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FDA panel rejects pimavanserin for Alzheimer’s psychosis
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
Updates in aspirin use, aducanumab, and CKD diagnostic criteria in geriatric medicine
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
Psychedelic drugs ‘truly have potential’ in headache care
DENVER – Psychedelics such as psilocybin “truly have the potential to transform how we treat a number of neuropsychiatric diseases, including headaches,” a neuropharmacologist told colleagues at the annual meeting of the American Headache Society.
However, Bryan Roth, MD, PhD, professor of pharmacology at the University of North Carolina at Chapel Hill, also offered a major cautionary note: There have been no randomized, phase 3 trials of psychedelics, and he bluntly said that “I do not recommend the use of psychedelics for any medical condition.”
The potential disease-altering powers of psychedelics have received a tremendous amount of research and media attention over the past several years. A landmark randomized, double-blind study released in 2016 triggered much of the interest, Dr. Roth said, when it suggested that high-dose psilocybin significantly lowered levels of depressed mood/anxiety in patients with life-threatening cancer. At 6 months, 80% of patients who took the dose reported moderate or greater improvement in well-being/life satisfaction.
“You have the potential – unprecedented in psychiatry – that a single dose of a therapeutic agent may induce a rapid, robust, and sustained antidepressant action,” he said. Also of note: The “vast majority” of subjects say their encounter with a psychedelic was “one of the most meaningful experiences of their lives.”
Dr. Roth said his own research suggests that psychedelics cause a “huge increase” in the asynchronous firing of neurons. “Noise is being injected into the system and is interpreted by the brain or the mind, which always likes to make a story about what’s going on. The story it makes up is idiosyncratic to every person and memorable for reasons that are not understood.”
Now, Dr. Roth said, he and colleagues are working to “create drugs that have this potential remarkable therapeutic efficacy in psychiatric and neurologic disorders without the psychedelic effects.” A $27 million grant from the Defense Advanced Research Projects Agency is providing support for their efforts, he said.
For the moment, he said, there’s no way to know if “the psychedelic experience is essential to the therapeutic action of these drugs. But it’s a testable hypothesis.”
As he noted, a tiny 2010 study of 2-bromo-lysergic acid diethylamide (LSD), which doesn’t cause hallucinations, showed promise as a treatment for cluster headaches.
For now, Dr. Roth said, his lab is synthesizing and testing new compounds that interact with the crucial 5-HT2A receptor.
Additional research
In another presentation at the AHS annual meeting, neurologist Emmanuelle A. D. Schindler, MD, PhD, of Yale School of Medicine, highlighted her 2021 study of an exploratory double-blind, placebo-controlled, cross-over study of psilocybin versus placebo for migraine headache. A single oral dose of the drug, the researchers found, reduced headache frequency and pain over 2 weeks. The study is small, with just 10 subjects, and multiple exclusion criteria.
She also revealed preliminary findings from an ongoing randomized, double-blind, placebo-controlled study of psilocybin versus placebo in cluster headaches. In 14 subjects, a psilocybin pulse was linked to fewer cluster attacks over 3 weeks, although the effect wasn’t statistically significant. However, there was a statistically significant reduction over 8 weeks in patients with chronic headache.
Dr. Schindler noted that “with these early studies, we only looked out to 2 weeks for migraine, and we only looked out to 2 months for cluster.” There are multiple other limitations, she acknowledged. “We have to do a lot more research and consider safety as well.”
However, “there is a really unique capacity for lasting effects after limited dosing,” she added, and the studies do show reductions in headache burden “that do not correlate with acute psychedelic effects.”
Moving forward, Dr. Roth cautioned that while U.S. states are allowing the use of psychedelics for medical purposes, “we don’t know if they ultimately are therapeutic. And we have strong reason to believe that microdosing or chronic dosing of these compounds is ultimately going to be deleterious to the health of our patients.”
Dr. Roth did not provide disclosure information. Dr. Schindler discloses research funding (Ceruvia Lifesciences, Wallace Research Foundation, Clusterbusters, Department of Veterans Affairs), serves on advisory boards (Ceruvia Lifesciences, Clusterbusters), and has a patent.
DENVER – Psychedelics such as psilocybin “truly have the potential to transform how we treat a number of neuropsychiatric diseases, including headaches,” a neuropharmacologist told colleagues at the annual meeting of the American Headache Society.
However, Bryan Roth, MD, PhD, professor of pharmacology at the University of North Carolina at Chapel Hill, also offered a major cautionary note: There have been no randomized, phase 3 trials of psychedelics, and he bluntly said that “I do not recommend the use of psychedelics for any medical condition.”
The potential disease-altering powers of psychedelics have received a tremendous amount of research and media attention over the past several years. A landmark randomized, double-blind study released in 2016 triggered much of the interest, Dr. Roth said, when it suggested that high-dose psilocybin significantly lowered levels of depressed mood/anxiety in patients with life-threatening cancer. At 6 months, 80% of patients who took the dose reported moderate or greater improvement in well-being/life satisfaction.
“You have the potential – unprecedented in psychiatry – that a single dose of a therapeutic agent may induce a rapid, robust, and sustained antidepressant action,” he said. Also of note: The “vast majority” of subjects say their encounter with a psychedelic was “one of the most meaningful experiences of their lives.”
Dr. Roth said his own research suggests that psychedelics cause a “huge increase” in the asynchronous firing of neurons. “Noise is being injected into the system and is interpreted by the brain or the mind, which always likes to make a story about what’s going on. The story it makes up is idiosyncratic to every person and memorable for reasons that are not understood.”
Now, Dr. Roth said, he and colleagues are working to “create drugs that have this potential remarkable therapeutic efficacy in psychiatric and neurologic disorders without the psychedelic effects.” A $27 million grant from the Defense Advanced Research Projects Agency is providing support for their efforts, he said.
For the moment, he said, there’s no way to know if “the psychedelic experience is essential to the therapeutic action of these drugs. But it’s a testable hypothesis.”
As he noted, a tiny 2010 study of 2-bromo-lysergic acid diethylamide (LSD), which doesn’t cause hallucinations, showed promise as a treatment for cluster headaches.
For now, Dr. Roth said, his lab is synthesizing and testing new compounds that interact with the crucial 5-HT2A receptor.
Additional research
In another presentation at the AHS annual meeting, neurologist Emmanuelle A. D. Schindler, MD, PhD, of Yale School of Medicine, highlighted her 2021 study of an exploratory double-blind, placebo-controlled, cross-over study of psilocybin versus placebo for migraine headache. A single oral dose of the drug, the researchers found, reduced headache frequency and pain over 2 weeks. The study is small, with just 10 subjects, and multiple exclusion criteria.
She also revealed preliminary findings from an ongoing randomized, double-blind, placebo-controlled study of psilocybin versus placebo in cluster headaches. In 14 subjects, a psilocybin pulse was linked to fewer cluster attacks over 3 weeks, although the effect wasn’t statistically significant. However, there was a statistically significant reduction over 8 weeks in patients with chronic headache.
Dr. Schindler noted that “with these early studies, we only looked out to 2 weeks for migraine, and we only looked out to 2 months for cluster.” There are multiple other limitations, she acknowledged. “We have to do a lot more research and consider safety as well.”
However, “there is a really unique capacity for lasting effects after limited dosing,” she added, and the studies do show reductions in headache burden “that do not correlate with acute psychedelic effects.”
Moving forward, Dr. Roth cautioned that while U.S. states are allowing the use of psychedelics for medical purposes, “we don’t know if they ultimately are therapeutic. And we have strong reason to believe that microdosing or chronic dosing of these compounds is ultimately going to be deleterious to the health of our patients.”
Dr. Roth did not provide disclosure information. Dr. Schindler discloses research funding (Ceruvia Lifesciences, Wallace Research Foundation, Clusterbusters, Department of Veterans Affairs), serves on advisory boards (Ceruvia Lifesciences, Clusterbusters), and has a patent.
DENVER – Psychedelics such as psilocybin “truly have the potential to transform how we treat a number of neuropsychiatric diseases, including headaches,” a neuropharmacologist told colleagues at the annual meeting of the American Headache Society.
However, Bryan Roth, MD, PhD, professor of pharmacology at the University of North Carolina at Chapel Hill, also offered a major cautionary note: There have been no randomized, phase 3 trials of psychedelics, and he bluntly said that “I do not recommend the use of psychedelics for any medical condition.”
The potential disease-altering powers of psychedelics have received a tremendous amount of research and media attention over the past several years. A landmark randomized, double-blind study released in 2016 triggered much of the interest, Dr. Roth said, when it suggested that high-dose psilocybin significantly lowered levels of depressed mood/anxiety in patients with life-threatening cancer. At 6 months, 80% of patients who took the dose reported moderate or greater improvement in well-being/life satisfaction.
“You have the potential – unprecedented in psychiatry – that a single dose of a therapeutic agent may induce a rapid, robust, and sustained antidepressant action,” he said. Also of note: The “vast majority” of subjects say their encounter with a psychedelic was “one of the most meaningful experiences of their lives.”
Dr. Roth said his own research suggests that psychedelics cause a “huge increase” in the asynchronous firing of neurons. “Noise is being injected into the system and is interpreted by the brain or the mind, which always likes to make a story about what’s going on. The story it makes up is idiosyncratic to every person and memorable for reasons that are not understood.”
Now, Dr. Roth said, he and colleagues are working to “create drugs that have this potential remarkable therapeutic efficacy in psychiatric and neurologic disorders without the psychedelic effects.” A $27 million grant from the Defense Advanced Research Projects Agency is providing support for their efforts, he said.
For the moment, he said, there’s no way to know if “the psychedelic experience is essential to the therapeutic action of these drugs. But it’s a testable hypothesis.”
As he noted, a tiny 2010 study of 2-bromo-lysergic acid diethylamide (LSD), which doesn’t cause hallucinations, showed promise as a treatment for cluster headaches.
For now, Dr. Roth said, his lab is synthesizing and testing new compounds that interact with the crucial 5-HT2A receptor.
