorders. More than one-half of individuals with severe mental illnesses are obese or overweight,1 resulting from multiple factors that may include psychiatric symptoms (eg, anergia and hyperphagia), poor dietary choices, sedentary lifestyle, underlying inflammatory processes, medical comorbidities, and iatrogenic consequences of certain medications. Unfortunately, numerous psychotropic medications can increase weight and appetite due to a variety of mechanisms, including antihistaminergic effects, direct appetite-stimulating effects, and proclivities to cause insulin resistance. While individual agents can vary, a recent review identified an overall 2-fold increased risk for rapid, significant weight gain during treatment with antipsychotics as a class.2 In addition to lifestyle modifications (diet and exercise), many pharmacologic strategies have been proposed to counter iatrogenic weight gain, including appetite suppressants (eg, pro-dopaminergic agents such as phentermine, stimulants, and amantadine), pro-anorectant anticonvulsants (eg, topiramate or zonisamide), opioid receptor antagonists (eg, olanzapine/samidorphan or naltrexone) and oral hypoglycemics such as metformin. However, the magnitude of impact for most of these agents to reverse iatrogenic weight gain tends to be modest, particularly once significant weight gain (ie, ≥7% of initial body weight) has already occurred.
Pharmacologic strategies to modulate or enhance the effects of insulin hold particular importance for combatting psychotropic-associated weight gain. Insulin transports glucose from the intravascular space to end organs for fuel consumption; to varying degrees, second-generation antipsychotics (SGAs) and some other psychotropic medications can cause insulin resistance. This in turn leads to excessive storage of underutilized glucose in the liver (glycogenesis), the potential for developing fatty liver (ie, nonalcoholic steatohepatitis), and conversion of excess carbohydrates to fatty acids and triglycerides, with subsequent storage in adipose tissue. Medications that can enhance the activity of insulin (so-called incretin mimetics) can help to overcome insulin resistance caused by SGAs (and potentially by other psychotropic medications) and essentially lead to weight loss through enhanced “fuel efficiency.”
Metformin, typically dosed up to 1,000 mg twice daily with meals, has increasingly become recognized as a first-line strategy to attenuate weight gain and glycemic dysregulation from SGAs via its ability to reduce insulin resistance. Yet meta-analyses have shown that although results are significantly better than placebo, overall long-term weight loss from metformin alone tends to be rather modest (<4 kg) and associated with a reduction in body mass index (BMI) of only approximately 1 point.3 Psychiatrists (and other clinicians who prescribe psychotropic medications that can cause weight gain or metabolic dysregulation) therefore need to become familiar with alternative or adjunctive weight loss options. The use of a relatively new class of incretin mimetics called glucagon-like peptide 1 (GLP-1) agonists (Table) has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation.
What are GLP-1 agonists?
GLP-1 is a hormone secreted by L cells in the intestinal mucosa in response to food. GLP-1 agonists reduce blood sugar by increasing insulin secretion, decreasing glucagon release (thus downregulating further increases in blood sugar), and reducing insulin resistance. GLP-1 agonists also reduce appetite by directly stimulating the satiety center and slowing gastric emptying and GI motility. In addition to GLP-1 agonism, some medications in this family (notably tirzepatide) also agonize a second hormone, glucose-dependent insulinotropic polypeptide, which can further induce insulin secretion as well as decrease stomach acid secretion, potentially delivering an even more substantial reduction in appetite and weight.
Routes of administration and FDA indications
Due to limited bioavailability, most GLP-1 agonists require subcutaneous (SC) injections (the sole exception is the Rybelsus brand of semaglutide, which comes in a daily pill form). Most are FDA-approved not specifically for weight loss but for patients with type 2 diabetes (defined as a hemoglobin A1C ≥6.5% or a fasting blood glucose level ≥126 mg/dL). Weight loss represents a secondary outcome for GLP-1 agonists FDA-approved for glycemic control in patients with type 2 diabetes. The 2 current exceptions to this classification are the Wegovy brand of semaglutide (ie, dosing of 2.4 mg) and the Saxenda brand of liraglutide, both of which carry FDA indications for chronic weight management alone (when paired with dietary and lifestyle modification) in individuals who are obese (BMI >30 kg/m2) regardless of the presence or absence of diabetes, or for persons who are overweight (BMI >27 kg/m2) and have ≥1 weight-related comorbid condition (eg, hypertension, type 2 diabetes, or dyslipidemia). Although patients at risk for diabetes (ie, prediabetes, defined as a hemoglobin A1C 5.7% to 6.4% or a fasting blood glucose level 100 to 125 mg/dL) were included in FDA registration trials of Saxenda or Wegovy, prediabetes is not an FDA indication for any GLP-1 agonist.
Data in weight loss
Most of the existing empirical data on weight loss with GLP-1 agonists come from studies of individuals who are overweight or obese, with or without type 2 diabetes, rather than from studies using these agents to counteract iatrogenic weight gain. In a retrospective cohort study of patients with type 2 diabetes, coadministration with serotonergic antidepressants (eg, citalopram/escitalopram) was associated with attenuation of the weight loss effects of GLP-1 agonists.4
Liraglutide currently is the sole GLP-1 agonist studied for treating SGA-associated weight gain. A 16-week randomized trial compared once-daily SC injected liraglutide vs placebo in patients with schizophrenia who incurred weight gain and prediabetes after taking olanzapine or clozapine.5 Significantly more patients taking liraglutide than placebo developed normal glucose tolerance (64% vs 16%), and body weight decreased by a mean of 5.3 kg.
Continue to: In studies of semaglutide...
In studies of semaglutide for overweight/obese patients with type 2 diabetes or prediabetes, clinical trials of oral semaglutide (Rybelsus) found a mean weight loss over 26 weeks of -1.0 kg with dosing at 7 mg/d and -2.6 kg with dosing at 14 mg/d.6 A 68-week placebo-controlled trial of semaglutide (dosed at 2.4 mg SC weekly) for overweight/obese adults who did not have diabetes yielded a -15.3 kg weight loss (vs -2.6 kg with placebo); one-half of those who received semaglutide lost 15% of their initial body weight (Figure 1A and Figure 1B).7 Similar findings with semaglutide 2.4 mg SC weekly (Wegovy) were observed in overweight/obese adolescents, with 73% of participants losing ≥5% of their baseline weight.8 A comparative randomized trial in patients with type 2 diabetes also found modestly but significantly greater weight loss with oral semaglutide than with SC liraglutide.9
In a 72-week study of tirzepatide specifically for weight loss in nondiabetic patients who were overweight or obese, findings were especially dramatic (Figure 2A and Figure 2B).10 An overall 15% decrease in body weight was observed with 5 mg/week dosing alongside a 19.5% decrease in body weight with 10 mg/week dosing and a 20.9% weight reduction with 15 mg/week dosing.10 As noted in Figure 2B, the observed pattern of weight loss occurred along an exponential decay curve. Notably, a comparative study of tirzepatide vs once-weekly semaglutide (1 mg) in patients with type 2 diabetes11 found significantly greater dose-dependent weight loss with tirzepatide than semaglutide (-1.9 kg at 5 mg, -3.6 kg at 10 mg, and -5.5 kg at 15 mg)—although the somewhat low dosing of semaglutide may have limited its optimal possible weight loss benefit.
Tolerability
Adverse effects with GLP-1 agonists are mainly gastrointestinal (eg, nausea, vomiting, abdominal pain, diarrhea, or constipation)5-11 and generally transient. SC administration is performed in fatty tissue of the abdomen, thigh, or upper arm; site rotation is recommended to minimize injection site pain. All GLP-1 agonists carry manufacturers’ warning and precaution statements identifying the rare potential for acute pancreatitis, acute gall bladder disease, acute kidney injury, and hypoglycemia. Animal studies also have suggested an increased, dose-dependent risk for thyroid C-cell tumors with GLP-1 agonists; this has not been observed in human trials, although postmarketing pharmacovigilance reports have identified cases of medullary thyroid carcinoma in patients who took liraglutide. A manufacturer’s boxed warning indicates that a personal or family history of medullary carcinoma of the thyroid poses a contraindication for taking semaglutide, liraglutide, or tirzepatide.
Initial evidence prompts additional questions
GLP-1 agonists represent an emerging class of novel agents that can modulate glycemic dysregulation and overweight/obesity, often with dramatic results whose magnitude rivals the efficacy of bariatric surgery. Once-weekly formulations of semaglutide (Wegovy) and daily liraglutide (Saxenda) are FDA-approved for weight loss in patients who are overweight or obese while other existing formulations are approved solely for patients with type 2 diabetes, although it is likely that broader indications for weight loss (regardless of glycemic status) are forthcoming. Targeted use of GLP-1 agonists to counteract SGA-associated weight gain is supported by a handful of preliminary reports, with additional studies likely to come. Unanswered questions include:
- When should GLP-1 agonists be considered within a treatment algorithm for iatrogenic weight gain relative to other antidote strategies such as metformin or appetite-suppressing anticonvulsants?
- How effective might GLP-1 agonists be for iatrogenic weight gain from non-SGA psychotropic medications, such as serotonergic antidepressants?
- When and how can GLP-1 agonists be safely coprescribed with other nonincretin mimetic weight loss medications?
- When should psychiatrists prescribe GLP-1 agonists, or do so collaboratively with primary care physicians or endocrinologists, particularly in patients with metabolic syndrome?
Followers of the rapidly emerging literature in this area will likely find themselves best positioned to address these and other questions about optimal management of psychotropic-induced weight gain for the patients they treat.
Bottom Line
The use of glucagon-like peptide 1 (GLP-1) agonists, a relatively new class of incretin mimetics, has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation. Preliminary reports support the potential targeted use of GLP-1 agonists to counteract weight gain associated with second-generation antipsychotics.
Related Resources
- Singh F, Allen A, Ianni A. Managing metabolic syndrome in patients with schizophrenia. Current Psychiatry. 2020;19(12):20-24,26. doi:10.12788/cp.0064
- Ard J, Fitch A, Fruh S, et al. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv Ther. 2021;38(6):2821- 2839. doi:10.1007/s12325-021-01710-0
Drug Brand Names
Amantadine • Gocovri
Citalopram • Celexa
Clozapine • Clozaril
Escitalopram • Lexapro
Liraglutide • Victoza, Saxenda
Metformin • Glucophage
Naltrexone • ReVia
Olanzapine • Zyprexa
Olanzapine/samidorphan • Lybalvi
Phentermine • Ionamin
Semaglutide • Rybelsus, Ozempic, Wegovy
Tirzepatide • Mounjaro
Topiramate • Topamax
Zonisamide • Zonegran
1. Afzal M, Siddiqi N, Ahmad B, et al. Prevalence of overweight and obesity in people with severe mental illness: systematic review and meta-analysis. Front Endocrinol (Lausanne). 2021;25;12:769309.
2. Barton BB, Segger F, Fischer K, et al. Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis. Expert Opin Drug Safety. 2020;19(3):295-314.
3. de Silva AV, Suraweera C, Ratnatunga SS, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.
4. Durell N, Franks R, Coon S, et al. Effects of antidepressants on glucagon-like peptide-1 receptor agonist-related weight loss. J Pharm Technol. 2022;38(5):283-288.
5. Larsen JR, Vedtofte L, Jakobsen MSL, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry. 2017;74(7):719-728.
6. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care. 2019;42(9):1724-1732.
7. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002.
8. Weghuber D, Barrett T, Barrientos-Pérez M, et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med. Published online November 2, 2022. doi:10.1056/NEJMoa2208601.
9. Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomized, double-blind, phase 3a trial. Lancet. 2019;394(10192):39-50.
10. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216.
11. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-515.
1. Afzal M, Siddiqi N, Ahmad B, et al. Prevalence of overweight and obesity in people with severe mental illness: systematic review and meta-analysis. Front Endocrinol (Lausanne). 2021;25;12:769309.
2. Barton BB, Segger F, Fischer K, et al. Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis. Expert Opin Drug Safety. 2020;19(3):295-314.
3. de Silva AV, Suraweera C, Ratnatunga SS, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.
4. Durell N, Franks R, Coon S, et al. Effects of antidepressants on glucagon-like peptide-1 receptor agonist-related weight loss. J Pharm Technol. 2022;38(5):283-288.
5. Larsen JR, Vedtofte L, Jakobsen MSL, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry. 2017;74(7):719-728.
6. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care. 2019;42(9):1724-1732.
7. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002.
8. Weghuber D, Barrett T, Barrientos-Pérez M, et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med. Published online November 2, 2022. doi:10.1056/NEJMoa2208601.
9. Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomized, double-blind, phase 3a trial. Lancet. 2019;394(10192):39-50.
10. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216.
11. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-515.
Managing excited catatonia: A suggested approach
Catatonia is often difficult to identify and treat. The excited catatonia subtype can be particularly challenging to diagnose because it can present with symptoms similar to those seen in mania or psychosis. In this article, we present 3 cases of excited catatonia that illustrate how to identify it, how to treat the catatonia as well as the underlying pathology, and factors to consider during this process to mitigate the risk of adverse outcomes. We also outline a treatment algorithm we used for the 3 cases. Although we describe using this approach for patients with excited catatonia, it is generalizable to other types of catatonia.
Many causes, varying presentations
Catatonia is a psychomotor syndrome characterized by mutism, negativism, stereotypy, waxy flexibility, and other symptoms.1 It is defined by the presence of ≥3 of the 12 symptoms listed in the Table.2 Causes of catatonia include metabolic abnormalities, endocrine disorders, drug intoxication, neurodevelopmental disorders, medication adverse effects, psychosis, and mood disorders.1,3
A subtype of this syndrome, excited catatonia, can present with restlessness, agitation, emotional lability, poor sleep, and altered mental status in addition to the more typical symptoms.1,4 Because excited catatonia can resemble mania or psychosis, it is particularly challenging to identify the underlying disorder causing it and appropriate treatment. Fink et al4 discussed how clinicians have interpreted the different presentations of excited catatonia to gain insight into the underlying diagnosis. If the patient’s thought process appears disorganized, psychosis may be suspected.4 If the patient is delusional and grandiose, they may be manic, and when altered mental status dominates the presentation, delirium may be the culprit.4
Regardless of the underlying cause, the first step is to treat the catatonia. Benzodiazepines and electroconvulsive therapy (ECT) are the most well validated treatments for catatonia and have been used to treat excited catatonia.1 Excited catatonia is often misdiagnosed and subsequently mistreated. In the following 3 cases, excited catatonia was successfully identified and treated using the same approach (Figure).
Case 1
Mr. A, age 27, has a history of bipolar I disorder. He was brought to the hospital by ambulance after being found to be yelling and acting belligerently, and he was admitted to the inpatient psychiatry unit for manic decompensation due to medication nonadherence. He was started on divalproex sodium 500 mg twice a day for mood stabilization, risperidone 1 mg twice a day for adjunct mood stabilization and psychosis, and lorazepam 1 mg 3 times a day for agitation. Mr. A exhibited odd behavior; he would take off his clothes in the hallway, run around the unit, and randomly yell at staff or to himself. At other times, he would stay silent, repeat the same statements, or oddly posture in the hallway for minutes at a time. These behaviors were seen primarily in the hour or 2 preceding lorazepam administration and improved after he received lorazepam.
Mr. A’s treating team completed the Bush-Francis Catatonia Rating Scale (BFCRS), which yielded a positive catatonia screen of 7/14. As a result, divalproex sodium and risperidone were held, and lorazepam was increased to 2 mg twice a day.
After several days, Mr. A was no longer acting oddly and was able to speak more spontaneously; however, he began to exhibit overt signs of mania. He would speak rapidly and make grandiose claims about managing millions of dollars as the CEO of a famous company. Divalproex sodium was restarted at 500 mg twice a day and increased to 500 mg 3 times a day for mood stabilization. Mr. A continued to receive lorazepam 2 mg 3 times a day for catatonia, and risperidone was restarted at 1 mg twice a day to more effectively target his manic symptoms. Risperidone was increased to 2 mg twice a day. After this change, Mr. A’s grandiosity dissipated, his speech normalized, and his thought process became organized. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium 500 mg 3 times a day, and risperidone 2 mg twice a day. Mr. A’s length of stay (LOS) for this admission was 11 days.
Continue to: Case 2
Case 2
Mr. B, age 49, presented with irritability and odd posturing. He has a history of schizoaffective disorder, bipolar type for which he was receiving a maintenance regimen of lithium 600 mg/d at bedtime and risperidone 2 mg/d at bedtime. He had multiple previous psychiatric admissions for catatonia. On this admission, Mr. B was irritable and difficult to redirect. He yelled at staff members and had a stiff gait. The BFCRS yielded a positive screening score of 3/14 and a severity score of 8/23. As a result, the treatment team conducted a lorazepam challenge.
After Mr. B received lorazepam 1 mg IM, his thought organization and irritability improved, which allowed him to have a coherent conversation with the interviewer. His gait stiffness also improved. His risperidone and lithium were held, and oral lorazepam 1 mg 3 times a day was started for catatonia. Lorazepam was gradually increased to 4 mg 3 times a day. Mr. B became euthymic and redirectable, and had an improved gait. However, he was also tangential and hyperverbal; these symptoms were indicative of the underlying mania that precipitated his catatonia.
Divalproex sodium extended release (ER) was started and increased to 1,500 mg/d at bedtime for mood stabilization. Lithium was restarted and increased to 300 mg twice a day for adjunct mood stabilization. Risperidone was not restarted. Toward the end of his admission, Mr. B was noted to be overly sedated, so the lorazepam dosage was decreased. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium ER 1,500 mg/d at bedtime, and lithium 300 mg twice a day. At discharge, Mr. B was calm and euthymic, with a linear thought process. His LOS was 25 days.
Case 3
Mr. C, age 62, presented to the emergency department (ED) because he had exhibited erratic behavior and had not slept for the past week. He has a history of bipolar I disorder, hypothyroidism, diabetes, and hypertension. For many years, he had been stable on divalproex sodium ER 2,500 mg/d at bedtime for mood stabilization and clozapine 100 mg/d at bedtime for adjunct mood stabilization and psychosis. In the ED, Mr. C was irritable, distractible, and tangential. On admission, he was speaking slowly with increased speech latency in response to questions, exhibiting stereotypy, repeating statements over and over, and walking very slowly.
The BFCRS yielded a positive screening score of 5/14 and a severity score of 10/23. Lorazepam 1 mg IM was administered. After 15 minutes, Mr. C’s speech, gait, and distractibility improved. As a result, clozapine and divalproex sodium were held, and he was started on oral lorazepam 1 mg 3 times a day. After several days, Mr. C was speaking fluently and no longer exhibiting stereotypy or having outbursts where he would make repetitive statements. However, he was tangential and irritable at times, which were signs of his underlying mania. Divalproex sodium ER was restarted at 250 mg/d at bedtime for mood stabilization and gradually increased to 2,500 mg/d at bedtime. Clozapine was also restarted at 25 mg/d at bedtime and gradually increased to 200 mg/d at bedtime. The lorazepam was gradually tapered and discontinued over the course of 3 weeks due to oversedation.
Continue to: At discharge...
At discharge, Mr. C was euthymic, calm, linear, and goal-directed. He was discharged on divalproex sodium ER 2,500 mg/d at bedtime and clozapine 200 mg/d at bedtime. His LOS for this admission was 22 days.
A stepwise approach can improve outcomes
The Figure outlines the method we used to manage excited catatonia in these 3 cases. Each of these patients exhibited signs of excited catatonia, but because those symptoms were nearly identical to those of mania, it was initially difficult to identify catatonia. Excited catatonia was suspected after more typical catatonic symptoms—such as a stiff gait, slowed speech, and stereotypy—were observed. The BFCRS was completed to get an objective measure of the likelihood that the patient was catatonic. In all 3 cases, the BFCRS resulted in a positive screen for catatonia. Following this, the patients described in Case 2 and Case 3 received a lorazepam challenge, which confirmed their catatonia. No lorazepam challenge was performed in Case 1 because the patient was already receiving lorazepam when the BFCRS was completed. Although most catatonic patients will respond to a lorazepam challenge, not all will. Therefore, clinicians should maintain some degree of suspicion for catatonia if a patient has a positive screen on the BFCRS but a negative lorazepam challenge.
In all 3 cases, after catatonia was confirmed, the patient’s psychotropic medications were discontinued. In all 3 cases, the antipsychotic was held to prevent progression to neuroleptic malignant syndrome (NMS) or malignant catatonia. Rasmussen et al3 found that 3.6% of the catatonic patients in their sample who were treated with antipsychotics developed NMS. A review of prospective studies looking at patients treated with antipsychotics found the incidence of NMS was .07% to 1.8%.5 Because NMS is often clinically indistinguishable from malignant catatonia,4,6 this incidence of NMS may have represented an increased incidence in malignant catatonia.
In all 3 cases, the mood stabilizer was held to prevent it from complicating the clinical picture. Discontinuing the mood stabilizer and focusing on treating the catatonia before targeting the underlying mania increased the likelihood of differentiating the patient’s catatonic symptoms from manic symptoms. This resulted in more precise medication selection and titration by allowing us to identify the specific symptoms that were being targeted by each medication.
Oral lorazepam was prescribed to target catatonia in all 3 cases, and the dosage was gradually increased until symptoms began to resolve. As the catatonia resolved, the manic symptoms became more easily identifiable, and at this point a mood stabilizer was started and titrated to a therapeutic dose to target the mania. In Case 1 and Case 3, the antipsychotic was restarted to treat the mania more effectively. It was not restarted in Case 2 because the patient’s mania was effectively being managed by 2 mood stabilizers. The risks and benefits of starting an antipsychotic in a catatonic or recently catatonic patient should be carefully considered. In the 2 cases where the antipsychotic was restarted, the patients were closely monitored, and there were no signs of NMS or malignant catatonia.
Continue to: As discharge approached...
As discharge approached, the dosages of oral lorazepam were reevaluated. Catatonic patients can typically tolerate high doses of benzodiazepines without becoming overly sedated, but each patient has a different threshold at which the dosage causes oversedation. In all 3 patients, lorazepam was initially titrated to a dose that treated their catatonic symptoms without causing intolerable sedation. In Case 2 and Case 3, as the catatonia began to resolve, the patients became increasingly sedated on their existing lorazepam dosage, so it was decreased. Because the patient in Case 1 did not become overly sedated, his lorazepam dosage did not need to be reduced.
For 2 of these patients, our approach resulted in a shorter LOS compared to their previous hospitalizations. The LOS in Case 2 was 25 days; 5 years earlier, he had a 49-day LOS for mania and catatonia. During the past admission, the identification and treatment of the catatonia was delayed, which resulted in the patient requiring multiple transfers to the medical unit for unstable vital signs. The LOS in Case 3 was 22 days; 6 months prior to this admission, the patient had 2 psychiatric admissions that totaled 37 days. Although the patient’s presentation in the 2 previous admissions was similar to his presentation as described in Case 3, catatonia had not been identified or treated in either admission. Since his catatonia and mania were treated in Case 3, he has not required a readmission. The patient in Case 1 was previously hospitalized, but information about the LOS of these admissions was not available. These results suggest that early identification and treatment of catatonia via the approach we used can improve patient outcomes.
Bottom Line
Excited catatonia can be challenging to diagnose and treat because it can present with symptoms similar to those seen in mania or psychosis. We describe 3 cases in which we used a stepwise approach to optimize treatment and improve outcomes for patients with excited catatonia. This approach may work equally well for other catatonia subtypes.
Related Resources
- Dubovsky SL, Dubovsky AN. Catatonia: how to identify and treat it. Current Psychiatry. 2018;17(8):16-26.
- Crouse EL, Joel B. Moran JB. Catatonia: recognition, management, and prevention of complications. Current Psychiatry. 2018;17(12):45-49.
Drug Brand Names
Clozapine • Clozaril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Risperidone • Risperdal
Divalproex sodium • Depakote
1. Fink M, Taylor MA. The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci. 2001;251(Suppl 1):8-13.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013:119-121.
3. Rasmussen SA, Mazurek MF, Rosebush PI. Catatonia: our current understanding of its diagnosis, treatment and pathophysiology. World J Psychiatry. 2016;6(4):391-398.
4. Fink M, Taylor MA. Catatonia: A Clinician’s Guide to Diagnosis and Treatment. Cambridge University Press; 2003.
5. Adityanjee, Aderibigbe YA, Matthews T. Epidemiology of neuroleptic malignant syndrome. Clin Neuropharmacol. 1999;22(3):151-158.
6. Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876.
Catatonia is often difficult to identify and treat. The excited catatonia subtype can be particularly challenging to diagnose because it can present with symptoms similar to those seen in mania or psychosis. In this article, we present 3 cases of excited catatonia that illustrate how to identify it, how to treat the catatonia as well as the underlying pathology, and factors to consider during this process to mitigate the risk of adverse outcomes. We also outline a treatment algorithm we used for the 3 cases. Although we describe using this approach for patients with excited catatonia, it is generalizable to other types of catatonia.
Many causes, varying presentations
Catatonia is a psychomotor syndrome characterized by mutism, negativism, stereotypy, waxy flexibility, and other symptoms.1 It is defined by the presence of ≥3 of the 12 symptoms listed in the Table.2 Causes of catatonia include metabolic abnormalities, endocrine disorders, drug intoxication, neurodevelopmental disorders, medication adverse effects, psychosis, and mood disorders.1,3
A subtype of this syndrome, excited catatonia, can present with restlessness, agitation, emotional lability, poor sleep, and altered mental status in addition to the more typical symptoms.1,4 Because excited catatonia can resemble mania or psychosis, it is particularly challenging to identify the underlying disorder causing it and appropriate treatment. Fink et al4 discussed how clinicians have interpreted the different presentations of excited catatonia to gain insight into the underlying diagnosis. If the patient’s thought process appears disorganized, psychosis may be suspected.4 If the patient is delusional and grandiose, they may be manic, and when altered mental status dominates the presentation, delirium may be the culprit.4
Regardless of the underlying cause, the first step is to treat the catatonia. Benzodiazepines and electroconvulsive therapy (ECT) are the most well validated treatments for catatonia and have been used to treat excited catatonia.1 Excited catatonia is often misdiagnosed and subsequently mistreated. In the following 3 cases, excited catatonia was successfully identified and treated using the same approach (Figure).
Case 1
Mr. A, age 27, has a history of bipolar I disorder. He was brought to the hospital by ambulance after being found to be yelling and acting belligerently, and he was admitted to the inpatient psychiatry unit for manic decompensation due to medication nonadherence. He was started on divalproex sodium 500 mg twice a day for mood stabilization, risperidone 1 mg twice a day for adjunct mood stabilization and psychosis, and lorazepam 1 mg 3 times a day for agitation. Mr. A exhibited odd behavior; he would take off his clothes in the hallway, run around the unit, and randomly yell at staff or to himself. At other times, he would stay silent, repeat the same statements, or oddly posture in the hallway for minutes at a time. These behaviors were seen primarily in the hour or 2 preceding lorazepam administration and improved after he received lorazepam.
Mr. A’s treating team completed the Bush-Francis Catatonia Rating Scale (BFCRS), which yielded a positive catatonia screen of 7/14. As a result, divalproex sodium and risperidone were held, and lorazepam was increased to 2 mg twice a day.
After several days, Mr. A was no longer acting oddly and was able to speak more spontaneously; however, he began to exhibit overt signs of mania. He would speak rapidly and make grandiose claims about managing millions of dollars as the CEO of a famous company. Divalproex sodium was restarted at 500 mg twice a day and increased to 500 mg 3 times a day for mood stabilization. Mr. A continued to receive lorazepam 2 mg 3 times a day for catatonia, and risperidone was restarted at 1 mg twice a day to more effectively target his manic symptoms. Risperidone was increased to 2 mg twice a day. After this change, Mr. A’s grandiosity dissipated, his speech normalized, and his thought process became organized. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium 500 mg 3 times a day, and risperidone 2 mg twice a day. Mr. A’s length of stay (LOS) for this admission was 11 days.
Continue to: Case 2
Case 2
Mr. B, age 49, presented with irritability and odd posturing. He has a history of schizoaffective disorder, bipolar type for which he was receiving a maintenance regimen of lithium 600 mg/d at bedtime and risperidone 2 mg/d at bedtime. He had multiple previous psychiatric admissions for catatonia. On this admission, Mr. B was irritable and difficult to redirect. He yelled at staff members and had a stiff gait. The BFCRS yielded a positive screening score of 3/14 and a severity score of 8/23. As a result, the treatment team conducted a lorazepam challenge.
After Mr. B received lorazepam 1 mg IM, his thought organization and irritability improved, which allowed him to have a coherent conversation with the interviewer. His gait stiffness also improved. His risperidone and lithium were held, and oral lorazepam 1 mg 3 times a day was started for catatonia. Lorazepam was gradually increased to 4 mg 3 times a day. Mr. B became euthymic and redirectable, and had an improved gait. However, he was also tangential and hyperverbal; these symptoms were indicative of the underlying mania that precipitated his catatonia.
Divalproex sodium extended release (ER) was started and increased to 1,500 mg/d at bedtime for mood stabilization. Lithium was restarted and increased to 300 mg twice a day for adjunct mood stabilization. Risperidone was not restarted. Toward the end of his admission, Mr. B was noted to be overly sedated, so the lorazepam dosage was decreased. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium ER 1,500 mg/d at bedtime, and lithium 300 mg twice a day. At discharge, Mr. B was calm and euthymic, with a linear thought process. His LOS was 25 days.
Case 3
Mr. C, age 62, presented to the emergency department (ED) because he had exhibited erratic behavior and had not slept for the past week. He has a history of bipolar I disorder, hypothyroidism, diabetes, and hypertension. For many years, he had been stable on divalproex sodium ER 2,500 mg/d at bedtime for mood stabilization and clozapine 100 mg/d at bedtime for adjunct mood stabilization and psychosis. In the ED, Mr. C was irritable, distractible, and tangential. On admission, he was speaking slowly with increased speech latency in response to questions, exhibiting stereotypy, repeating statements over and over, and walking very slowly.
The BFCRS yielded a positive screening score of 5/14 and a severity score of 10/23. Lorazepam 1 mg IM was administered. After 15 minutes, Mr. C’s speech, gait, and distractibility improved. As a result, clozapine and divalproex sodium were held, and he was started on oral lorazepam 1 mg 3 times a day. After several days, Mr. C was speaking fluently and no longer exhibiting stereotypy or having outbursts where he would make repetitive statements. However, he was tangential and irritable at times, which were signs of his underlying mania. Divalproex sodium ER was restarted at 250 mg/d at bedtime for mood stabilization and gradually increased to 2,500 mg/d at bedtime. Clozapine was also restarted at 25 mg/d at bedtime and gradually increased to 200 mg/d at bedtime. The lorazepam was gradually tapered and discontinued over the course of 3 weeks due to oversedation.
Continue to: At discharge...
At discharge, Mr. C was euthymic, calm, linear, and goal-directed. He was discharged on divalproex sodium ER 2,500 mg/d at bedtime and clozapine 200 mg/d at bedtime. His LOS for this admission was 22 days.
A stepwise approach can improve outcomes
The Figure outlines the method we used to manage excited catatonia in these 3 cases. Each of these patients exhibited signs of excited catatonia, but because those symptoms were nearly identical to those of mania, it was initially difficult to identify catatonia. Excited catatonia was suspected after more typical catatonic symptoms—such as a stiff gait, slowed speech, and stereotypy—were observed. The BFCRS was completed to get an objective measure of the likelihood that the patient was catatonic. In all 3 cases, the BFCRS resulted in a positive screen for catatonia. Following this, the patients described in Case 2 and Case 3 received a lorazepam challenge, which confirmed their catatonia. No lorazepam challenge was performed in Case 1 because the patient was already receiving lorazepam when the BFCRS was completed. Although most catatonic patients will respond to a lorazepam challenge, not all will. Therefore, clinicians should maintain some degree of suspicion for catatonia if a patient has a positive screen on the BFCRS but a negative lorazepam challenge.
In all 3 cases, after catatonia was confirmed, the patient’s psychotropic medications were discontinued. In all 3 cases, the antipsychotic was held to prevent progression to neuroleptic malignant syndrome (NMS) or malignant catatonia. Rasmussen et al3 found that 3.6% of the catatonic patients in their sample who were treated with antipsychotics developed NMS. A review of prospective studies looking at patients treated with antipsychotics found the incidence of NMS was .07% to 1.8%.5 Because NMS is often clinically indistinguishable from malignant catatonia,4,6 this incidence of NMS may have represented an increased incidence in malignant catatonia.
In all 3 cases, the mood stabilizer was held to prevent it from complicating the clinical picture. Discontinuing the mood stabilizer and focusing on treating the catatonia before targeting the underlying mania increased the likelihood of differentiating the patient’s catatonic symptoms from manic symptoms. This resulted in more precise medication selection and titration by allowing us to identify the specific symptoms that were being targeted by each medication.
Oral lorazepam was prescribed to target catatonia in all 3 cases, and the dosage was gradually increased until symptoms began to resolve. As the catatonia resolved, the manic symptoms became more easily identifiable, and at this point a mood stabilizer was started and titrated to a therapeutic dose to target the mania. In Case 1 and Case 3, the antipsychotic was restarted to treat the mania more effectively. It was not restarted in Case 2 because the patient’s mania was effectively being managed by 2 mood stabilizers. The risks and benefits of starting an antipsychotic in a catatonic or recently catatonic patient should be carefully considered. In the 2 cases where the antipsychotic was restarted, the patients were closely monitored, and there were no signs of NMS or malignant catatonia.
Continue to: As discharge approached...
As discharge approached, the dosages of oral lorazepam were reevaluated. Catatonic patients can typically tolerate high doses of benzodiazepines without becoming overly sedated, but each patient has a different threshold at which the dosage causes oversedation. In all 3 patients, lorazepam was initially titrated to a dose that treated their catatonic symptoms without causing intolerable sedation. In Case 2 and Case 3, as the catatonia began to resolve, the patients became increasingly sedated on their existing lorazepam dosage, so it was decreased. Because the patient in Case 1 did not become overly sedated, his lorazepam dosage did not need to be reduced.
For 2 of these patients, our approach resulted in a shorter LOS compared to their previous hospitalizations. The LOS in Case 2 was 25 days; 5 years earlier, he had a 49-day LOS for mania and catatonia. During the past admission, the identification and treatment of the catatonia was delayed, which resulted in the patient requiring multiple transfers to the medical unit for unstable vital signs. The LOS in Case 3 was 22 days; 6 months prior to this admission, the patient had 2 psychiatric admissions that totaled 37 days. Although the patient’s presentation in the 2 previous admissions was similar to his presentation as described in Case 3, catatonia had not been identified or treated in either admission. Since his catatonia and mania were treated in Case 3, he has not required a readmission. The patient in Case 1 was previously hospitalized, but information about the LOS of these admissions was not available. These results suggest that early identification and treatment of catatonia via the approach we used can improve patient outcomes.
Bottom Line
Excited catatonia can be challenging to diagnose and treat because it can present with symptoms similar to those seen in mania or psychosis. We describe 3 cases in which we used a stepwise approach to optimize treatment and improve outcomes for patients with excited catatonia. This approach may work equally well for other catatonia subtypes.
Related Resources
- Dubovsky SL, Dubovsky AN. Catatonia: how to identify and treat it. Current Psychiatry. 2018;17(8):16-26.
- Crouse EL, Joel B. Moran JB. Catatonia: recognition, management, and prevention of complications. Current Psychiatry. 2018;17(12):45-49.
Drug Brand Names
Clozapine • Clozaril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Risperidone • Risperdal
Divalproex sodium • Depakote
Catatonia is often difficult to identify and treat. The excited catatonia subtype can be particularly challenging to diagnose because it can present with symptoms similar to those seen in mania or psychosis. In this article, we present 3 cases of excited catatonia that illustrate how to identify it, how to treat the catatonia as well as the underlying pathology, and factors to consider during this process to mitigate the risk of adverse outcomes. We also outline a treatment algorithm we used for the 3 cases. Although we describe using this approach for patients with excited catatonia, it is generalizable to other types of catatonia.
Many causes, varying presentations
Catatonia is a psychomotor syndrome characterized by mutism, negativism, stereotypy, waxy flexibility, and other symptoms.1 It is defined by the presence of ≥3 of the 12 symptoms listed in the Table.2 Causes of catatonia include metabolic abnormalities, endocrine disorders, drug intoxication, neurodevelopmental disorders, medication adverse effects, psychosis, and mood disorders.1,3
A subtype of this syndrome, excited catatonia, can present with restlessness, agitation, emotional lability, poor sleep, and altered mental status in addition to the more typical symptoms.1,4 Because excited catatonia can resemble mania or psychosis, it is particularly challenging to identify the underlying disorder causing it and appropriate treatment. Fink et al4 discussed how clinicians have interpreted the different presentations of excited catatonia to gain insight into the underlying diagnosis. If the patient’s thought process appears disorganized, psychosis may be suspected.4 If the patient is delusional and grandiose, they may be manic, and when altered mental status dominates the presentation, delirium may be the culprit.4
Regardless of the underlying cause, the first step is to treat the catatonia. Benzodiazepines and electroconvulsive therapy (ECT) are the most well validated treatments for catatonia and have been used to treat excited catatonia.1 Excited catatonia is often misdiagnosed and subsequently mistreated. In the following 3 cases, excited catatonia was successfully identified and treated using the same approach (Figure).