Additional research
In another presentation at the AHS annual meeting, neurologist Emmanuelle A. D. Schindler, MD, PhD, of Yale School of Medicine, highlighted her 2021 study of an exploratory double-blind, placebo-controlled, cross-over study of psilocybin versus placebo for migraine headache. A single oral dose of the drug, the researchers found, reduced headache frequency and pain over 2 weeks. The study is small, with just 10 subjects, and multiple exclusion criteria.
She also revealed preliminary findings from an ongoing randomized, double-blind, placebo-controlled study of psilocybin versus placebo in cluster headaches. In 14 subjects, a psilocybin pulse was linked to fewer cluster attacks over 3 weeks, although the effect wasn’t statistically significant. However, there was a statistically significant reduction over 8 weeks in patients with chronic headache.
Dr. Schindler noted that “with these early studies, we only looked out to 2 weeks for migraine, and we only looked out to 2 months for cluster.” There are multiple other limitations, she acknowledged. “We have to do a lot more research and consider safety as well.”
However, “there is a really unique capacity for lasting effects after limited dosing,” she added, and the studies do show reductions in headache burden “that do not correlate with acute psychedelic effects.”
Moving forward, Dr. Roth cautioned that while U.S. states are allowing the use of psychedelics for medical purposes, “we don’t know if they ultimately are therapeutic. And we have strong reason to believe that microdosing or chronic dosing of these compounds is ultimately going to be deleterious to the health of our patients.”
Dr. Roth did not provide disclosure information. Dr. Schindler discloses research funding (Ceruvia Lifesciences, Wallace Research Foundation, Clusterbusters, Department of Veterans Affairs), serves on advisory boards (Ceruvia Lifesciences, Clusterbusters), and has a patent.
FROM AHS 2022
Disappointing results for investigational Alzheimer’s drug
, new research suggests.
Top-line results for a phase 2 trial showed the novel drug, a monoclonal antibody designed to neutralize neurotoxic oligomers (a form of beta-amyloid), was not statistically superior to placebo in terms of cognitive ability or episodic memory function among cognitively unimpaired individuals with a genetic mutation for early-onset AD.
Genentech announced the negative results on June 16 together with Banner Alzheimer’s Institute, Phoenix.
During a press briefing, company representatives and researchers expressed disappointment with the initial results – but stressed numerous ongoing analyses have yet to be completed.
“This is the beginning of the story, but by no means the end of it,” Pierre N. Tariot, MD, director, Banner Alzheimer’s Institute, and one of the study leaders, said at the briefing.
API ADAD trial
The prospective, double-blind parallel-group Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) phase 2 trial enrolled 252 members of the world’s largest extended family with ADAD in Colombia. A total of 94% of the participants completed the study.
Two-thirds of participants carried the Presenilin 1 (PSEN1) E280A mutation, which virtually guarantees that carriers will develop AD at an average age of 44 years and dementia at an average age of 49 years.
Study participants were randomly assigned to receive crenezumab or placebo over a period of 5-8 years. The dose of crenezumab was increased at different time points during the trial as knowledge about potential treatment approaches for AD evolved.
Dr. Tariot noted the maximum dose was not provided for the entire treatment period. “The longest people received the highest dose was about 2 years,” he added.
Coprimary endpoints were rate of change in cognitive abilities, as measured by the API ADAD composite cognitive score, or episodic memory function, measured by the Free and Cued Selective Reminding Test Cueing Index.
Results showed these outcomes were not statistically significant for those receiving the active medication.
In addition to a range of cognitive measures, researchers also assessed amyloid PET and, later in the study, tau PET. MRI and cerebrospinal fluid (CSF) measures were also examined.
The investigators did find small numerical differences favoring crenezumab across the coprimary and multiple secondary and exploratory endpoints, but these were also not statistically significant.
Finally, no new safety issues were identified with crenezumab during the study.
Further analyses of data are ongoing and additional brain imaging and CSF biomarker results will be presented at the Alzheimer’s Association International Conference on Aug. 2.
While the study was not positive, it demonstrated that prevention trials are possible, even in less-than-ideal circumstances and generated a wealth of useful data, the investigators note.
“There were some differences between the treated and untreated patients, and we still need to understand which patients were most likely to experience those differences,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, told briefing attendees.
“We need to understand the biomarkers involved and what [they’re] telling us about the disease and the timing of the intervention,” Dr. Doody said.
Prevention “needs to be one of our targeted therapeutic approaches but probably not our only one,” she added.
Beyond amyloid?
Commenting on the negative results, Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said they demonstrate the need to focus beyond amyloid and more on the biology of aging.
“This broader approach coupled with advances in novel biomarkers is bringing us closer to the day when physicians will be able to zero in on the root causes of each patient’s Alzheimer’s – and tailor combinations of drug therapies to provide precision medicine,” Dr. Fillit, who was not involved with the research, said in statement.
Genentech is also evaluating the potential of gantenerumab for ADAD and for the prevention of sporadic AD and treatment of early Alzheimer’s in late-stage clinical trials. Results from the phase 3 GRADUATE studies of gantenerumab in early AD are expected by the end of the year.
The study was supported by the National Institute on Aging, contributions to Banner Alzheimer’s Foundation, and Genentech.
A version of this article first appeared on Medscape.com.
, new research suggests.
Top-line results for a phase 2 trial showed the novel drug, a monoclonal antibody designed to neutralize neurotoxic oligomers (a form of beta-amyloid), was not statistically superior to placebo in terms of cognitive ability or episodic memory function among cognitively unimpaired individuals with a genetic mutation for early-onset AD.
Genentech announced the negative results on June 16 together with Banner Alzheimer’s Institute, Phoenix.
During a press briefing, company representatives and researchers expressed disappointment with the initial results – but stressed numerous ongoing analyses have yet to be completed.
“This is the beginning of the story, but by no means the end of it,” Pierre N. Tariot, MD, director, Banner Alzheimer’s Institute, and one of the study leaders, said at the briefing.
API ADAD trial
The prospective, double-blind parallel-group Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) phase 2 trial enrolled 252 members of the world’s largest extended family with ADAD in Colombia. A total of 94% of the participants completed the study.
Two-thirds of participants carried the Presenilin 1 (PSEN1) E280A mutation, which virtually guarantees that carriers will develop AD at an average age of 44 years and dementia at an average age of 49 years.
Study participants were randomly assigned to receive crenezumab or placebo over a period of 5-8 years. The dose of crenezumab was increased at different time points during the trial as knowledge about potential treatment approaches for AD evolved.
Dr. Tariot noted the maximum dose was not provided for the entire treatment period. “The longest people received the highest dose was about 2 years,” he added.
Coprimary endpoints were rate of change in cognitive abilities, as measured by the API ADAD composite cognitive score, or episodic memory function, measured by the Free and Cued Selective Reminding Test Cueing Index.
Results showed these outcomes were not statistically significant for those receiving the active medication.
In addition to a range of cognitive measures, researchers also assessed amyloid PET and, later in the study, tau PET. MRI and cerebrospinal fluid (CSF) measures were also examined.
The investigators did find small numerical differences favoring crenezumab across the coprimary and multiple secondary and exploratory endpoints, but these were also not statistically significant.
Finally, no new safety issues were identified with crenezumab during the study.
Further analyses of data are ongoing and additional brain imaging and CSF biomarker results will be presented at the Alzheimer’s Association International Conference on Aug. 2.
While the study was not positive, it demonstrated that prevention trials are possible, even in less-than-ideal circumstances and generated a wealth of useful data, the investigators note.
“There were some differences between the treated and untreated patients, and we still need to understand which patients were most likely to experience those differences,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, told briefing attendees.
“We need to understand the biomarkers involved and what [they’re] telling us about the disease and the timing of the intervention,” Dr. Doody said.
Prevention “needs to be one of our targeted therapeutic approaches but probably not our only one,” she added.
Beyond amyloid?
Commenting on the negative results, Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said they demonstrate the need to focus beyond amyloid and more on the biology of aging.
“This broader approach coupled with advances in novel biomarkers is bringing us closer to the day when physicians will be able to zero in on the root causes of each patient’s Alzheimer’s – and tailor combinations of drug therapies to provide precision medicine,” Dr. Fillit, who was not involved with the research, said in statement.
Genentech is also evaluating the potential of gantenerumab for ADAD and for the prevention of sporadic AD and treatment of early Alzheimer’s in late-stage clinical trials. Results from the phase 3 GRADUATE studies of gantenerumab in early AD are expected by the end of the year.
The study was supported by the National Institute on Aging, contributions to Banner Alzheimer’s Foundation, and Genentech.
A version of this article first appeared on Medscape.com.
, new research suggests.
Top-line results for a phase 2 trial showed the novel drug, a monoclonal antibody designed to neutralize neurotoxic oligomers (a form of beta-amyloid), was not statistically superior to placebo in terms of cognitive ability or episodic memory function among cognitively unimpaired individuals with a genetic mutation for early-onset AD.
Genentech announced the negative results on June 16 together with Banner Alzheimer’s Institute, Phoenix.
During a press briefing, company representatives and researchers expressed disappointment with the initial results – but stressed numerous ongoing analyses have yet to be completed.
“This is the beginning of the story, but by no means the end of it,” Pierre N. Tariot, MD, director, Banner Alzheimer’s Institute, and one of the study leaders, said at the briefing.
API ADAD trial
The prospective, double-blind parallel-group Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) phase 2 trial enrolled 252 members of the world’s largest extended family with ADAD in Colombia. A total of 94% of the participants completed the study.
Two-thirds of participants carried the Presenilin 1 (PSEN1) E280A mutation, which virtually guarantees that carriers will develop AD at an average age of 44 years and dementia at an average age of 49 years.
Study participants were randomly assigned to receive crenezumab or placebo over a period of 5-8 years. The dose of crenezumab was increased at different time points during the trial as knowledge about potential treatment approaches for AD evolved.
Dr. Tariot noted the maximum dose was not provided for the entire treatment period. “The longest people received the highest dose was about 2 years,” he added.
Coprimary endpoints were rate of change in cognitive abilities, as measured by the API ADAD composite cognitive score, or episodic memory function, measured by the Free and Cued Selective Reminding Test Cueing Index.