Case 1
Mr. A, age 27, has a history of bipolar I disorder. He was brought to the hospital by ambulance after being found to be yelling and acting belligerently, and he was admitted to the inpatient psychiatry unit for manic decompensation due to medication nonadherence. He was started on divalproex sodium 500 mg twice a day for mood stabilization, risperidone 1 mg twice a day for adjunct mood stabilization and psychosis, and lorazepam 1 mg 3 times a day for agitation. Mr. A exhibited odd behavior; he would take off his clothes in the hallway, run around the unit, and randomly yell at staff or to himself. At other times, he would stay silent, repeat the same statements, or oddly posture in the hallway for minutes at a time. These behaviors were seen primarily in the hour or 2 preceding lorazepam administration and improved after he received lorazepam.
Mr. A’s treating team completed the Bush-Francis Catatonia Rating Scale (BFCRS), which yielded a positive catatonia screen of 7/14. As a result, divalproex sodium and risperidone were held, and lorazepam was increased to 2 mg twice a day.
After several days, Mr. A was no longer acting oddly and was able to speak more spontaneously; however, he began to exhibit overt signs of mania. He would speak rapidly and make grandiose claims about managing millions of dollars as the CEO of a famous company. Divalproex sodium was restarted at 500 mg twice a day and increased to 500 mg 3 times a day for mood stabilization. Mr. A continued to receive lorazepam 2 mg 3 times a day for catatonia, and risperidone was restarted at 1 mg twice a day to more effectively target his manic symptoms. Risperidone was increased to 2 mg twice a day. After this change, Mr. A’s grandiosity dissipated, his speech normalized, and his thought process became organized. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium 500 mg 3 times a day, and risperidone 2 mg twice a day. Mr. A’s length of stay (LOS) for this admission was 11 days.
Continue to: Case 2
Case 2
Mr. B, age 49, presented with irritability and odd posturing. He has a history of schizoaffective disorder, bipolar type for which he was receiving a maintenance regimen of lithium 600 mg/d at bedtime and risperidone 2 mg/d at bedtime. He had multiple previous psychiatric admissions for catatonia. On this admission, Mr. B was irritable and difficult to redirect. He yelled at staff members and had a stiff gait. The BFCRS yielded a positive screening score of 3/14 and a severity score of 8/23. As a result, the treatment team conducted a lorazepam challenge.
After Mr. B received lorazepam 1 mg IM, his thought organization and irritability improved, which allowed him to have a coherent conversation with the interviewer. His gait stiffness also improved. His risperidone and lithium were held, and oral lorazepam 1 mg 3 times a day was started for catatonia. Lorazepam was gradually increased to 4 mg 3 times a day. Mr. B became euthymic and redirectable, and had an improved gait. However, he was also tangential and hyperverbal; these symptoms were indicative of the underlying mania that precipitated his catatonia.
Divalproex sodium extended release (ER) was started and increased to 1,500 mg/d at bedtime for mood stabilization. Lithium was restarted and increased to 300 mg twice a day for adjunct mood stabilization. Risperidone was not restarted. Toward the end of his admission, Mr. B was noted to be overly sedated, so the lorazepam dosage was decreased. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium ER 1,500 mg/d at bedtime, and lithium 300 mg twice a day. At discharge, Mr. B was calm and euthymic, with a linear thought process. His LOS was 25 days.
Case 3
Mr. C, age 62, presented to the emergency department (ED) because he had exhibited erratic behavior and had not slept for the past week. He has a history of bipolar I disorder, hypothyroidism, diabetes, and hypertension. For many years, he had been stable on divalproex sodium ER 2,500 mg/d at bedtime for mood stabilization and clozapine 100 mg/d at bedtime for adjunct mood stabilization and psychosis. In the ED, Mr. C was irritable, distractible, and tangential. On admission, he was speaking slowly with increased speech latency in response to questions, exhibiting stereotypy, repeating statements over and over, and walking very slowly.
The BFCRS yielded a positive screening score of 5/14 and a severity score of 10/23. Lorazepam 1 mg IM was administered. After 15 minutes, Mr. C’s speech, gait, and distractibility improved. As a result, clozapine and divalproex sodium were held, and he was started on oral lorazepam 1 mg 3 times a day. After several days, Mr. C was speaking fluently and no longer exhibiting stereotypy or having outbursts where he would make repetitive statements. However, he was tangential and irritable at times, which were signs of his underlying mania. Divalproex sodium ER was restarted at 250 mg/d at bedtime for mood stabilization and gradually increased to 2,500 mg/d at bedtime. Clozapine was also restarted at 25 mg/d at bedtime and gradually increased to 200 mg/d at bedtime. The lorazepam was gradually tapered and discontinued over the course of 3 weeks due to oversedation.
Continue to: At discharge...
At discharge, Mr. C was euthymic, calm, linear, and goal-directed. He was discharged on divalproex sodium ER 2,500 mg/d at bedtime and clozapine 200 mg/d at bedtime. His LOS for this admission was 22 days.
A stepwise approach can improve outcomes
The Figure outlines the method we used to manage excited catatonia in these 3 cases. Each of these patients exhibited signs of excited catatonia, but because those symptoms were nearly identical to those of mania, it was initially difficult to identify catatonia. Excited catatonia was suspected after more typical catatonic symptoms—such as a stiff gait, slowed speech, and stereotypy—were observed. The BFCRS was completed to get an objective measure of the likelihood that the patient was catatonic. In all 3 cases, the BFCRS resulted in a positive screen for catatonia. Following this, the patients described in Case 2 and Case 3 received a lorazepam challenge, which confirmed their catatonia. No lorazepam challenge was performed in Case 1 because the patient was already receiving lorazepam when the BFCRS was completed. Although most catatonic patients will respond to a lorazepam challenge, not all will. Therefore, clinicians should maintain some degree of suspicion for catatonia if a patient has a positive screen on the BFCRS but a negative lorazepam challenge.
In all 3 cases, after catatonia was confirmed, the patient’s psychotropic medications were discontinued. In all 3 cases, the antipsychotic was held to prevent progression to neuroleptic malignant syndrome (NMS) or malignant catatonia. Rasmussen et al3 found that 3.6% of the catatonic patients in their sample who were treated with antipsychotics developed NMS. A review of prospective studies looking at patients treated with antipsychotics found the incidence of NMS was .07% to 1.8%.5 Because NMS is often clinically indistinguishable from malignant catatonia,4,6 this incidence of NMS may have represented an increased incidence in malignant catatonia.
In all 3 cases, the mood stabilizer was held to prevent it from complicating the clinical picture. Discontinuing the mood stabilizer and focusing on treating the catatonia before targeting the underlying mania increased the likelihood of differentiating the patient’s catatonic symptoms from manic symptoms. This resulted in more precise medication selection and titration by allowing us to identify the specific symptoms that were being targeted by each medication.
Oral lorazepam was prescribed to target catatonia in all 3 cases, and the dosage was gradually increased until symptoms began to resolve. As the catatonia resolved, the manic symptoms became more easily identifiable, and at this point a mood stabilizer was started and titrated to a therapeutic dose to target the mania. In Case 1 and Case 3, the antipsychotic was restarted to treat the mania more effectively. It was not restarted in Case 2 because the patient’s mania was effectively being managed by 2 mood stabilizers. The risks and benefits of starting an antipsychotic in a catatonic or recently catatonic patient should be carefully considered. In the 2 cases where the antipsychotic was restarted, the patients were closely monitored, and there were no signs of NMS or malignant catatonia.
Continue to: As discharge approached...
As discharge approached, the dosages of oral lorazepam were reevaluated. Catatonic patients can typically tolerate high doses of benzodiazepines without becoming overly sedated, but each patient has a different threshold at which the dosage causes oversedation. In all 3 patients, lorazepam was initially titrated to a dose that treated their catatonic symptoms without causing intolerable sedation. In Case 2 and Case 3, as the catatonia began to resolve, the patients became increasingly sedated on their existing lorazepam dosage, so it was decreased. Because the patient in Case 1 did not become overly sedated, his lorazepam dosage did not need to be reduced.
For 2 of these patients, our approach resulted in a shorter LOS compared to their previous hospitalizations. The LOS in Case 2 was 25 days; 5 years earlier, he had a 49-day LOS for mania and catatonia. During the past admission, the identification and treatment of the catatonia was delayed, which resulted in the patient requiring multiple transfers to the medical unit for unstable vital signs. The LOS in Case 3 was 22 days; 6 months prior to this admission, the patient had 2 psychiatric admissions that totaled 37 days. Although the patient’s presentation in the 2 previous admissions was similar to his presentation as described in Case 3, catatonia had not been identified or treated in either admission. Since his catatonia and mania were treated in Case 3, he has not required a readmission. The patient in Case 1 was previously hospitalized, but information about the LOS of these admissions was not available. These results suggest that early identification and treatment of catatonia via the approach we used can improve patient outcomes.
Bottom Line
Excited catatonia can be challenging to diagnose and treat because it can present with symptoms similar to those seen in mania or psychosis. We describe 3 cases in which we used a stepwise approach to optimize treatment and improve outcomes for patients with excited catatonia. This approach may work equally well for other catatonia subtypes.
Related Resources
- Dubovsky SL, Dubovsky AN. Catatonia: how to identify and treat it. Current Psychiatry. 2018;17(8):16-26.
- Crouse EL, Joel B. Moran JB. Catatonia: recognition, management, and prevention of complications. Current Psychiatry. 2018;17(12):45-49.
Drug Brand Names
Clozapine • Clozaril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Risperidone • Risperdal
Divalproex sodium • Depakote
1. Fink M, Taylor MA. The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci. 2001;251(Suppl 1):8-13.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013:119-121.
3. Rasmussen SA, Mazurek MF, Rosebush PI. Catatonia: our current understanding of its diagnosis, treatment and pathophysiology. World J Psychiatry. 2016;6(4):391-398.
4. Fink M, Taylor MA. Catatonia: A Clinician’s Guide to Diagnosis and Treatment. Cambridge University Press; 2003.
5. Adityanjee, Aderibigbe YA, Matthews T. Epidemiology of neuroleptic malignant syndrome. Clin Neuropharmacol. 1999;22(3):151-158.
6. Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876.
1. Fink M, Taylor MA. The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci. 2001;251(Suppl 1):8-13.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013:119-121.
3. Rasmussen SA, Mazurek MF, Rosebush PI. Catatonia: our current understanding of its diagnosis, treatment and pathophysiology. World J Psychiatry. 2016;6(4):391-398.
4. Fink M, Taylor MA. Catatonia: A Clinician’s Guide to Diagnosis and Treatment. Cambridge University Press; 2003.
5. Adityanjee, Aderibigbe YA, Matthews T. Epidemiology of neuroleptic malignant syndrome. Clin Neuropharmacol. 1999;22(3):151-158.
6. Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876.
Intentional deaths continue to rise among U.S. children
The homicide rate among children in the United States rose by more than 4% per year since 2013 but jumped nearly 28% from 2019 to 2020, new data show.
Although long-term trends varied by region and demographics, with some groups and areas seeing declines in killings, the increases were the highest among Black children and boys aged 11-17, according to the researchers, who attribute the surge in violent deaths to a recent rise in firearm-related killings in children. Gun violence is now the leading cause of death for children in the United States, claiming what the American Academy of Pediatrics has equated to a classroomful of lives each day.
“There are troubling recent rate increases among several groups, warranting immediate attention, with some racial and ethnic disparities persisting for more than 20 years,” said Rebecca F. Wilson, PhD, of the U.S. Centers for Disease Control and Prevention, who helped conduct the study.
Dr. Wilson and her colleagues, whose findings appear in JAMA Pediatrics, examined data on 38,362 homicide victims in the United States aged 0-17 years who were killed between 1999 and 2020.
The nation’s overall homicide rate for youth fell by 5.6% per year from 2007 to 2013 before reversing course. Between 2013 and 2020, the overall rate rose 4.3% annually.
The figures show that not all children are affected equally. The rate of child homicide has fallen significantly for girls, infants, and children ages 5 years and under – whose deaths often result from caregiver neglect or violence – as well as Asian or Pacific Islanders, Whites, and those living in the Northeast.
But the child homicide rate in the South increased 6.4% per year between 2013 and 2020, while that of children in both rural America and in cities is also rising after years of decline, according to the researchers.
The suspected perpetrator was known in about 64% of child killings. Nearly 80% of those perpetrators were male.
Dr. Wilson and her colleagues also note that the COVID-19 pandemic appears to have precipitated a wave of gun-related violence among children – a link borne out by another recent paper in JAMA Pediatrics. (Recent data suggest that intentional firearm injuries are often misclassified as accidental.)