Results showed these outcomes were not statistically significant for those receiving the active medication.
In addition to a range of cognitive measures, researchers also assessed amyloid PET and, later in the study, tau PET. MRI and cerebrospinal fluid (CSF) measures were also examined.
The investigators did find small numerical differences favoring crenezumab across the coprimary and multiple secondary and exploratory endpoints, but these were also not statistically significant.
Finally, no new safety issues were identified with crenezumab during the study.
Further analyses of data are ongoing and additional brain imaging and CSF biomarker results will be presented at the Alzheimer’s Association International Conference on Aug. 2.
While the study was not positive, it demonstrated that prevention trials are possible, even in less-than-ideal circumstances and generated a wealth of useful data, the investigators note.
“There were some differences between the treated and untreated patients, and we still need to understand which patients were most likely to experience those differences,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, told briefing attendees.
“We need to understand the biomarkers involved and what [they’re] telling us about the disease and the timing of the intervention,” Dr. Doody said.
Prevention “needs to be one of our targeted therapeutic approaches but probably not our only one,” she added.
Beyond amyloid?
Commenting on the negative results, Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said they demonstrate the need to focus beyond amyloid and more on the biology of aging.
“This broader approach coupled with advances in novel biomarkers is bringing us closer to the day when physicians will be able to zero in on the root causes of each patient’s Alzheimer’s – and tailor combinations of drug therapies to provide precision medicine,” Dr. Fillit, who was not involved with the research, said in statement.
Genentech is also evaluating the potential of gantenerumab for ADAD and for the prevention of sporadic AD and treatment of early Alzheimer’s in late-stage clinical trials. Results from the phase 3 GRADUATE studies of gantenerumab in early AD are expected by the end of the year.
The study was supported by the National Institute on Aging, contributions to Banner Alzheimer’s Foundation, and Genentech.
A version of this article first appeared on Medscape.com.
Don’t overlook this cause of falls
I enjoyed reading “How to identify balance disorders and reduce fall risk” (J Fam Pract. 2022;71:20-30) from the January/February issue. I was, however, disappointed to see that normal pressure hydrocephalus (NPH) was not discussed in the article or tables.
Recently, I took care of a 72-year-old patient who presented after multiple falls. In conjunction with Neurology, the presumptive diagnosis of Parkinson disease was made. However, the patient continued to experience a health decline that included cognitive changes, nocturia, and the classic “magnetic gait” of NPH (mnemonic for diagnosing this triad of symptoms: weird, wet, wobbly). The presumptive diagnosis was then changed when the results of a fluorodopa F18 positron emission tomography scan (also known as a DaT scan) returned as normal, essentially excluding the diagnosis of Parkinson disease.
The patient has since seen a dramatic improvement in gait and cognitive and urinary symptoms following a high-volume lumbar puncture and placement of a ventriculoperitoneal shunt.
This case demonstrates the importance of considering NPH in the differential diagnosis for patients with balance disorders. Prompt diagnosis and management can result in a variable, but at times dramatic, reversal of symptoms.
Ernestine Lee, MD, MPH
Austin, TX
I enjoyed reading “How to identify balance disorders and reduce fall risk” (J Fam Pract. 2022;71:20-30) from the January/February issue. I was, however, disappointed to see that normal pressure hydrocephalus (NPH) was not discussed in the article or tables.
Recently, I took care of a 72-year-old patient who presented after multiple falls. In conjunction with Neurology, the presumptive diagnosis of Parkinson disease was made. However, the patient continued to experience a health decline that included cognitive changes, nocturia, and the classic “magnetic gait” of NPH (mnemonic for diagnosing this triad of symptoms: weird, wet, wobbly). The presumptive diagnosis was then changed when the results of a fluorodopa F18 positron emission tomography scan (also known as a DaT scan) returned as normal, essentially excluding the diagnosis of Parkinson disease.
The patient has since seen a dramatic improvement in gait and cognitive and urinary symptoms following a high-volume lumbar puncture and placement of a ventriculoperitoneal shunt.
This case demonstrates the importance of considering NPH in the differential diagnosis for patients with balance disorders. Prompt diagnosis and management can result in a variable, but at times dramatic, reversal of symptoms.
Ernestine Lee, MD, MPH
Austin, TX
I enjoyed reading “How to identify balance disorders and reduce fall risk” (J Fam Pract. 2022;71:20-30) from the January/February issue. I was, however, disappointed to see that normal pressure hydrocephalus (NPH) was not discussed in the article or tables.
Recently, I took care of a 72-year-old patient who presented after multiple falls. In conjunction with Neurology, the presumptive diagnosis of Parkinson disease was made. However, the patient continued to experience a health decline that included cognitive changes, nocturia, and the classic “magnetic gait” of NPH (mnemonic for diagnosing this triad of symptoms: weird, wet, wobbly). The presumptive diagnosis was then changed when the results of a fluorodopa F18 positron emission tomography scan (also known as a DaT scan) returned as normal, essentially excluding the diagnosis of Parkinson disease.
The patient has since seen a dramatic improvement in gait and cognitive and urinary symptoms following a high-volume lumbar puncture and placement of a ventriculoperitoneal shunt.
This case demonstrates the importance of considering NPH in the differential diagnosis for patients with balance disorders. Prompt diagnosis and management can result in a variable, but at times dramatic, reversal of symptoms.
Ernestine Lee, MD, MPH
Austin, TX
Findings raise questions about migraine and sleep
CHARLOTTE, N.C. – What may be the largest case-based study of patients with migraine and sleep-disordered breathing to date has found that, counter to prevailing thought, they may not be at higher risk of having obstructive sleep apnea (OSA) than nonmigraine patients, although further prospective studies are needed to validate that finding.
“This in no way for me changes the fact that, for patients that complain of headaches, sleep apnea remains to be something that should be considered as possible cause of their headaches,” neurologist and Cleveland Clinic postdoctoral fellow Eric Gruenthal, MD, said in an interview after he presented his results at the annual meeting of the Associated Professional Sleep Societies.
The study suggested that patients with migraine may have an OSA risk that “may be a little lower” than their nonmigraine counterparts, Dr. Gruenthal said. “But we have really yet to determine whether that’s true or not.”
Large case-based study
The retrospective case study included 4,783 migraine cases from the Cleveland Clinic electronic health record database who were case matched on a 1:3 basis with 14,287 controls. Patients with migraine had an average age of 47.5 years (±13.3) and body mass index of 33.7 kg/m2 (±8.6), and 76.4% were White. All patients had polysomnography (PSG) at a Cleveland Clinic facility from 1998 to 2021.
The analysis evaluated the collected data in two domains: sleep architecture, consisting of arousal index (AI), total sleep time (TST) and percentage of sleep stage time; and sleep-disordered breathing, including apnea hypopnea index (AHI) and mean oxygen saturation. The key findings of the migraine patients versus controls include:
- Lower AI, 19.6 (95% confidence interval, 12.8-30.9) versus 22.6 (95% CI, 14.7-34.9; P < .001).
- Shorter TST, 359 (95% CI, 307-421) versus 363 (95% CI, 306-432.5) minutes (P = .01).
- With regard to sleep stage, the percentage of N2 sleep was higher, 67.8% (95% CI, 59.6%-75.6%) versus 67% (95% CI, 58.4%-74.8%; P < .001); but the percentage of REM was lower at 16.7% (95% CI, 10%-22%) versus 17% (95% CI, 11.1%-22.2%; P = .012).
- Lower AHI, 7.4 (95% CI, 2.6-17) versus 9.5 (95% CI, 3.7-22.1, P < .001).
- Higher mean oxygen saturation, 93.7 (±2.4) versus 93.3% (±2.6; P < .001).
“Also,” Dr. Gruenthal added, “we found that the percentage of sleep time with oxygen saturation below 90% was lower among patients with migraine, at 1.3% versus 2.4%” (P < .001).
A unique profile?
The goal of the study was to determine whether migraine patients would have a unique PSG profile, Dr. Gruenthal said. “We were trying to overcome some of the limitations of previous studies, most notably those that use small sample sizes, and in some cases a lack of controls.”
The findings that migraine patients would have higher AI and elevated AHI ran counter to the study’s hypotheses, but fell in line with the expectation that they would have reduced TST, Dr. Gruenthal said.
Patients with migraine “may, in fact, exhibit a lower burden of sleep-disordered breathing, and that’s based on our findings such as the lower AHI and decreased burden of hypoxemia,” he said. “We theorized that this may be related to patients with migraine having a unique CGRP [calcitonin gene-related peptide] and serotonin physiology.” He noted that previously published research has shown that sleep CGRP and serotonin have a central role in causing arousal in response to rising CO2 levels during sleep, which can occur during apneas and hypopneas.
Dr. Gruenthal noted that the researchers are still analyzing the findings. “We theorized that possible indication bias may be present in our study,” he said. “It may be the case that patients with migraine are more likely to get their PSG done because of their headache and not for things like snoring and witnessed apneas, which may be more predictive of significant sleep apnea.” They’re also evaluating the “question of medicine confounding.”
Dr. Gruenthal added that “the big unanswered question out there is, if you have a patient with migraine who also has sleep apnea, by treating the sleep apnea will that improve their migraine?”
More questions than answers
Commenting on the study, Donald Bliwise, PhD, professor of neurology at Emory Sleep Center, Atlanta, said the study findings shouldn’t change how clinicians approach migraine in relation to sleep.
“It’s a case series, it’s retrospective,” said Dr. Bliwise, who was not involved in the study. “It’s the largest study that I know of that has ever looked at the diagnosis of migraine in relation to polysomnographic measures of sleep, but it’s imprecise to the extent that migraine is a clinical diagnosis, so not everyone that carries the diagnosis of migraine has the diagnosis made by a neurologist.”
The study raises more questions than it answers, he said, “but that’s not necessarily a bad thing. I think we need more prospective studies.” Those studies should be more granular in how they analyze sleep in migraine patients “Since migraine is an intermittent event, and sleep quality and length, and percentage of REM sleep and even sleep apnea can vary from night to night, it would be fascinating to look at headaches over a month in relation to sleep over a month.”