The study found that gun-related injuries in youth remained elevated through 2021, with non-Hispanic Black children and those with public insurance making up greater proportions of victims during the pandemic. The researchers identified 1,815 firearm injuries per month before the pandemic and 2,759 per month during the outbreak, a 52% increase.
Although the two studies look at different data, both show that Black children are most affected by gun violence, experts said.
“This demonstrates a critical issue for the medical, public health, and legal communities: While homicide is often presented as a criminal justice problem, it is increasingly a racial justice problem,” said Katherine E. Hoops, MD, of the Center for Gun Violence Solutions at Johns Hopkins Bloomberg School of Public Health, Baltimore.
In an editorial about the homicide study, researchers at the University of Pennsylvania, Philadelphia, called the violent deaths “preventable and unacceptable.” Eliminating such deaths “must be among our first priorities,” they wrote.
The editorial authors also noted that researchers know relatively little about nonfatal violent injuries such as those involving firearms. “These injuries are important not only because they may have life-altering consequences for children and families but also because understanding only the most severe form of any health condition (death) will hamper our ability to design and evaluate prevention strategies,” they wrote.
Dr. Wilson’s group identified different causes of youth homicide for different age groups – and the potential interventions for each differ. Although the youngest children are more likely to die from abuse or neglect, those aged 6-10 years were most likely to die by firearm, often associated with abuse that ends in suicide. Meanwhile, adolescents aged 11-17 were more subject to peer violence.
For Dr. Hoops, “each of these differences has important policy implications, including the need for policies that address structural racism, poverty, and systematic disadvantage – but also firearm safe storage to prevent youth violence and suicide [and] reduction of access to lethal means, such as through extreme risk protective orders when someone is at risk of harming themselves or others.”
Dr. Wilson agreed. “We know child homicides are preventable,” she said. “The rate decrease for some groups is encouraging, yet more can be done to protect all children.”
A version of this article first appeared on Medscape.com.
The homicide rate among children in the United States rose by more than 4% per year since 2013 but jumped nearly 28% from 2019 to 2020, new data show.
Although long-term trends varied by region and demographics, with some groups and areas seeing declines in killings, the increases were the highest among Black children and boys aged 11-17, according to the researchers, who attribute the surge in violent deaths to a recent rise in firearm-related killings in children. Gun violence is now the leading cause of death for children in the United States, claiming what the American Academy of Pediatrics has equated to a classroomful of lives each day.
“There are troubling recent rate increases among several groups, warranting immediate attention, with some racial and ethnic disparities persisting for more than 20 years,” said Rebecca F. Wilson, PhD, of the U.S. Centers for Disease Control and Prevention, who helped conduct the study.
Dr. Wilson and her colleagues, whose findings appear in JAMA Pediatrics, examined data on 38,362 homicide victims in the United States aged 0-17 years who were killed between 1999 and 2020.
The nation’s overall homicide rate for youth fell by 5.6% per year from 2007 to 2013 before reversing course. Between 2013 and 2020, the overall rate rose 4.3% annually.
The figures show that not all children are affected equally. The rate of child homicide has fallen significantly for girls, infants, and children ages 5 years and under – whose deaths often result from caregiver neglect or violence – as well as Asian or Pacific Islanders, Whites, and those living in the Northeast.
But the child homicide rate in the South increased 6.4% per year between 2013 and 2020, while that of children in both rural America and in cities is also rising after years of decline, according to the researchers.
The suspected perpetrator was known in about 64% of child killings. Nearly 80% of those perpetrators were male.
Dr. Wilson and her colleagues also note that the COVID-19 pandemic appears to have precipitated a wave of gun-related violence among children – a link borne out by another recent paper in JAMA Pediatrics. (Recent data suggest that intentional firearm injuries are often misclassified as accidental.)
The study found that gun-related injuries in youth remained elevated through 2021, with non-Hispanic Black children and those with public insurance making up greater proportions of victims during the pandemic. The researchers identified 1,815 firearm injuries per month before the pandemic and 2,759 per month during the outbreak, a 52% increase.
Although the two studies look at different data, both show that Black children are most affected by gun violence, experts said.
“This demonstrates a critical issue for the medical, public health, and legal communities: While homicide is often presented as a criminal justice problem, it is increasingly a racial justice problem,” said Katherine E. Hoops, MD, of the Center for Gun Violence Solutions at Johns Hopkins Bloomberg School of Public Health, Baltimore.
In an editorial about the homicide study, researchers at the University of Pennsylvania, Philadelphia, called the violent deaths “preventable and unacceptable.” Eliminating such deaths “must be among our first priorities,” they wrote.
The editorial authors also noted that researchers know relatively little about nonfatal violent injuries such as those involving firearms. “These injuries are important not only because they may have life-altering consequences for children and families but also because understanding only the most severe form of any health condition (death) will hamper our ability to design and evaluate prevention strategies,” they wrote.
Dr. Wilson’s group identified different causes of youth homicide for different age groups – and the potential interventions for each differ. Although the youngest children are more likely to die from abuse or neglect, those aged 6-10 years were most likely to die by firearm, often associated with abuse that ends in suicide. Meanwhile, adolescents aged 11-17 were more subject to peer violence.
For Dr. Hoops, “each of these differences has important policy implications, including the need for policies that address structural racism, poverty, and systematic disadvantage – but also firearm safe storage to prevent youth violence and suicide [and] reduction of access to lethal means, such as through extreme risk protective orders when someone is at risk of harming themselves or others.”
Dr. Wilson agreed. “We know child homicides are preventable,” she said. “The rate decrease for some groups is encouraging, yet more can be done to protect all children.”
A version of this article first appeared on Medscape.com.
The homicide rate among children in the United States rose by more than 4% per year since 2013 but jumped nearly 28% from 2019 to 2020, new data show.
Although long-term trends varied by region and demographics, with some groups and areas seeing declines in killings, the increases were the highest among Black children and boys aged 11-17, according to the researchers, who attribute the surge in violent deaths to a recent rise in firearm-related killings in children. Gun violence is now the leading cause of death for children in the United States, claiming what the American Academy of Pediatrics has equated to a classroomful of lives each day.
“There are troubling recent rate increases among several groups, warranting immediate attention, with some racial and ethnic disparities persisting for more than 20 years,” said Rebecca F. Wilson, PhD, of the U.S. Centers for Disease Control and Prevention, who helped conduct the study.
Dr. Wilson and her colleagues, whose findings appear in JAMA Pediatrics, examined data on 38,362 homicide victims in the United States aged 0-17 years who were killed between 1999 and 2020.
The nation’s overall homicide rate for youth fell by 5.6% per year from 2007 to 2013 before reversing course. Between 2013 and 2020, the overall rate rose 4.3% annually.
The figures show that not all children are affected equally. The rate of child homicide has fallen significantly for girls, infants, and children ages 5 years and under – whose deaths often result from caregiver neglect or violence – as well as Asian or Pacific Islanders, Whites, and those living in the Northeast.
But the child homicide rate in the South increased 6.4% per year between 2013 and 2020, while that of children in both rural America and in cities is also rising after years of decline, according to the researchers.
The suspected perpetrator was known in about 64% of child killings. Nearly 80% of those perpetrators were male.
Dr. Wilson and her colleagues also note that the COVID-19 pandemic appears to have precipitated a wave of gun-related violence among children – a link borne out by another recent paper in JAMA Pediatrics. (Recent data suggest that intentional firearm injuries are often misclassified as accidental.)
The study found that gun-related injuries in youth remained elevated through 2021, with non-Hispanic Black children and those with public insurance making up greater proportions of victims during the pandemic. The researchers identified 1,815 firearm injuries per month before the pandemic and 2,759 per month during the outbreak, a 52% increase.
Although the two studies look at different data, both show that Black children are most affected by gun violence, experts said.
“This demonstrates a critical issue for the medical, public health, and legal communities: While homicide is often presented as a criminal justice problem, it is increasingly a racial justice problem,” said Katherine E. Hoops, MD, of the Center for Gun Violence Solutions at Johns Hopkins Bloomberg School of Public Health, Baltimore.
In an editorial about the homicide study, researchers at the University of Pennsylvania, Philadelphia, called the violent deaths “preventable and unacceptable.” Eliminating such deaths “must be among our first priorities,” they wrote.
The editorial authors also noted that researchers know relatively little about nonfatal violent injuries such as those involving firearms. “These injuries are important not only because they may have life-altering consequences for children and families but also because understanding only the most severe form of any health condition (death) will hamper our ability to design and evaluate prevention strategies,” they wrote.
Dr. Wilson’s group identified different causes of youth homicide for different age groups – and the potential interventions for each differ. Although the youngest children are more likely to die from abuse or neglect, those aged 6-10 years were most likely to die by firearm, often associated with abuse that ends in suicide. Meanwhile, adolescents aged 11-17 were more subject to peer violence.
For Dr. Hoops, “each of these differences has important policy implications, including the need for policies that address structural racism, poverty, and systematic disadvantage – but also firearm safe storage to prevent youth violence and suicide [and] reduction of access to lethal means, such as through extreme risk protective orders when someone is at risk of harming themselves or others.”
Dr. Wilson agreed. “We know child homicides are preventable,” she said. “The rate decrease for some groups is encouraging, yet more can be done to protect all children.”
A version of this article first appeared on Medscape.com.
Cluster headache tied to high risk of mental and neurologic disorders
, leading to significant disability and absenteeism, new research shows.
Results from a Swedish register-based study also showed that patients with cluster headache had a sixfold increased risk for central nervous system disorders and a twofold increased risk for musculoskeletal disorders.
Although cluster headaches are often more prevalent in men, researchers found that multimorbidity rates were significantly higher in women. In addition, rates of external injuries were significantly higher among individuals with cluster headache than among persons without cluster headache.
“The findings very clearly indicate that cluster headache patients suffer from other health issues as well and that they are at risk of having longer periods of times when they cannot work,” said lead investigator Caroline Ran, PhD, a research specialist in the department of neuroscience at the Karolinska Institutet, Stockholm.
“It’s really important for clinicians to look at cluster headache from a broader perspective and make sure that patients are followed up so that they don’t risk ending up in a situation where they have several comorbidities,” Dr. Ran added.
The findings were published online in Neurology.
‘Striking’ finding
Cluster headache is one of the most severe and debilitating types of headache. It causes intense pain behind the eyes, which has been described as being worse than pain associated with childbirth or kidney stones.
Attacks can occur multiple times in a single day and can last up to 3 hours. Cluster headache is rare, occurring in about 1 in 1,000 individuals, and is more common in men. Underdiagnosis is common – especially in women.
The study drew on two Swedish population-based registries and included 3,240 patients with cluster headache aged 16-64 years and 16,200 matched control persons. The analysis covered medical visits from 2001 to 2010.
Results showed that 91.9% of participants with cluster headache had some type of multimorbidity. By comparison, 77.6% of the control group had some type of multimorbidity (odds ratio, 3.26; P < .0001).
Prior studies have shown a higher incidence of mental health and behavioral disorders among patients with cluster headache. However, when the researchers removed those conditions along with external injuries from the dataset, patients with headache were still significantly more likely to have multiple co-occurring illnesses (86.7% vs. 68.8%; OR, 2.95; P < .0001).
The most common comorbid conditions in the overall cluster headache group were diseases of the nervous system (OR, 5.9; 95% CI, 5.46 -6.42); 51.8% of the cluster headache group reported these disorders, compared with just 15.4% of the control group.
Diseases of the eye, the respiratory, gastrointestinal, and musculoskeletal systems, and connective tissue were also significantly more common among patients with cluster headache.
“For each diagnosis that we investigated, we found a higher incidence in the cluster headache group, and we thought this was a very striking finding and worth discussing in the clinical setting that these patients are at risk of general ill health,” Dr. Ran said.
Risky behavior?
Another novel finding was the higher rate of external injuries among the cluster headache group, compared with the control group. The finding seems to back up the theory that patients with cluster headache are more likely to engage in risky behaviors, the researchers noted.
In the cluster headache group, external injuries were reported by 47.1% of men and 41% of women, versus 34.9% and 26.0%, respectively, in the control group.
“Now we can also show that cluster headache patients have more injuries and that is totally unrelated to the biological health of the individuals, so that could also indicate higher risk taking,” Dr. Ran said.
Overall multimorbidity rates and diagnoses in each medical category except external injury were higher among women with cluster headache than men with headaches. In addition, the mean number of days on sick leave and disability pension was higher among women with cluster headache than among men with cluster headache (83.71 days vs. 52.56 days).