Dr. Gruenthal and Dr. Bliwise have no disclosures. The Association of Migraine Disorders provided funding for the study.
CHARLOTTE, N.C. – What may be the largest case-based study of patients with migraine and sleep-disordered breathing to date has found that, counter to prevailing thought, they may not be at higher risk of having obstructive sleep apnea (OSA) than nonmigraine patients, although further prospective studies are needed to validate that finding.
“This in no way for me changes the fact that, for patients that complain of headaches, sleep apnea remains to be something that should be considered as possible cause of their headaches,” neurologist and Cleveland Clinic postdoctoral fellow Eric Gruenthal, MD, said in an interview after he presented his results at the annual meeting of the Associated Professional Sleep Societies.
The study suggested that patients with migraine may have an OSA risk that “may be a little lower” than their nonmigraine counterparts, Dr. Gruenthal said. “But we have really yet to determine whether that’s true or not.”
Large case-based study
The retrospective case study included 4,783 migraine cases from the Cleveland Clinic electronic health record database who were case matched on a 1:3 basis with 14,287 controls. Patients with migraine had an average age of 47.5 years (±13.3) and body mass index of 33.7 kg/m2 (±8.6), and 76.4% were White. All patients had polysomnography (PSG) at a Cleveland Clinic facility from 1998 to 2021.
The analysis evaluated the collected data in two domains: sleep architecture, consisting of arousal index (AI), total sleep time (TST) and percentage of sleep stage time; and sleep-disordered breathing, including apnea hypopnea index (AHI) and mean oxygen saturation. The key findings of the migraine patients versus controls include:
- Lower AI, 19.6 (95% confidence interval, 12.8-30.9) versus 22.6 (95% CI, 14.7-34.9; P < .001).
- Shorter TST, 359 (95% CI, 307-421) versus 363 (95% CI, 306-432.5) minutes (P = .01).
- With regard to sleep stage, the percentage of N2 sleep was higher, 67.8% (95% CI, 59.6%-75.6%) versus 67% (95% CI, 58.4%-74.8%; P < .001); but the percentage of REM was lower at 16.7% (95% CI, 10%-22%) versus 17% (95% CI, 11.1%-22.2%; P = .012).
- Lower AHI, 7.4 (95% CI, 2.6-17) versus 9.5 (95% CI, 3.7-22.1, P < .001).
- Higher mean oxygen saturation, 93.7 (±2.4) versus 93.3% (±2.6; P < .001).
“Also,” Dr. Gruenthal added, “we found that the percentage of sleep time with oxygen saturation below 90% was lower among patients with migraine, at 1.3% versus 2.4%” (P < .001).
A unique profile?
The goal of the study was to determine whether migraine patients would have a unique PSG profile, Dr. Gruenthal said. “We were trying to overcome some of the limitations of previous studies, most notably those that use small sample sizes, and in some cases a lack of controls.”
The findings that migraine patients would have higher AI and elevated AHI ran counter to the study’s hypotheses, but fell in line with the expectation that they would have reduced TST, Dr. Gruenthal said.
Patients with migraine “may, in fact, exhibit a lower burden of sleep-disordered breathing, and that’s based on our findings such as the lower AHI and decreased burden of hypoxemia,” he said. “We theorized that this may be related to patients with migraine having a unique CGRP [calcitonin gene-related peptide] and serotonin physiology.” He noted that previously published research has shown that sleep CGRP and serotonin have a central role in causing arousal in response to rising CO2 levels during sleep, which can occur during apneas and hypopneas.
Dr. Gruenthal noted that the researchers are still analyzing the findings. “We theorized that possible indication bias may be present in our study,” he said. “It may be the case that patients with migraine are more likely to get their PSG done because of their headache and not for things like snoring and witnessed apneas, which may be more predictive of significant sleep apnea.” They’re also evaluating the “question of medicine confounding.”
Dr. Gruenthal added that “the big unanswered question out there is, if you have a patient with migraine who also has sleep apnea, by treating the sleep apnea will that improve their migraine?”
More questions than answers
Commenting on the study, Donald Bliwise, PhD, professor of neurology at Emory Sleep Center, Atlanta, said the study findings shouldn’t change how clinicians approach migraine in relation to sleep.
“It’s a case series, it’s retrospective,” said Dr. Bliwise, who was not involved in the study. “It’s the largest study that I know of that has ever looked at the diagnosis of migraine in relation to polysomnographic measures of sleep, but it’s imprecise to the extent that migraine is a clinical diagnosis, so not everyone that carries the diagnosis of migraine has the diagnosis made by a neurologist.”
The study raises more questions than it answers, he said, “but that’s not necessarily a bad thing. I think we need more prospective studies.” Those studies should be more granular in how they analyze sleep in migraine patients “Since migraine is an intermittent event, and sleep quality and length, and percentage of REM sleep and even sleep apnea can vary from night to night, it would be fascinating to look at headaches over a month in relation to sleep over a month.”
Dr. Gruenthal and Dr. Bliwise have no disclosures. The Association of Migraine Disorders provided funding for the study.
CHARLOTTE, N.C. – What may be the largest case-based study of patients with migraine and sleep-disordered breathing to date has found that, counter to prevailing thought, they may not be at higher risk of having obstructive sleep apnea (OSA) than nonmigraine patients, although further prospective studies are needed to validate that finding.
“This in no way for me changes the fact that, for patients that complain of headaches, sleep apnea remains to be something that should be considered as possible cause of their headaches,” neurologist and Cleveland Clinic postdoctoral fellow Eric Gruenthal, MD, said in an interview after he presented his results at the annual meeting of the Associated Professional Sleep Societies.
The study suggested that patients with migraine may have an OSA risk that “may be a little lower” than their nonmigraine counterparts, Dr. Gruenthal said. “But we have really yet to determine whether that’s true or not.”
Large case-based study
The retrospective case study included 4,783 migraine cases from the Cleveland Clinic electronic health record database who were case matched on a 1:3 basis with 14,287 controls. Patients with migraine had an average age of 47.5 years (±13.3) and body mass index of 33.7 kg/m2 (±8.6), and 76.4% were White. All patients had polysomnography (PSG) at a Cleveland Clinic facility from 1998 to 2021.
The analysis evaluated the collected data in two domains: sleep architecture, consisting of arousal index (AI), total sleep time (TST) and percentage of sleep stage time; and sleep-disordered breathing, including apnea hypopnea index (AHI) and mean oxygen saturation. The key findings of the migraine patients versus controls include:
- Lower AI, 19.6 (95% confidence interval, 12.8-30.9) versus 22.6 (95% CI, 14.7-34.9; P < .001).
- Shorter TST, 359 (95% CI, 307-421) versus 363 (95% CI, 306-432.5) minutes (P = .01).
- With regard to sleep stage, the percentage of N2 sleep was higher, 67.8% (95% CI, 59.6%-75.6%) versus 67% (95% CI, 58.4%-74.8%; P < .001); but the percentage of REM was lower at 16.7% (95% CI, 10%-22%) versus 17% (95% CI, 11.1%-22.2%; P = .012).
- Lower AHI, 7.4 (95% CI, 2.6-17) versus 9.5 (95% CI, 3.7-22.1, P < .001).
- Higher mean oxygen saturation, 93.7 (±2.4) versus 93.3% (±2.6; P < .001).
“Also,” Dr. Gruenthal added, “we found that the percentage of sleep time with oxygen saturation below 90% was lower among patients with migraine, at 1.3% versus 2.4%” (P < .001).
A unique profile?
The goal of the study was to determine whether migraine patients would have a unique PSG profile, Dr. Gruenthal said. “We were trying to overcome some of the limitations of previous studies, most notably those that use small sample sizes, and in some cases a lack of controls.”
The findings that migraine patients would have higher AI and elevated AHI ran counter to the study’s hypotheses, but fell in line with the expectation that they would have reduced TST, Dr. Gruenthal said.
Patients with migraine “may, in fact, exhibit a lower burden of sleep-disordered breathing, and that’s based on our findings such as the lower AHI and decreased burden of hypoxemia,” he said. “We theorized that this may be related to patients with migraine having a unique CGRP [calcitonin gene-related peptide] and serotonin physiology.” He noted that previously published research has shown that sleep CGRP and serotonin have a central role in causing arousal in response to rising CO2 levels during sleep, which can occur during apneas and hypopneas.
Dr. Gruenthal noted that the researchers are still analyzing the findings. “We theorized that possible indication bias may be present in our study,” he said. “It may be the case that patients with migraine are more likely to get their PSG done because of their headache and not for things like snoring and witnessed apneas, which may be more predictive of significant sleep apnea.” They’re also evaluating the “question of medicine confounding.”
Dr. Gruenthal added that “the big unanswered question out there is, if you have a patient with migraine who also has sleep apnea, by treating the sleep apnea will that improve their migraine?”
More questions than answers
Commenting on the study, Donald Bliwise, PhD, professor of neurology at Emory Sleep Center, Atlanta, said the study findings shouldn’t change how clinicians approach migraine in relation to sleep.
“It’s a case series, it’s retrospective,” said Dr. Bliwise, who was not involved in the study. “It’s the largest study that I know of that has ever looked at the diagnosis of migraine in relation to polysomnographic measures of sleep, but it’s imprecise to the extent that migraine is a clinical diagnosis, so not everyone that carries the diagnosis of migraine has the diagnosis made by a neurologist.”
The study raises more questions than it answers, he said, “but that’s not necessarily a bad thing. I think we need more prospective studies.” Those studies should be more granular in how they analyze sleep in migraine patients “Since migraine is an intermittent event, and sleep quality and length, and percentage of REM sleep and even sleep apnea can vary from night to night, it would be fascinating to look at headaches over a month in relation to sleep over a month.”
Dr. Gruenthal and Dr. Bliwise have no disclosures. The Association of Migraine Disorders provided funding for the study.
AT SLEEP 2022
Helping patients move forward following traumatic brain injury
THE CASE
Declan M*, a 42-year-old man, presents as a new patient for general medical care. One year ago, he sustained a severe frontal traumatic brain injury (TBI) when he was hit by a car while crossing a street. He developed a subdural hematoma and was in a coma for 6 days. He also had fractured ribs and a fractured left foot. When he regained consciousness, he had posttraumatic amnesia. He also had executive function deficits and memory difficulties, so a guardian was appointed.
Mr. M no longer works as an auto mechanic, a career he once greatly enjoyed. Mr. M’s guardian reports that recently, Mr. M has lost interest in activities he’d previously enjoyed, is frequently irritable, has poor sleep, is socially isolated, and is spending increasing amounts of time at home. When his new primary care physician (PCP) enters the examining room, Mr. M is seated in a chair with his arms folded across his chest. He states that he is “fine” and just needs to “get a doctor.”
●
*This patient is an amalgam of patients for whom the author has provided care.
TBI ranges from mild to severe and can produce a number of profound effects that are a direct—or indirect—result of the physical injury.1 The location and the severity of the injury affect symptoms.2 Even mild TBI can cause impairment, and severe TBI can lead to broad cognitive, behavioral, and physical difficulties. As numbers of TBI cases increase globally, primary care providers need to recognize the symptoms and assess accordingly.1 The Acute Concussion Evaluation (ACE; Physician/Clinician Office Version) facilitates a structured evaluation for patients presenting with possible TBI symptoms. It can easily be accessed on the Centers for Disease Control and Prevention website.3
Direct effects of TBI include impulsivity, depression, reduced frustration tolerance, reduced motivation, low awareness, and insomnia and other sleep difficulties.4,5 Depression may also result indirectly from, or be exacerbated by, new posttraumatic limitations and lifestyle changes as well as loss of career and community.4 Both direct and indirect depression often manifest as feelings of hopelessness and worthlessness and a lack of interest in once enjoyable activities. Depression can worsen other TBI sequelae such as difficulty concentrating, lack of initiation, flat affect, irritability, reduced independence, reduced functional performance, loss of inhibition, and physical pain.6
Nationwide, most mental health concerns continue to be addressed in the primary care setting.7 Individuals with TBI experience major depression at a rate 5 to 6 times higher than those in the general population, with a prevalence rate of 45%.8
Suicide. The subject of suicide must be explored with survivors of TBI; evidence suggests a correlation between TBI, depression, and increased risk for suicide.9 Among those who have TBI, as many as 22% experience suicidal ideation; the risk of suicide in survivors of severe TBI is 3 to 4 times the risk in the general population.10 Additionally, suicidality in this context appears to be a chronic concern; therefore, carefully assess for its presence no matter how long ago the TBI occurred.10
Additional TBI-associated health concerns
Grief and loss. We so often focus on death as the only cause for grief, but grief can occur for other types of loss, as well. Individuals with TBI often experience a radical negative change in self-concept after their injury, which is associated with feelings of grief.11 Helping patients recognize that they are grieving the loss of the person they once were can help set a framework for their experience.
Continue to: Relationship loss
Relationship loss. Many people with TBI lose close relationships.12 This can be due to life changes such as job loss, loss of function or ability to do previously enjoyed activities, or personality changes. These relationship losses can affect a person profoundly.12 Going forward, they may have difficulty trusting others, for example.
Existential issues. Many people with TBI also find that cognitive deficits prevent them from engaging in formerly meaningful work. For example, Mr. M lost his longstanding career as an auto mechanic and therefore part of his identity. Not being able to find purpose and meaning can be a strong contributor to coping difficulties in those with TBI.13
Chronic pain. More than half of people with TBI experience chronic pain. Headaches are the most common pain condition among all TBI survivors.14
Substance use disorders. The directionality of substance use disorders and TBI is not always clear; however, most evidence suggests that substance abuse is highly prevalent, premorbid, and often a contributing factor in TBI (eg, car accidents).15 Alcohol abuse is the most common risk factor, followed by drug abuse.16 Substance abuse may be exacerbated after TBI when it becomes a coping mechanism under worsening stressors; additionally, executive function deficits or other neurologic problems may result in poor decision-making with regard to substance use.15 While substance abuse may decline in the immediate post-TBI period, it can return to pre-injury levels within a year.17
Selective serotonin reuptake inhibitors may help
Few studies have explored the efficacy of antidepressant medication in TBI survivors. In a controlled study of patients with TBI, Fann and colleagues18 found no significant improvement in depression symptoms between sertraline and a placebo. However, they did note some possibilities for this lack of significance: socially isolated TBI survivors in the placebo group may have demonstrated improvement in depression symptoms because of increased social interaction;
Continue to: Other research has found...
Other research has found that sertraline improved both depression and quality of life for men with post-TBI depression.19 In a meta-analysis of 4 studies, Paraschakis and Katsanos20 found that sertraline demonstrated a “trend toward significance” in the treatment of depression among patients with TBI. Silverberg and Panenka21 argue that selective serotonin reuptake inhibitors should be used as first-line treatment for depression in survivors of TBI. They note that in non-randomized studies, treatment effects with antidepressants are significant. Additionally, patients who do not respond to the first antidepressant prescribed will often respond to adjunctive or different medications. Finally, they argue that depression measures can capture symptoms related to the physical brain injury, in addition to symptoms of depression, thus confounding results.
THE CASE
Mr. M’s chart showed that he was not taking any medication and that he had no history of substance abuse or tobacco use. He refused to fill out the Patient Health Questionnaire (PHQ)-2. His guardian said that Mr. M was spending much of his time at home, and that he used to be an avid painter and guitar player but had not engaged in either activity for months. Furthermore, Mr. M used to enjoy working out but did so rarely now.
During the interview, the PCP was careful to make eye contact with Mr. M as well as his guardian, thereby making sure Mr. M was part of the conversation about his care. Pacing of questions was deliberate and unhurried; a return visit would be scheduled to further explore any concerns not covered in this visit. This collaborative, inclusive, patient-centered approach to the clinical interview seemed to place Mr. M at ease. When his guardian said he thought Mr. M was depressed, Mr. M agreed. Although Mr. M still refused to fill out the PHQ-2, he was now willing to answer questions about depression. He acknowledged that he was feeling hopeless and took little pleasure in activities he used to enjoy, thereby indicating a positive screen for depression.
The PCP opted to read the PHQ-9 questions aloud, and Mr. M agreed with most of the items but strongly denied suicidal ideation, citing his religious faith.
The PCP determined that Mr. M’s depression was likely a combination of the direct and indirect effects of his TBI. A quantitative estimate based on Mr. M’s report yielded a PHQ-9 score of 17, indicating moderately severe depression.
Continue to: In addition to building rapport...
In addition to building rapport, careful listening garnered important information about Mr. M. For example, until his accident and subsequent depression, Mr. M had long prioritized his physical health through diet and exercise. He followed a vegetarian diet but recently had little appetite and was eating one microwaveable meal a day. He had an irregular sleep schedule and struggled with insomnia. He lost his closest long-term relationship after his accident due to difficulties with affect regulation. He also lost his job as he could no longer cognitively handle the tasks required.
Hearing Mr. M’s story provided the opportunity to customize education about self-management skills including regular diet, exercise, and sleep hygiene. Due to limited visit time, the PCP elected to use this first visit to focus on sleep and depression. As cognitive behavioral therapy (CBT) for insomnia is first-line treatment for both primary insomnia and insomnia due to a medical condition such as TBI,5 a sleep aid was not prescribed. Fortunately, the clinic psychologist who offered CBT was able to join the interview to meet Mr. M and explain the treatment.
Mr. M expressed some initial reluctance to try an antidepressant. However, acknowledging he “just hasn’t been the same” since his TBI, he agreed to a prescription for sertraline and said he hoped it could make him “more like [he] was.”
RETURN VISIT
Four weeks after Mr. M began taking sertraline and participating in weekly CBT sessions, he returned for a follow-up visit with his PCP. He had a noticeably brighter affect, and his guardian reported that he had been playing the guitar again. Mr. M said that he had more energy as a result of improved sleep and mood, and that he felt like his “thinking was clearer.” Mr. M noted that he never thought he would meet with a psychologist but was finding CBT for insomnia helpful.
The psychologist’s notes proposed a treatment plan that would also include targeted grief and existential therapies to address Mr. M’s sudden life changes. At this visit, Mr. M admitted that his reading comprehension and speed were negatively affected by the accident and said this is why he did not wish to fill out the PHQ-2. But he was again willing to have the PHQ-9 questions read to him with his guardian’s support. Results showed a score of 6, indicating mild depression.
A follow-up appointment with Mr. M was scheduled for 6 weeks later, and the team was confident he was getting the behavioral and mental health support he needed through medication and therapy.
CORRESPONDENCE
Elizabeth Imbesi, PhD, VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105; elizabeth.imbesi@va.gov
1. CDC. Traumatic brain injury & concussion. 2020. Accessed May 19, 2022. www.cdc.gov/traumaticbraininjury/index.html
2. Finset A, Anderson S. Coping strategies in patients with acquired brain injury: relationships between coping, apathy, depression and lesion location. Brain Inj. 2009;14:887-905. doi: 10.1080/026990500445718
3. CDC. Gioia G, Collins M. Acute concussion evaluation. 2006. Accessed May 19, 2022. www.cdc.gov/headsup/pdfs/providers/ace_v2-a.pdf
4. Prigatano GP. Psychotherapy and the process of coping with a brain disorder. Oral presentation at: American Psychological Association annual convention. August 2015; Toronto, Canada.
5. Ouellet M, Beaulieu-Bonneau S, Savard J, Morin C. Insomnia and Fatigue After Traumatic Brain Injury: A CBT Approach to Assessment and Treatment. Elsevier Academic Press: 2019.
6. Lewis FD, Horn GH. Depression following traumatic brain injury: impact on post-hospital residential rehabilitation outcomes. NeuroRehabilitation. 2017;40:401-410. doi: 10.3233/NRE-161427
7. Barkil-Oteo A. Collaborative care for depression in primary care: how psychiatry could “troubleshoot” current treatments and practices. Yale J Bio Med. 2013;86:139-146.