Overall, the mean number of sickness absence and disability pension net days in 2010 was nearly twice as high in the cluster headache group as in the control group (63.15 days vs. 34.08 days).
Removing mental and behavioral health disorders from the mix did not lower those numbers.
“Our numbers indicate that the mental health issues that are related to cluster headache might not impact their work situation as much as the other comorbidities,” Dr. Ran said.
Struggle is real
Commenting on the findings, Heidi Schwarz, MD, professor of clinical neurology at the University of Rochester (N.Y.) Medical Center, called the study a “valuable contribution” to the field and to the treatment of cluster headache.
“It’s a good study that addresses factors that really need to be considered as you take care of these patients,” said Dr. Schwarz, who was not involved with the research.
“The most salient features of this is that cluster headache is quite disabling, and if you add a comorbidity to it, it’s even more disabling,” she said.
Dr. Schwarz noted that cluster headache is often misdiagnosed as migraine or is overlooked altogether, especially in women. These data underscore that, although cluster headache is more common in men, it affects women too and could lead to even greater disability.
“This has a direct impact on patient quality of life, and in the end, that really should be what we’re looking to enhance,” Dr. Schwarz said. “When a patient with cluster comes in and they tell you they’re really struggling, believe them because it’s quite real.”
The findings also fill a gap in the literature and offer the kind of data that could not be collected in the United States, she noted. Sweden provides paid sick time for all workers aged 16 and older and offers a disability pension to all workers whose ability to work is temporarily or permanently inhibited because of illness or injury.
“You will never get this kind of data in the United States because this kind of data comes from two datasets that are extremely inclusive and detailed in a society, Sweden, where they have a social support system,” Dr. Schwarz said.
The study was funded by the Swedish Research Council, the Swedish Brain Foundation, and Mellby Gård, Region Stockholm, Märta Lundkvist stiftelse and Karolinska Institutet research funds. Dr. Ran and Dr. Schwarz report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, leading to significant disability and absenteeism, new research shows.
Results from a Swedish register-based study also showed that patients with cluster headache had a sixfold increased risk for central nervous system disorders and a twofold increased risk for musculoskeletal disorders.
Although cluster headaches are often more prevalent in men, researchers found that multimorbidity rates were significantly higher in women. In addition, rates of external injuries were significantly higher among individuals with cluster headache than among persons without cluster headache.
“The findings very clearly indicate that cluster headache patients suffer from other health issues as well and that they are at risk of having longer periods of times when they cannot work,” said lead investigator Caroline Ran, PhD, a research specialist in the department of neuroscience at the Karolinska Institutet, Stockholm.
“It’s really important for clinicians to look at cluster headache from a broader perspective and make sure that patients are followed up so that they don’t risk ending up in a situation where they have several comorbidities,” Dr. Ran added.
The findings were published online in Neurology.
‘Striking’ finding
Cluster headache is one of the most severe and debilitating types of headache. It causes intense pain behind the eyes, which has been described as being worse than pain associated with childbirth or kidney stones.
Attacks can occur multiple times in a single day and can last up to 3 hours. Cluster headache is rare, occurring in about 1 in 1,000 individuals, and is more common in men. Underdiagnosis is common – especially in women.
The study drew on two Swedish population-based registries and included 3,240 patients with cluster headache aged 16-64 years and 16,200 matched control persons. The analysis covered medical visits from 2001 to 2010.
Results showed that 91.9% of participants with cluster headache had some type of multimorbidity. By comparison, 77.6% of the control group had some type of multimorbidity (odds ratio, 3.26; P < .0001).
Prior studies have shown a higher incidence of mental health and behavioral disorders among patients with cluster headache. However, when the researchers removed those conditions along with external injuries from the dataset, patients with headache were still significantly more likely to have multiple co-occurring illnesses (86.7% vs. 68.8%; OR, 2.95; P < .0001).
The most common comorbid conditions in the overall cluster headache group were diseases of the nervous system (OR, 5.9; 95% CI, 5.46 -6.42); 51.8% of the cluster headache group reported these disorders, compared with just 15.4% of the control group.
Diseases of the eye, the respiratory, gastrointestinal, and musculoskeletal systems, and connective tissue were also significantly more common among patients with cluster headache.
“For each diagnosis that we investigated, we found a higher incidence in the cluster headache group, and we thought this was a very striking finding and worth discussing in the clinical setting that these patients are at risk of general ill health,” Dr. Ran said.
Risky behavior?
Another novel finding was the higher rate of external injuries among the cluster headache group, compared with the control group. The finding seems to back up the theory that patients with cluster headache are more likely to engage in risky behaviors, the researchers noted.
In the cluster headache group, external injuries were reported by 47.1% of men and 41% of women, versus 34.9% and 26.0%, respectively, in the control group.
“Now we can also show that cluster headache patients have more injuries and that is totally unrelated to the biological health of the individuals, so that could also indicate higher risk taking,” Dr. Ran said.
Overall multimorbidity rates and diagnoses in each medical category except external injury were higher among women with cluster headache than men with headaches. In addition, the mean number of days on sick leave and disability pension was higher among women with cluster headache than among men with cluster headache (83.71 days vs. 52.56 days).
Overall, the mean number of sickness absence and disability pension net days in 2010 was nearly twice as high in the cluster headache group as in the control group (63.15 days vs. 34.08 days).
Removing mental and behavioral health disorders from the mix did not lower those numbers.
“Our numbers indicate that the mental health issues that are related to cluster headache might not impact their work situation as much as the other comorbidities,” Dr. Ran said.
Struggle is real
Commenting on the findings, Heidi Schwarz, MD, professor of clinical neurology at the University of Rochester (N.Y.) Medical Center, called the study a “valuable contribution” to the field and to the treatment of cluster headache.
“It’s a good study that addresses factors that really need to be considered as you take care of these patients,” said Dr. Schwarz, who was not involved with the research.
“The most salient features of this is that cluster headache is quite disabling, and if you add a comorbidity to it, it’s even more disabling,” she said.
Dr. Schwarz noted that cluster headache is often misdiagnosed as migraine or is overlooked altogether, especially in women. These data underscore that, although cluster headache is more common in men, it affects women too and could lead to even greater disability.
“This has a direct impact on patient quality of life, and in the end, that really should be what we’re looking to enhance,” Dr. Schwarz said. “When a patient with cluster comes in and they tell you they’re really struggling, believe them because it’s quite real.”
The findings also fill a gap in the literature and offer the kind of data that could not be collected in the United States, she noted. Sweden provides paid sick time for all workers aged 16 and older and offers a disability pension to all workers whose ability to work is temporarily or permanently inhibited because of illness or injury.
“You will never get this kind of data in the United States because this kind of data comes from two datasets that are extremely inclusive and detailed in a society, Sweden, where they have a social support system,” Dr. Schwarz said.
The study was funded by the Swedish Research Council, the Swedish Brain Foundation, and Mellby Gård, Region Stockholm, Märta Lundkvist stiftelse and Karolinska Institutet research funds. Dr. Ran and Dr. Schwarz report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, leading to significant disability and absenteeism, new research shows.
Results from a Swedish register-based study also showed that patients with cluster headache had a sixfold increased risk for central nervous system disorders and a twofold increased risk for musculoskeletal disorders.
Although cluster headaches are often more prevalent in men, researchers found that multimorbidity rates were significantly higher in women. In addition, rates of external injuries were significantly higher among individuals with cluster headache than among persons without cluster headache.
“The findings very clearly indicate that cluster headache patients suffer from other health issues as well and that they are at risk of having longer periods of times when they cannot work,” said lead investigator Caroline Ran, PhD, a research specialist in the department of neuroscience at the Karolinska Institutet, Stockholm.
“It’s really important for clinicians to look at cluster headache from a broader perspective and make sure that patients are followed up so that they don’t risk ending up in a situation where they have several comorbidities,” Dr. Ran added.
The findings were published online in Neurology.
‘Striking’ finding
Cluster headache is one of the most severe and debilitating types of headache. It causes intense pain behind the eyes, which has been described as being worse than pain associated with childbirth or kidney stones.
Attacks can occur multiple times in a single day and can last up to 3 hours. Cluster headache is rare, occurring in about 1 in 1,000 individuals, and is more common in men. Underdiagnosis is common – especially in women.
The study drew on two Swedish population-based registries and included 3,240 patients with cluster headache aged 16-64 years and 16,200 matched control persons. The analysis covered medical visits from 2001 to 2010.
Results showed that 91.9% of participants with cluster headache had some type of multimorbidity. By comparison, 77.6% of the control group had some type of multimorbidity (odds ratio, 3.26; P < .0001).
Prior studies have shown a higher incidence of mental health and behavioral disorders among patients with cluster headache. However, when the researchers removed those conditions along with external injuries from the dataset, patients with headache were still significantly more likely to have multiple co-occurring illnesses (86.7% vs. 68.8%; OR, 2.95; P < .0001).
The most common comorbid conditions in the overall cluster headache group were diseases of the nervous system (OR, 5.9; 95% CI, 5.46 -6.42); 51.8% of the cluster headache group reported these disorders, compared with just 15.4% of the control group.
Diseases of the eye, the respiratory, gastrointestinal, and musculoskeletal systems, and connective tissue were also significantly more common among patients with cluster headache.
“For each diagnosis that we investigated, we found a higher incidence in the cluster headache group, and we thought this was a very striking finding and worth discussing in the clinical setting that these patients are at risk of general ill health,” Dr. Ran said.
Risky behavior?
Another novel finding was the higher rate of external injuries among the cluster headache group, compared with the control group. The finding seems to back up the theory that patients with cluster headache are more likely to engage in risky behaviors, the researchers noted.
In the cluster headache group, external injuries were reported by 47.1% of men and 41% of women, versus 34.9% and 26.0%, respectively, in the control group.
“Now we can also show that cluster headache patients have more injuries and that is totally unrelated to the biological health of the individuals, so that could also indicate higher risk taking,” Dr. Ran said.
Overall multimorbidity rates and diagnoses in each medical category except external injury were higher among women with cluster headache than men with headaches. In addition, the mean number of days on sick leave and disability pension was higher among women with cluster headache than among men with cluster headache (83.71 days vs. 52.56 days).
Overall, the mean number of sickness absence and disability pension net days in 2010 was nearly twice as high in the cluster headache group as in the control group (63.15 days vs. 34.08 days).
Removing mental and behavioral health disorders from the mix did not lower those numbers.
“Our numbers indicate that the mental health issues that are related to cluster headache might not impact their work situation as much as the other comorbidities,” Dr. Ran said.
Struggle is real
Commenting on the findings, Heidi Schwarz, MD, professor of clinical neurology at the University of Rochester (N.Y.) Medical Center, called the study a “valuable contribution” to the field and to the treatment of cluster headache.
“It’s a good study that addresses factors that really need to be considered as you take care of these patients,” said Dr. Schwarz, who was not involved with the research.
“The most salient features of this is that cluster headache is quite disabling, and if you add a comorbidity to it, it’s even more disabling,” she said.
Dr. Schwarz noted that cluster headache is often misdiagnosed as migraine or is overlooked altogether, especially in women. These data underscore that, although cluster headache is more common in men, it affects women too and could lead to even greater disability.
“This has a direct impact on patient quality of life, and in the end, that really should be what we’re looking to enhance,” Dr. Schwarz said. “When a patient with cluster comes in and they tell you they’re really struggling, believe them because it’s quite real.”
The findings also fill a gap in the literature and offer the kind of data that could not be collected in the United States, she noted. Sweden provides paid sick time for all workers aged 16 and older and offers a disability pension to all workers whose ability to work is temporarily or permanently inhibited because of illness or injury.
“You will never get this kind of data in the United States because this kind of data comes from two datasets that are extremely inclusive and detailed in a society, Sweden, where they have a social support system,” Dr. Schwarz said.
The study was funded by the Swedish Research Council, the Swedish Brain Foundation, and Mellby Gård, Region Stockholm, Märta Lundkvist stiftelse and Karolinska Institutet research funds. Dr. Ran and Dr. Schwarz report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
AAP offers new guidance on child exploitation and sex trafficking
In a new updated report, the American Academy of Pediatrics urges pediatricians to understand signs of exploitation and labor/sex trafficking and learn how to support children and adolescents who are targeted.
“It’s incredibly scary when you encounter someone you worry is a victim, and you don’t know how to help them, and they’re not saying what’s going on,” pediatrician and report coauthor Dana Kaplan, MD, of Staten Island (N.Y.) University Hospital, said in an interview. “Every case is so unique and different: There’s no algorithm of ‘If A, then B, then C.’ You have to approach each person as an individual, and it takes time to make sure you’re thinking things through about how to provide what’s needed.”