8. Whelan-Goodinson R, Ponsford J, Johnston L, et al. Psychiatric disorders following traumatic brain injury: their nature and frequency. J Head Trauma Rehabil. 2009;24:324-332. doi: 10.1097/HTR.0b013e3181a712aa
9. Reeves RR, Laizer JT. Traumatic brain injury and suicide. J Psychosoc Nurs Ment Health Serv. 2012;50:32-38. doi: 10.3928/02793695-20120207-02
10. Simpson G, Tate R. Suicidality in people surviving a traumatic brain injury: Prevalence, risk factors and implications for clinical management. Brain Inj. 2007;21:1335-1351. doi: 10.1080/02699050701785542
11. Carroll E, Coetzer R. Identity, grief and self-awareness after traumatic brain injury. Neuropsychol Rehabil. 2011;21:289-305. doi: 10.1080/09602011.2011.555972
12. Salas CE, Casassus M, Rowlands L, et al. “Relating through sameness”: a qualitative study of friendship and social isolation in chronic traumatic brain injury. Neuropsychol Rehabil. 2018;28:1161-1178. doi: 10.1080/09602011.2016.1247730
13. Hinkebein JA, Stucky R. Coping with traumatic brain injury: existential challenges and managing hope. In: Martz E, Livneh H, eds. Coping with Chronic Illness and Disability: Theoretical, Empirical, and Clinical Aspects. Springer Science & Business Media; 2007:389-409.
14. Khoury S, Benavides R. Pain with traumatic brain injury and psychological disorders. Prog Neuropsychopharmacol and Biol Psychiatry. 2018;87:224-233. doi: 10.1016/j.pnpbp.2017.06.007
15. Bjork JM, Grant SJ. Does traumatic brain injury increase risk for substance abuse? J Neurotrauma. 2009;26:1077-1082. doi: 10.1089/neu.2008.0849
16. Unsworth DJ, Mathias JL. Traumatic brain injury and alcohol/substance abuse: a Bayesian meta-analysis comparing the outcomes of people with and without a history of abuse. J Clin Exp Neuropsychol. 2017,39:547-562. doi: 10.1080/13803395.2016.1248812
17. Beaulieu-Bonneau S, St-Onge F, Blackburn M, et al. Alcohol and drug use before and during the first year after traumatic brain injury. J Head Trauma Rehabil. 2018;33:E51-E60. doi: 10.1097/HTR.0000000000000341
18. Fann JR, Bombardier CH, Temkin N, et al. Sertraline for major depression during the year following traumatic brain injury: a randomized control trial. J Head Trauma Rehabil. 2017;32:332-342. doi: 10.1097/HTR.0000000000000322
19. Ansari A, Jain A, Sharma A, et al. Role of sertraline in posttraumatic brain injury depression and quality of life in TBI. Asian J Neurosurg. 2014;9:182-188. doi: 10.4103/1793-5482.146597
20. Paraschakis A, Katsanos AH. Antidepressants for depression associated with traumatic brain injury: a meta-analytical study of randomized control trials. East Asian Arch Psychiatry. 2017;27:142-149.
21. Silverberg ND, Panenka WJ. Antidepressants for depression after concussion and traumatic brain injury are still best practice. BMC Psychiatry. 2019;19:100. doi: 10.1186/s12888-019-2076-9
THE CASE
Declan M*, a 42-year-old man, presents as a new patient for general medical care. One year ago, he sustained a severe frontal traumatic brain injury (TBI) when he was hit by a car while crossing a street. He developed a subdural hematoma and was in a coma for 6 days. He also had fractured ribs and a fractured left foot. When he regained consciousness, he had posttraumatic amnesia. He also had executive function deficits and memory difficulties, so a guardian was appointed.
Mr. M no longer works as an auto mechanic, a career he once greatly enjoyed. Mr. M’s guardian reports that recently, Mr. M has lost interest in activities he’d previously enjoyed, is frequently irritable, has poor sleep, is socially isolated, and is spending increasing amounts of time at home. When his new primary care physician (PCP) enters the examining room, Mr. M is seated in a chair with his arms folded across his chest. He states that he is “fine” and just needs to “get a doctor.”
●
*This patient is an amalgam of patients for whom the author has provided care.
TBI ranges from mild to severe and can produce a number of profound effects that are a direct—or indirect—result of the physical injury.1 The location and the severity of the injury affect symptoms.2 Even mild TBI can cause impairment, and severe TBI can lead to broad cognitive, behavioral, and physical difficulties. As numbers of TBI cases increase globally, primary care providers need to recognize the symptoms and assess accordingly.1 The Acute Concussion Evaluation (ACE; Physician/Clinician Office Version) facilitates a structured evaluation for patients presenting with possible TBI symptoms. It can easily be accessed on the Centers for Disease Control and Prevention website.3
Direct effects of TBI include impulsivity, depression, reduced frustration tolerance, reduced motivation, low awareness, and insomnia and other sleep difficulties.4,5 Depression may also result indirectly from, or be exacerbated by, new posttraumatic limitations and lifestyle changes as well as loss of career and community.4 Both direct and indirect depression often manifest as feelings of hopelessness and worthlessness and a lack of interest in once enjoyable activities. Depression can worsen other TBI sequelae such as difficulty concentrating, lack of initiation, flat affect, irritability, reduced independence, reduced functional performance, loss of inhibition, and physical pain.6
Nationwide, most mental health concerns continue to be addressed in the primary care setting.7 Individuals with TBI experience major depression at a rate 5 to 6 times higher than those in the general population, with a prevalence rate of 45%.8
Suicide. The subject of suicide must be explored with survivors of TBI; evidence suggests a correlation between TBI, depression, and increased risk for suicide.9 Among those who have TBI, as many as 22% experience suicidal ideation; the risk of suicide in survivors of severe TBI is 3 to 4 times the risk in the general population.10 Additionally, suicidality in this context appears to be a chronic concern; therefore, carefully assess for its presence no matter how long ago the TBI occurred.10
Additional TBI-associated health concerns
Grief and loss. We so often focus on death as the only cause for grief, but grief can occur for other types of loss, as well. Individuals with TBI often experience a radical negative change in self-concept after their injury, which is associated with feelings of grief.11 Helping patients recognize that they are grieving the loss of the person they once were can help set a framework for their experience.
Continue to: Relationship loss
Relationship loss. Many people with TBI lose close relationships.12 This can be due to life changes such as job loss, loss of function or ability to do previously enjoyed activities, or personality changes. These relationship losses can affect a person profoundly.12 Going forward, they may have difficulty trusting others, for example.
Existential issues. Many people with TBI also find that cognitive deficits prevent them from engaging in formerly meaningful work. For example, Mr. M lost his longstanding career as an auto mechanic and therefore part of his identity. Not being able to find purpose and meaning can be a strong contributor to coping difficulties in those with TBI.13
Chronic pain. More than half of people with TBI experience chronic pain. Headaches are the most common pain condition among all TBI survivors.14
Substance use disorders. The directionality of substance use disorders and TBI is not always clear; however, most evidence suggests that substance abuse is highly prevalent, premorbid, and often a contributing factor in TBI (eg, car accidents).15 Alcohol abuse is the most common risk factor, followed by drug abuse.16 Substance abuse may be exacerbated after TBI when it becomes a coping mechanism under worsening stressors; additionally, executive function deficits or other neurologic problems may result in poor decision-making with regard to substance use.15 While substance abuse may decline in the immediate post-TBI period, it can return to pre-injury levels within a year.17
Selective serotonin reuptake inhibitors may help
Few studies have explored the efficacy of antidepressant medication in TBI survivors. In a controlled study of patients with TBI, Fann and colleagues18 found no significant improvement in depression symptoms between sertraline and a placebo. However, they did note some possibilities for this lack of significance: socially isolated TBI survivors in the placebo group may have demonstrated improvement in depression symptoms because of increased social interaction;
Continue to: Other research has found...
Other research has found that sertraline improved both depression and quality of life for men with post-TBI depression.19 In a meta-analysis of 4 studies, Paraschakis and Katsanos20 found that sertraline demonstrated a “trend toward significance” in the treatment of depression among patients with TBI. Silverberg and Panenka21 argue that selective serotonin reuptake inhibitors should be used as first-line treatment for depression in survivors of TBI. They note that in non-randomized studies, treatment effects with antidepressants are significant. Additionally, patients who do not respond to the first antidepressant prescribed will often respond to adjunctive or different medications. Finally, they argue that depression measures can capture symptoms related to the physical brain injury, in addition to symptoms of depression, thus confounding results.
THE CASE
Mr. M’s chart showed that he was not taking any medication and that he had no history of substance abuse or tobacco use. He refused to fill out the Patient Health Questionnaire (PHQ)-2. His guardian said that Mr. M was spending much of his time at home, and that he used to be an avid painter and guitar player but had not engaged in either activity for months. Furthermore, Mr. M used to enjoy working out but did so rarely now.
During the interview, the PCP was careful to make eye contact with Mr. M as well as his guardian, thereby making sure Mr. M was part of the conversation about his care. Pacing of questions was deliberate and unhurried; a return visit would be scheduled to further explore any concerns not covered in this visit. This collaborative, inclusive, patient-centered approach to the clinical interview seemed to place Mr. M at ease. When his guardian said he thought Mr. M was depressed, Mr. M agreed. Although Mr. M still refused to fill out the PHQ-2, he was now willing to answer questions about depression. He acknowledged that he was feeling hopeless and took little pleasure in activities he used to enjoy, thereby indicating a positive screen for depression.
The PCP opted to read the PHQ-9 questions aloud, and Mr. M agreed with most of the items but strongly denied suicidal ideation, citing his religious faith.
The PCP determined that Mr. M’s depression was likely a combination of the direct and indirect effects of his TBI. A quantitative estimate based on Mr. M’s report yielded a PHQ-9 score of 17, indicating moderately severe depression.
Continue to: In addition to building rapport...
In addition to building rapport, careful listening garnered important information about Mr. M. For example, until his accident and subsequent depression, Mr. M had long prioritized his physical health through diet and exercise. He followed a vegetarian diet but recently had little appetite and was eating one microwaveable meal a day. He had an irregular sleep schedule and struggled with insomnia. He lost his closest long-term relationship after his accident due to difficulties with affect regulation. He also lost his job as he could no longer cognitively handle the tasks required.