The AAP published the clinical report, which is intended to provide guidance to pediatricians, in the January 2023 issue of Pediatrics. The organization previously tackled this topic in a 2017 clinical report, and Dr. Kaplan said the new report includes updated recommendations.
As the new report notes, there aren’t reliable estimates of exploited children in the United States, although millions are thought to be trafficked and subjected to forced labor around the world. “By virtue of their young age, children and adolescents are vulnerable to manipulation and exploitation, because they have limited life experiences, a need for attachment and acceptance, an immature prefrontal cortex ... and limited options for action,” the report says.
Dr. Kaplan puts it this way: “By the nature of being a child, you’re vulnerable.”
Still, health care professionals often aren’t trained in regard to human trafficking, the report says, even though it’s clear that they “must remain alert for the possibility.”
Dr. Kaplan, who has special training in child abuse and often sees children at risk, cautioned that children usually don’t directly say that they need help. “That’s generally not the case. They don’t articulate what’s going on around them as unsafe, or concerning, or dangerous. If you go and see a doctor for 10 minutes, are you going to tell them everything?
Instead, clinicians must often rely on their own observations. The report lists multiple possible signs of exploitation.
- The patient is accompanied by a domineering adult who does not allow the child to answer questions or accompanied by an unrelated adult. Inconsistent information is provided by the patient or companion. There’s a delay in seeking medical care.
- The patient has multiple sexually transmitted infections, previous pregnancy or termination, and/or frequent visits for emergency contraception. There are signs of prior sexual abuse, assault, or other maltreatment.
- The patient is withdrawn, fearful, hostile, or has a suspicious demeanor. The patient is constantly checking his or her phone and appears anxious or afraid.
What should clinicians do if they suspect exploitation? The report recommends that health care organizations develop guidelines for workers to follow. For her part, Dr. Kaplan advises colleagues to let patients lead conversations and not dig too deeply into their lives.
“Don’t turn into an investigator. This is not [Law & Order] SVU,” she said. “Stay focused on what you’re trained to do – provide health care.”
That doesn’t mean clinicians should ignore signs of trouble. It’s crucial to develop trust with the patient over time, she said, and turn to a specialist in your community or institution if you have suspicions.
And be careful to not portray victims as perpetrators. The new report emphasizes that “it’s important for health care providers to emphasize to authorities that the patient is a victim of exploitation who needs services rather than a juvenile offender.”
The report also highlights the importance of creating an environment that supports clinicians themselves: “Self-care for the clinician is critical in preventing and addressing secondary traumatic stress. A work environment that fosters peer support, encourages open discussion of work-related stress, and implements reasonable work-life balance policies can help protect providers from secondary stress and its consequences.”
Resources for clinicians include the National Human Trafficking Hotline, the federal Office of Trafficking in Persons, and the Centers for Disease Control and Prevention’s domestic refugee screening guidelines.
The study has no external funding. The authors report no disclosures.
In a new updated report, the American Academy of Pediatrics urges pediatricians to understand signs of exploitation and labor/sex trafficking and learn how to support children and adolescents who are targeted.
“It’s incredibly scary when you encounter someone you worry is a victim, and you don’t know how to help them, and they’re not saying what’s going on,” pediatrician and report coauthor Dana Kaplan, MD, of Staten Island (N.Y.) University Hospital, said in an interview. “Every case is so unique and different: There’s no algorithm of ‘If A, then B, then C.’ You have to approach each person as an individual, and it takes time to make sure you’re thinking things through about how to provide what’s needed.”
The AAP published the clinical report, which is intended to provide guidance to pediatricians, in the January 2023 issue of Pediatrics. The organization previously tackled this topic in a 2017 clinical report, and Dr. Kaplan said the new report includes updated recommendations.
As the new report notes, there aren’t reliable estimates of exploited children in the United States, although millions are thought to be trafficked and subjected to forced labor around the world. “By virtue of their young age, children and adolescents are vulnerable to manipulation and exploitation, because they have limited life experiences, a need for attachment and acceptance, an immature prefrontal cortex ... and limited options for action,” the report says.
Dr. Kaplan puts it this way: “By the nature of being a child, you’re vulnerable.”
Still, health care professionals often aren’t trained in regard to human trafficking, the report says, even though it’s clear that they “must remain alert for the possibility.”
Dr. Kaplan, who has special training in child abuse and often sees children at risk, cautioned that children usually don’t directly say that they need help. “That’s generally not the case. They don’t articulate what’s going on around them as unsafe, or concerning, or dangerous. If you go and see a doctor for 10 minutes, are you going to tell them everything?
Instead, clinicians must often rely on their own observations. The report lists multiple possible signs of exploitation.
- The patient is accompanied by a domineering adult who does not allow the child to answer questions or accompanied by an unrelated adult. Inconsistent information is provided by the patient or companion. There’s a delay in seeking medical care.
- The patient has multiple sexually transmitted infections, previous pregnancy or termination, and/or frequent visits for emergency contraception. There are signs of prior sexual abuse, assault, or other maltreatment.
- The patient is withdrawn, fearful, hostile, or has a suspicious demeanor. The patient is constantly checking his or her phone and appears anxious or afraid.
What should clinicians do if they suspect exploitation? The report recommends that health care organizations develop guidelines for workers to follow. For her part, Dr. Kaplan advises colleagues to let patients lead conversations and not dig too deeply into their lives.
“Don’t turn into an investigator. This is not [Law & Order] SVU,” she said. “Stay focused on what you’re trained to do – provide health care.”
That doesn’t mean clinicians should ignore signs of trouble. It’s crucial to develop trust with the patient over time, she said, and turn to a specialist in your community or institution if you have suspicions.
And be careful to not portray victims as perpetrators. The new report emphasizes that “it’s important for health care providers to emphasize to authorities that the patient is a victim of exploitation who needs services rather than a juvenile offender.”
The report also highlights the importance of creating an environment that supports clinicians themselves: “Self-care for the clinician is critical in preventing and addressing secondary traumatic stress. A work environment that fosters peer support, encourages open discussion of work-related stress, and implements reasonable work-life balance policies can help protect providers from secondary stress and its consequences.”
Resources for clinicians include the National Human Trafficking Hotline, the federal Office of Trafficking in Persons, and the Centers for Disease Control and Prevention’s domestic refugee screening guidelines.
The study has no external funding. The authors report no disclosures.
In a new updated report, the American Academy of Pediatrics urges pediatricians to understand signs of exploitation and labor/sex trafficking and learn how to support children and adolescents who are targeted.
“It’s incredibly scary when you encounter someone you worry is a victim, and you don’t know how to help them, and they’re not saying what’s going on,” pediatrician and report coauthor Dana Kaplan, MD, of Staten Island (N.Y.) University Hospital, said in an interview. “Every case is so unique and different: There’s no algorithm of ‘If A, then B, then C.’ You have to approach each person as an individual, and it takes time to make sure you’re thinking things through about how to provide what’s needed.”
The AAP published the clinical report, which is intended to provide guidance to pediatricians, in the January 2023 issue of Pediatrics. The organization previously tackled this topic in a 2017 clinical report, and Dr. Kaplan said the new report includes updated recommendations.
As the new report notes, there aren’t reliable estimates of exploited children in the United States, although millions are thought to be trafficked and subjected to forced labor around the world. “By virtue of their young age, children and adolescents are vulnerable to manipulation and exploitation, because they have limited life experiences, a need for attachment and acceptance, an immature prefrontal cortex ... and limited options for action,” the report says.
Dr. Kaplan puts it this way: “By the nature of being a child, you’re vulnerable.”
Still, health care professionals often aren’t trained in regard to human trafficking, the report says, even though it’s clear that they “must remain alert for the possibility.”
Dr. Kaplan, who has special training in child abuse and often sees children at risk, cautioned that children usually don’t directly say that they need help. “That’s generally not the case. They don’t articulate what’s going on around them as unsafe, or concerning, or dangerous. If you go and see a doctor for 10 minutes, are you going to tell them everything?
Instead, clinicians must often rely on their own observations. The report lists multiple possible signs of exploitation.
- The patient is accompanied by a domineering adult who does not allow the child to answer questions or accompanied by an unrelated adult. Inconsistent information is provided by the patient or companion. There’s a delay in seeking medical care.
- The patient has multiple sexually transmitted infections, previous pregnancy or termination, and/or frequent visits for emergency contraception. There are signs of prior sexual abuse, assault, or other maltreatment.
- The patient is withdrawn, fearful, hostile, or has a suspicious demeanor. The patient is constantly checking his or her phone and appears anxious or afraid.
What should clinicians do if they suspect exploitation? The report recommends that health care organizations develop guidelines for workers to follow. For her part, Dr. Kaplan advises colleagues to let patients lead conversations and not dig too deeply into their lives.
“Don’t turn into an investigator. This is not [Law & Order] SVU,” she said. “Stay focused on what you’re trained to do – provide health care.”
That doesn’t mean clinicians should ignore signs of trouble. It’s crucial to develop trust with the patient over time, she said, and turn to a specialist in your community or institution if you have suspicions.
And be careful to not portray victims as perpetrators. The new report emphasizes that “it’s important for health care providers to emphasize to authorities that the patient is a victim of exploitation who needs services rather than a juvenile offender.”
The report also highlights the importance of creating an environment that supports clinicians themselves: “Self-care for the clinician is critical in preventing and addressing secondary traumatic stress. A work environment that fosters peer support, encourages open discussion of work-related stress, and implements reasonable work-life balance policies can help protect providers from secondary stress and its consequences.”
Resources for clinicians include the National Human Trafficking Hotline, the federal Office of Trafficking in Persons, and the Centers for Disease Control and Prevention’s domestic refugee screening guidelines.
The study has no external funding. The authors report no disclosures.
FROM PEDIATRICS
FDA calls for withdrawal of multiple myeloma drug Pepaxto
(melphalan flufenamide), the company announced in a press release.
The drug was granted an accelerated approval by the FDA in February 2021, for use in combination with dexamethasone in adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy.
However, the phase 3 OCEAN study raised concerns about safety, as it showed a higher mortality associated with melphalan flufenamide in the experimental arm, compared with pomalidomide (Pomalyst).
The FDA already flagged this issue in July 2021, issuing a safety alert flagging the increased risk for death observed in the OCEAN trial among patients receiving melphalan flufenamide versus pomalidomide (47.6% vs. 43.4%) and a 5.3-month shorter overall survival.
The issue was also discussed in September 2022 by FDA’s Oncologic Drugs Advisory Committee, which voted 14-to-2 against maintaining the accelerated approval, citing an unfavorable risk/benefit profile.
The company stopped marketing the drug in the United States in October 2021 at the FDA’s request but continued to make it available for patients already undergoing treatment.
However, in March 2022, Oncopeptides rescinded the letter that voluntarily withdrew the agent from market, after further review of overall survival data from the OCEAN trial led the company to reconsider its decision. Notably, marketing efforts were still discontinued while the company worked with the FDA to interpret the data, it stated in the press release.
That review of the data showed that progression-free survival was 42% higher with melphalan flufenamide versus pomalidomide and overall response rates were 32.1% versus 26.5%, respectively.
Now, the FDA has requested that the company withdraw its U.S. marketing authorization.
“We respect FDA’s accelerated approval regulations,” Jakob Lindberg, CEO of Oncopeptides commented in the press release.
However, he also added, “multiple myeloma remains an incurable disease, and the treatment options for patients with triple-class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for multiple myeloma patients, in particular for nontransplanted elderly patients where the unmet medical need remains very high.”
Commercialization of the drug in Europe, under the brand name Pepaxti, is ongoing.
“Pepaxti has a full approval from the European Medicines Agency, EMA, since Aug. 18, 2022, and was approved by the Medicines and Healthcare Products Regulatory Agency, MHRA, in the U.K. on Nov 11, 2022,” the company noted.
A version of this article first appeared on Medscape.com.
(melphalan flufenamide), the company announced in a press release.
The drug was granted an accelerated approval by the FDA in February 2021, for use in combination with dexamethasone in adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy.
However, the phase 3 OCEAN study raised concerns about safety, as it showed a higher mortality associated with melphalan flufenamide in the experimental arm, compared with pomalidomide (Pomalyst).
The FDA already flagged this issue in July 2021, issuing a safety alert flagging the increased risk for death observed in the OCEAN trial among patients receiving melphalan flufenamide versus pomalidomide (47.6% vs. 43.4%) and a 5.3-month shorter overall survival.
The issue was also discussed in September 2022 by FDA’s Oncologic Drugs Advisory Committee, which voted 14-to-2 against maintaining the accelerated approval, citing an unfavorable risk/benefit profile.