Hearing Mr. M’s story provided the opportunity to customize education about self-management skills including regular diet, exercise, and sleep hygiene. Due to limited visit time, the PCP elected to use this first visit to focus on sleep and depression. As cognitive behavioral therapy (CBT) for insomnia is first-line treatment for both primary insomnia and insomnia due to a medical condition such as TBI,5 a sleep aid was not prescribed. Fortunately, the clinic psychologist who offered CBT was able to join the interview to meet Mr. M and explain the treatment.
Mr. M expressed some initial reluctance to try an antidepressant. However, acknowledging he “just hasn’t been the same” since his TBI, he agreed to a prescription for sertraline and said he hoped it could make him “more like [he] was.”
RETURN VISIT
Four weeks after Mr. M began taking sertraline and participating in weekly CBT sessions, he returned for a follow-up visit with his PCP. He had a noticeably brighter affect, and his guardian reported that he had been playing the guitar again. Mr. M said that he had more energy as a result of improved sleep and mood, and that he felt like his “thinking was clearer.” Mr. M noted that he never thought he would meet with a psychologist but was finding CBT for insomnia helpful.
The psychologist’s notes proposed a treatment plan that would also include targeted grief and existential therapies to address Mr. M’s sudden life changes. At this visit, Mr. M admitted that his reading comprehension and speed were negatively affected by the accident and said this is why he did not wish to fill out the PHQ-2. But he was again willing to have the PHQ-9 questions read to him with his guardian’s support. Results showed a score of 6, indicating mild depression.
A follow-up appointment with Mr. M was scheduled for 6 weeks later, and the team was confident he was getting the behavioral and mental health support he needed through medication and therapy.
CORRESPONDENCE
Elizabeth Imbesi, PhD, VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105; elizabeth.imbesi@va.gov
THE CASE
Declan M*, a 42-year-old man, presents as a new patient for general medical care. One year ago, he sustained a severe frontal traumatic brain injury (TBI) when he was hit by a car while crossing a street. He developed a subdural hematoma and was in a coma for 6 days. He also had fractured ribs and a fractured left foot. When he regained consciousness, he had posttraumatic amnesia. He also had executive function deficits and memory difficulties, so a guardian was appointed.
Mr. M no longer works as an auto mechanic, a career he once greatly enjoyed. Mr. M’s guardian reports that recently, Mr. M has lost interest in activities he’d previously enjoyed, is frequently irritable, has poor sleep, is socially isolated, and is spending increasing amounts of time at home. When his new primary care physician (PCP) enters the examining room, Mr. M is seated in a chair with his arms folded across his chest. He states that he is “fine” and just needs to “get a doctor.”
●
*This patient is an amalgam of patients for whom the author has provided care.
TBI ranges from mild to severe and can produce a number of profound effects that are a direct—or indirect—result of the physical injury.1 The location and the severity of the injury affect symptoms.2 Even mild TBI can cause impairment, and severe TBI can lead to broad cognitive, behavioral, and physical difficulties. As numbers of TBI cases increase globally, primary care providers need to recognize the symptoms and assess accordingly.1 The Acute Concussion Evaluation (ACE; Physician/Clinician Office Version) facilitates a structured evaluation for patients presenting with possible TBI symptoms. It can easily be accessed on the Centers for Disease Control and Prevention website.3
Direct effects of TBI include impulsivity, depression, reduced frustration tolerance, reduced motivation, low awareness, and insomnia and other sleep difficulties.4,5 Depression may also result indirectly from, or be exacerbated by, new posttraumatic limitations and lifestyle changes as well as loss of career and community.4 Both direct and indirect depression often manifest as feelings of hopelessness and worthlessness and a lack of interest in once enjoyable activities. Depression can worsen other TBI sequelae such as difficulty concentrating, lack of initiation, flat affect, irritability, reduced independence, reduced functional performance, loss of inhibition, and physical pain.6
Nationwide, most mental health concerns continue to be addressed in the primary care setting.7 Individuals with TBI experience major depression at a rate 5 to 6 times higher than those in the general population, with a prevalence rate of 45%.8
Suicide. The subject of suicide must be explored with survivors of TBI; evidence suggests a correlation between TBI, depression, and increased risk for suicide.9 Among those who have TBI, as many as 22% experience suicidal ideation; the risk of suicide in survivors of severe TBI is 3 to 4 times the risk in the general population.10 Additionally, suicidality in this context appears to be a chronic concern; therefore, carefully assess for its presence no matter how long ago the TBI occurred.10
Additional TBI-associated health concerns
Grief and loss. We so often focus on death as the only cause for grief, but grief can occur for other types of loss, as well. Individuals with TBI often experience a radical negative change in self-concept after their injury, which is associated with feelings of grief.11 Helping patients recognize that they are grieving the loss of the person they once were can help set a framework for their experience.
Continue to: Relationship loss
Relationship loss. Many people with TBI lose close relationships.12 This can be due to life changes such as job loss, loss of function or ability to do previously enjoyed activities, or personality changes. These relationship losses can affect a person profoundly.12 Going forward, they may have difficulty trusting others, for example.
Existential issues. Many people with TBI also find that cognitive deficits prevent them from engaging in formerly meaningful work. For example, Mr. M lost his longstanding career as an auto mechanic and therefore part of his identity. Not being able to find purpose and meaning can be a strong contributor to coping difficulties in those with TBI.13
Chronic pain. More than half of people with TBI experience chronic pain. Headaches are the most common pain condition among all TBI survivors.14
Substance use disorders. The directionality of substance use disorders and TBI is not always clear; however, most evidence suggests that substance abuse is highly prevalent, premorbid, and often a contributing factor in TBI (eg, car accidents).15 Alcohol abuse is the most common risk factor, followed by drug abuse.16 Substance abuse may be exacerbated after TBI when it becomes a coping mechanism under worsening stressors; additionally, executive function deficits or other neurologic problems may result in poor decision-making with regard to substance use.15 While substance abuse may decline in the immediate post-TBI period, it can return to pre-injury levels within a year.17
Selective serotonin reuptake inhibitors may help
Few studies have explored the efficacy of antidepressant medication in TBI survivors. In a controlled study of patients with TBI, Fann and colleagues18 found no significant improvement in depression symptoms between sertraline and a placebo. However, they did note some possibilities for this lack of significance: socially isolated TBI survivors in the placebo group may have demonstrated improvement in depression symptoms because of increased social interaction;
Continue to: Other research has found...
Other research has found that sertraline improved both depression and quality of life for men with post-TBI depression.19 In a meta-analysis of 4 studies, Paraschakis and Katsanos20 found that sertraline demonstrated a “trend toward significance” in the treatment of depression among patients with TBI. Silverberg and Panenka21 argue that selective serotonin reuptake inhibitors should be used as first-line treatment for depression in survivors of TBI. They note that in non-randomized studies, treatment effects with antidepressants are significant. Additionally, patients who do not respond to the first antidepressant prescribed will often respond to adjunctive or different medications. Finally, they argue that depression measures can capture symptoms related to the physical brain injury, in addition to symptoms of depression, thus confounding results.
THE CASE
Mr. M’s chart showed that he was not taking any medication and that he had no history of substance abuse or tobacco use. He refused to fill out the Patient Health Questionnaire (PHQ)-2. His guardian said that Mr. M was spending much of his time at home, and that he used to be an avid painter and guitar player but had not engaged in either activity for months. Furthermore, Mr. M used to enjoy working out but did so rarely now.
During the interview, the PCP was careful to make eye contact with Mr. M as well as his guardian, thereby making sure Mr. M was part of the conversation about his care. Pacing of questions was deliberate and unhurried; a return visit would be scheduled to further explore any concerns not covered in this visit. This collaborative, inclusive, patient-centered approach to the clinical interview seemed to place Mr. M at ease. When his guardian said he thought Mr. M was depressed, Mr. M agreed. Although Mr. M still refused to fill out the PHQ-2, he was now willing to answer questions about depression. He acknowledged that he was feeling hopeless and took little pleasure in activities he used to enjoy, thereby indicating a positive screen for depression.
The PCP opted to read the PHQ-9 questions aloud, and Mr. M agreed with most of the items but strongly denied suicidal ideation, citing his religious faith.
The PCP determined that Mr. M’s depression was likely a combination of the direct and indirect effects of his TBI. A quantitative estimate based on Mr. M’s report yielded a PHQ-9 score of 17, indicating moderately severe depression.
Continue to: In addition to building rapport...
In addition to building rapport, careful listening garnered important information about Mr. M. For example, until his accident and subsequent depression, Mr. M had long prioritized his physical health through diet and exercise. He followed a vegetarian diet but recently had little appetite and was eating one microwaveable meal a day. He had an irregular sleep schedule and struggled with insomnia. He lost his closest long-term relationship after his accident due to difficulties with affect regulation. He also lost his job as he could no longer cognitively handle the tasks required.
Hearing Mr. M’s story provided the opportunity to customize education about self-management skills including regular diet, exercise, and sleep hygiene. Due to limited visit time, the PCP elected to use this first visit to focus on sleep and depression. As cognitive behavioral therapy (CBT) for insomnia is first-line treatment for both primary insomnia and insomnia due to a medical condition such as TBI,5 a sleep aid was not prescribed. Fortunately, the clinic psychologist who offered CBT was able to join the interview to meet Mr. M and explain the treatment.
Mr. M expressed some initial reluctance to try an antidepressant. However, acknowledging he “just hasn’t been the same” since his TBI, he agreed to a prescription for sertraline and said he hoped it could make him “more like [he] was.”
RETURN VISIT
Four weeks after Mr. M began taking sertraline and participating in weekly CBT sessions, he returned for a follow-up visit with his PCP. He had a noticeably brighter affect, and his guardian reported that he had been playing the guitar again. Mr. M said that he had more energy as a result of improved sleep and mood, and that he felt like his “thinking was clearer.” Mr. M noted that he never thought he would meet with a psychologist but was finding CBT for insomnia helpful.