The company stopped marketing the drug in the United States in October 2021 at the FDA’s request but continued to make it available for patients already undergoing treatment.
However, in March 2022, Oncopeptides rescinded the letter that voluntarily withdrew the agent from market, after further review of overall survival data from the OCEAN trial led the company to reconsider its decision. Notably, marketing efforts were still discontinued while the company worked with the FDA to interpret the data, it stated in the press release.
That review of the data showed that progression-free survival was 42% higher with melphalan flufenamide versus pomalidomide and overall response rates were 32.1% versus 26.5%, respectively.
Now, the FDA has requested that the company withdraw its U.S. marketing authorization.
“We respect FDA’s accelerated approval regulations,” Jakob Lindberg, CEO of Oncopeptides commented in the press release.
However, he also added, “multiple myeloma remains an incurable disease, and the treatment options for patients with triple-class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for multiple myeloma patients, in particular for nontransplanted elderly patients where the unmet medical need remains very high.”
Commercialization of the drug in Europe, under the brand name Pepaxti, is ongoing.
“Pepaxti has a full approval from the European Medicines Agency, EMA, since Aug. 18, 2022, and was approved by the Medicines and Healthcare Products Regulatory Agency, MHRA, in the U.K. on Nov 11, 2022,” the company noted.
A version of this article first appeared on Medscape.com.
(melphalan flufenamide), the company announced in a press release.
The drug was granted an accelerated approval by the FDA in February 2021, for use in combination with dexamethasone in adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy.
However, the phase 3 OCEAN study raised concerns about safety, as it showed a higher mortality associated with melphalan flufenamide in the experimental arm, compared with pomalidomide (Pomalyst).
The FDA already flagged this issue in July 2021, issuing a safety alert flagging the increased risk for death observed in the OCEAN trial among patients receiving melphalan flufenamide versus pomalidomide (47.6% vs. 43.4%) and a 5.3-month shorter overall survival.
The issue was also discussed in September 2022 by FDA’s Oncologic Drugs Advisory Committee, which voted 14-to-2 against maintaining the accelerated approval, citing an unfavorable risk/benefit profile.
The company stopped marketing the drug in the United States in October 2021 at the FDA’s request but continued to make it available for patients already undergoing treatment.
However, in March 2022, Oncopeptides rescinded the letter that voluntarily withdrew the agent from market, after further review of overall survival data from the OCEAN trial led the company to reconsider its decision. Notably, marketing efforts were still discontinued while the company worked with the FDA to interpret the data, it stated in the press release.
That review of the data showed that progression-free survival was 42% higher with melphalan flufenamide versus pomalidomide and overall response rates were 32.1% versus 26.5%, respectively.
Now, the FDA has requested that the company withdraw its U.S. marketing authorization.
“We respect FDA’s accelerated approval regulations,” Jakob Lindberg, CEO of Oncopeptides commented in the press release.
However, he also added, “multiple myeloma remains an incurable disease, and the treatment options for patients with triple-class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for multiple myeloma patients, in particular for nontransplanted elderly patients where the unmet medical need remains very high.”
Commercialization of the drug in Europe, under the brand name Pepaxti, is ongoing.
“Pepaxti has a full approval from the European Medicines Agency, EMA, since Aug. 18, 2022, and was approved by the Medicines and Healthcare Products Regulatory Agency, MHRA, in the U.K. on Nov 11, 2022,” the company noted.
A version of this article first appeared on Medscape.com.
Sleep-disordered breathing promotes elevated arterial stiffness and preeclampsia
, based on data from 181 individuals.
The intermittent hypoxia resulting from sleep-disordered breathing (SDB) has been linked to cardiovascular disease and hypertension, wrote Kim Phan, PhD, of McGill University, Montreal, and colleagues.
SDB has been associated with increased preeclampsia risk, and women with preeclampsia show increased arterial stiffness, but an association between SDB and arterial stiffness in pregnancy has not been explored, they said.
In a study published in the American Journal of Obstetrics & Gynecology, the researchers reviewed data from 181 women with high-risk singleton pregnancies recruited from two tertiary obstetrics clinics in Montreal. High-risk pregnancy was defined as meeting at least one of the following criteria: age 35 years and older, body mass index 25 kg/m2 or higher, chronic hypertension, preexisting diabetes mellitus, preexisting renal disease, or personal or first-degree relative with a history of preeclampsia.
Participants were assessed at each trimester via the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Restless Legs Syndrome questionnaire. Sleep-disordered breathing was defined as loud snoring or witnessed sleep apneas at least three times a week. Arterial stiffness was assessed via applanation tonometry every 4 weeks from baseline throughout pregnancy.
Overall, 23% of the study population met the criteria for SDB; SDB in the first or second trimester was associated with a significantly increased risk of preeclampsia (odds ratio 3.4). The effect of SDB on preeclampsia was increased in women who reported excessive daytime sleepiness, defined as scores higher than 10 on the Epworth Sleepiness Scale. The odds ratio for preeclampsia in the first or second trimester increased to 5.7 in women with hypersomnolence in addition to SDB. The risk of preeclampsia was even higher (OR 8.2) in the third trimester.
Self-reported total sleep time decreased in the second and third trimesters compared with the first, but reports of excessive daytime sleepiness remained consistent throughout the pregnancies, the researchers noted.
The results highlight the need to screen pregnant women for SDB in all three trimesters; however, “future studies will need to assess the incremental benefit of integrating SDB into risk assessment calculators in pregnancy,” the researchers wrote in their discussion. Randomized trials are needed to determine the value of interventions such as continuous positive airway pressure to reduce arterial stiffness and the risks of hypertensive disorders of pregnancy, they said. More data also are needed to examine the role of excessive daytime sleepiness as a modifier of arterial stiffness and preeclampsia risk, they noted.
The findings were limited by the prospective design, which prevents conclusions of causality, the researchers noted. Other limitations included the focus on high-risk pregnancy, which may limit generalizability, and the use of symptoms, not sleep recordings, to identify SDB, they said.
However, the results show an independent association between SDB and arterial stiffness during pregnancy, and offer potentially useful insights into the mechanisms of SDB-associated cardiovascular conditions, they noted.
“This work may inform future studies exploring the value of using arterial stiffness, as an early noninvasive indicator of subclinical vascular dysfunction in pregnant women with SDB,” they concluded.
The study was supported by the Fonds de recherche du Quebec – Sante (FRQS), Heart and Stroke Foundation of Canada, McGill University’s academic enrichment fund, and the Canadian Foundation for Women’s Health. The researchers had no financial conflicts to disclose.
, based on data from 181 individuals.
The intermittent hypoxia resulting from sleep-disordered breathing (SDB) has been linked to cardiovascular disease and hypertension, wrote Kim Phan, PhD, of McGill University, Montreal, and colleagues.
SDB has been associated with increased preeclampsia risk, and women with preeclampsia show increased arterial stiffness, but an association between SDB and arterial stiffness in pregnancy has not been explored, they said.
In a study published in the American Journal of Obstetrics & Gynecology, the researchers reviewed data from 181 women with high-risk singleton pregnancies recruited from two tertiary obstetrics clinics in Montreal. High-risk pregnancy was defined as meeting at least one of the following criteria: age 35 years and older, body mass index 25 kg/m2 or higher, chronic hypertension, preexisting diabetes mellitus, preexisting renal disease, or personal or first-degree relative with a history of preeclampsia.
Participants were assessed at each trimester via the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Restless Legs Syndrome questionnaire. Sleep-disordered breathing was defined as loud snoring or witnessed sleep apneas at least three times a week. Arterial stiffness was assessed via applanation tonometry every 4 weeks from baseline throughout pregnancy.
Overall, 23% of the study population met the criteria for SDB; SDB in the first or second trimester was associated with a significantly increased risk of preeclampsia (odds ratio 3.4). The effect of SDB on preeclampsia was increased in women who reported excessive daytime sleepiness, defined as scores higher than 10 on the Epworth Sleepiness Scale. The odds ratio for preeclampsia in the first or second trimester increased to 5.7 in women with hypersomnolence in addition to SDB. The risk of preeclampsia was even higher (OR 8.2) in the third trimester.
Self-reported total sleep time decreased in the second and third trimesters compared with the first, but reports of excessive daytime sleepiness remained consistent throughout the pregnancies, the researchers noted.
The results highlight the need to screen pregnant women for SDB in all three trimesters; however, “future studies will need to assess the incremental benefit of integrating SDB into risk assessment calculators in pregnancy,” the researchers wrote in their discussion. Randomized trials are needed to determine the value of interventions such as continuous positive airway pressure to reduce arterial stiffness and the risks of hypertensive disorders of pregnancy, they said. More data also are needed to examine the role of excessive daytime sleepiness as a modifier of arterial stiffness and preeclampsia risk, they noted.
The findings were limited by the prospective design, which prevents conclusions of causality, the researchers noted. Other limitations included the focus on high-risk pregnancy, which may limit generalizability, and the use of symptoms, not sleep recordings, to identify SDB, they said.
However, the results show an independent association between SDB and arterial stiffness during pregnancy, and offer potentially useful insights into the mechanisms of SDB-associated cardiovascular conditions, they noted.
“This work may inform future studies exploring the value of using arterial stiffness, as an early noninvasive indicator of subclinical vascular dysfunction in pregnant women with SDB,” they concluded.
The study was supported by the Fonds de recherche du Quebec – Sante (FRQS), Heart and Stroke Foundation of Canada, McGill University’s academic enrichment fund, and the Canadian Foundation for Women’s Health. The researchers had no financial conflicts to disclose.
, based on data from 181 individuals.
The intermittent hypoxia resulting from sleep-disordered breathing (SDB) has been linked to cardiovascular disease and hypertension, wrote Kim Phan, PhD, of McGill University, Montreal, and colleagues.
SDB has been associated with increased preeclampsia risk, and women with preeclampsia show increased arterial stiffness, but an association between SDB and arterial stiffness in pregnancy has not been explored, they said.
In a study published in the American Journal of Obstetrics & Gynecology, the researchers reviewed data from 181 women with high-risk singleton pregnancies recruited from two tertiary obstetrics clinics in Montreal. High-risk pregnancy was defined as meeting at least one of the following criteria: age 35 years and older, body mass index 25 kg/m2 or higher, chronic hypertension, preexisting diabetes mellitus, preexisting renal disease, or personal or first-degree relative with a history of preeclampsia.
Participants were assessed at each trimester via the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Restless Legs Syndrome questionnaire. Sleep-disordered breathing was defined as loud snoring or witnessed sleep apneas at least three times a week. Arterial stiffness was assessed via applanation tonometry every 4 weeks from baseline throughout pregnancy.
Overall, 23% of the study population met the criteria for SDB; SDB in the first or second trimester was associated with a significantly increased risk of preeclampsia (odds ratio 3.4). The effect of SDB on preeclampsia was increased in women who reported excessive daytime sleepiness, defined as scores higher than 10 on the Epworth Sleepiness Scale. The odds ratio for preeclampsia in the first or second trimester increased to 5.7 in women with hypersomnolence in addition to SDB. The risk of preeclampsia was even higher (OR 8.2) in the third trimester.
Self-reported total sleep time decreased in the second and third trimesters compared with the first, but reports of excessive daytime sleepiness remained consistent throughout the pregnancies, the researchers noted.
The results highlight the need to screen pregnant women for SDB in all three trimesters; however, “future studies will need to assess the incremental benefit of integrating SDB into risk assessment calculators in pregnancy,” the researchers wrote in their discussion. Randomized trials are needed to determine the value of interventions such as continuous positive airway pressure to reduce arterial stiffness and the risks of hypertensive disorders of pregnancy, they said. More data also are needed to examine the role of excessive daytime sleepiness as a modifier of arterial stiffness and preeclampsia risk, they noted.
The findings were limited by the prospective design, which prevents conclusions of causality, the researchers noted. Other limitations included the focus on high-risk pregnancy, which may limit generalizability, and the use of symptoms, not sleep recordings, to identify SDB, they said.
However, the results show an independent association between SDB and arterial stiffness during pregnancy, and offer potentially useful insights into the mechanisms of SDB-associated cardiovascular conditions, they noted.
“This work may inform future studies exploring the value of using arterial stiffness, as an early noninvasive indicator of subclinical vascular dysfunction in pregnant women with SDB,” they concluded.
The study was supported by the Fonds de recherche du Quebec – Sante (FRQS), Heart and Stroke Foundation of Canada, McGill University’s academic enrichment fund, and the Canadian Foundation for Women’s Health. The researchers had no financial conflicts to disclose.
FROM THE AMERICAN JOURNAL OF OBSTETRICS & GYNECOLOGY