The psychologist’s notes proposed a treatment plan that would also include targeted grief and existential therapies to address Mr. M’s sudden life changes. At this visit, Mr. M admitted that his reading comprehension and speed were negatively affected by the accident and said this is why he did not wish to fill out the PHQ-2. But he was again willing to have the PHQ-9 questions read to him with his guardian’s support. Results showed a score of 6, indicating mild depression.
A follow-up appointment with Mr. M was scheduled for 6 weeks later, and the team was confident he was getting the behavioral and mental health support he needed through medication and therapy.
CORRESPONDENCE
Elizabeth Imbesi, PhD, VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105; elizabeth.imbesi@va.gov
1. CDC. Traumatic brain injury & concussion. 2020. Accessed May 19, 2022. www.cdc.gov/traumaticbraininjury/index.html
2. Finset A, Anderson S. Coping strategies in patients with acquired brain injury: relationships between coping, apathy, depression and lesion location. Brain Inj. 2009;14:887-905. doi: 10.1080/026990500445718
3. CDC. Gioia G, Collins M. Acute concussion evaluation. 2006. Accessed May 19, 2022. www.cdc.gov/headsup/pdfs/providers/ace_v2-a.pdf
4. Prigatano GP. Psychotherapy and the process of coping with a brain disorder. Oral presentation at: American Psychological Association annual convention. August 2015; Toronto, Canada.
5. Ouellet M, Beaulieu-Bonneau S, Savard J, Morin C. Insomnia and Fatigue After Traumatic Brain Injury: A CBT Approach to Assessment and Treatment. Elsevier Academic Press: 2019.
6. Lewis FD, Horn GH. Depression following traumatic brain injury: impact on post-hospital residential rehabilitation outcomes. NeuroRehabilitation. 2017;40:401-410. doi: 10.3233/NRE-161427
7. Barkil-Oteo A. Collaborative care for depression in primary care: how psychiatry could “troubleshoot” current treatments and practices. Yale J Bio Med. 2013;86:139-146.
8. Whelan-Goodinson R, Ponsford J, Johnston L, et al. Psychiatric disorders following traumatic brain injury: their nature and frequency. J Head Trauma Rehabil. 2009;24:324-332. doi: 10.1097/HTR.0b013e3181a712aa
9. Reeves RR, Laizer JT. Traumatic brain injury and suicide. J Psychosoc Nurs Ment Health Serv. 2012;50:32-38. doi: 10.3928/02793695-20120207-02
10. Simpson G, Tate R. Suicidality in people surviving a traumatic brain injury: Prevalence, risk factors and implications for clinical management. Brain Inj. 2007;21:1335-1351. doi: 10.1080/02699050701785542
11. Carroll E, Coetzer R. Identity, grief and self-awareness after traumatic brain injury. Neuropsychol Rehabil. 2011;21:289-305. doi: 10.1080/09602011.2011.555972
12. Salas CE, Casassus M, Rowlands L, et al. “Relating through sameness”: a qualitative study of friendship and social isolation in chronic traumatic brain injury. Neuropsychol Rehabil. 2018;28:1161-1178. doi: 10.1080/09602011.2016.1247730
13. Hinkebein JA, Stucky R. Coping with traumatic brain injury: existential challenges and managing hope. In: Martz E, Livneh H, eds. Coping with Chronic Illness and Disability: Theoretical, Empirical, and Clinical Aspects. Springer Science & Business Media; 2007:389-409.
14. Khoury S, Benavides R. Pain with traumatic brain injury and psychological disorders. Prog Neuropsychopharmacol and Biol Psychiatry. 2018;87:224-233. doi: 10.1016/j.pnpbp.2017.06.007
15. Bjork JM, Grant SJ. Does traumatic brain injury increase risk for substance abuse? J Neurotrauma. 2009;26:1077-1082. doi: 10.1089/neu.2008.0849
16. Unsworth DJ, Mathias JL. Traumatic brain injury and alcohol/substance abuse: a Bayesian meta-analysis comparing the outcomes of people with and without a history of abuse. J Clin Exp Neuropsychol. 2017,39:547-562. doi: 10.1080/13803395.2016.1248812
17. Beaulieu-Bonneau S, St-Onge F, Blackburn M, et al. Alcohol and drug use before and during the first year after traumatic brain injury. J Head Trauma Rehabil. 2018;33:E51-E60. doi: 10.1097/HTR.0000000000000341
18. Fann JR, Bombardier CH, Temkin N, et al. Sertraline for major depression during the year following traumatic brain injury: a randomized control trial. J Head Trauma Rehabil. 2017;32:332-342. doi: 10.1097/HTR.0000000000000322
19. Ansari A, Jain A, Sharma A, et al. Role of sertraline in posttraumatic brain injury depression and quality of life in TBI. Asian J Neurosurg. 2014;9:182-188. doi: 10.4103/1793-5482.146597
20. Paraschakis A, Katsanos AH. Antidepressants for depression associated with traumatic brain injury: a meta-analytical study of randomized control trials. East Asian Arch Psychiatry. 2017;27:142-149.
21. Silverberg ND, Panenka WJ. Antidepressants for depression after concussion and traumatic brain injury are still best practice. BMC Psychiatry. 2019;19:100. doi: 10.1186/s12888-019-2076-9
1. CDC. Traumatic brain injury & concussion. 2020. Accessed May 19, 2022. www.cdc.gov/traumaticbraininjury/index.html
2. Finset A, Anderson S. Coping strategies in patients with acquired brain injury: relationships between coping, apathy, depression and lesion location. Brain Inj. 2009;14:887-905. doi: 10.1080/026990500445718
3. CDC. Gioia G, Collins M. Acute concussion evaluation. 2006. Accessed May 19, 2022. www.cdc.gov/headsup/pdfs/providers/ace_v2-a.pdf
4. Prigatano GP. Psychotherapy and the process of coping with a brain disorder. Oral presentation at: American Psychological Association annual convention. August 2015; Toronto, Canada.
5. Ouellet M, Beaulieu-Bonneau S, Savard J, Morin C. Insomnia and Fatigue After Traumatic Brain Injury: A CBT Approach to Assessment and Treatment. Elsevier Academic Press: 2019.
6. Lewis FD, Horn GH. Depression following traumatic brain injury: impact on post-hospital residential rehabilitation outcomes. NeuroRehabilitation. 2017;40:401-410. doi: 10.3233/NRE-161427
7. Barkil-Oteo A. Collaborative care for depression in primary care: how psychiatry could “troubleshoot” current treatments and practices. Yale J Bio Med. 2013;86:139-146.
8. Whelan-Goodinson R, Ponsford J, Johnston L, et al. Psychiatric disorders following traumatic brain injury: their nature and frequency. J Head Trauma Rehabil. 2009;24:324-332. doi: 10.1097/HTR.0b013e3181a712aa
9. Reeves RR, Laizer JT. Traumatic brain injury and suicide. J Psychosoc Nurs Ment Health Serv. 2012;50:32-38. doi: 10.3928/02793695-20120207-02
10. Simpson G, Tate R. Suicidality in people surviving a traumatic brain injury: Prevalence, risk factors and implications for clinical management. Brain Inj. 2007;21:1335-1351. doi: 10.1080/02699050701785542
11. Carroll E, Coetzer R. Identity, grief and self-awareness after traumatic brain injury. Neuropsychol Rehabil. 2011;21:289-305. doi: 10.1080/09602011.2011.555972
12. Salas CE, Casassus M, Rowlands L, et al. “Relating through sameness”: a qualitative study of friendship and social isolation in chronic traumatic brain injury. Neuropsychol Rehabil. 2018;28:1161-1178. doi: 10.1080/09602011.2016.1247730
13. Hinkebein JA, Stucky R. Coping with traumatic brain injury: existential challenges and managing hope. In: Martz E, Livneh H, eds. Coping with Chronic Illness and Disability: Theoretical, Empirical, and Clinical Aspects. Springer Science & Business Media; 2007:389-409.
14. Khoury S, Benavides R. Pain with traumatic brain injury and psychological disorders. Prog Neuropsychopharmacol and Biol Psychiatry. 2018;87:224-233. doi: 10.1016/j.pnpbp.2017.06.007
15. Bjork JM, Grant SJ. Does traumatic brain injury increase risk for substance abuse? J Neurotrauma. 2009;26:1077-1082. doi: 10.1089/neu.2008.0849
16. Unsworth DJ, Mathias JL. Traumatic brain injury and alcohol/substance abuse: a Bayesian meta-analysis comparing the outcomes of people with and without a history of abuse. J Clin Exp Neuropsychol. 2017,39:547-562. doi: 10.1080/13803395.2016.1248812
17. Beaulieu-Bonneau S, St-Onge F, Blackburn M, et al. Alcohol and drug use before and during the first year after traumatic brain injury. J Head Trauma Rehabil. 2018;33:E51-E60. doi: 10.1097/HTR.0000000000000341
18. Fann JR, Bombardier CH, Temkin N, et al. Sertraline for major depression during the year following traumatic brain injury: a randomized control trial. J Head Trauma Rehabil. 2017;32:332-342. doi: 10.1097/HTR.0000000000000322
19. Ansari A, Jain A, Sharma A, et al. Role of sertraline in posttraumatic brain injury depression and quality of life in TBI. Asian J Neurosurg. 2014;9:182-188. doi: 10.4103/1793-5482.146597
20. Paraschakis A, Katsanos AH. Antidepressants for depression associated with traumatic brain injury: a meta-analytical study of randomized control trials. East Asian Arch Psychiatry. 2017;27:142-149.
21. Silverberg ND, Panenka WJ. Antidepressants for depression after concussion and traumatic brain injury are still best practice. BMC Psychiatry. 2019;19:100. doi: 10.1186/s12888-019-2076-9
Migraine relief in 20 minutes using eyedrops?
ILLUSTRATIVE CASE
A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?
Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.2 The prevalence of migraine is between 2.6% and 21.7% across multiple countries.3 On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).4
Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs),
Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine5) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved
Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.7 Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.10 A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.8 A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.9 However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.
STUDY SUMMARY
Crossover study achieved primary endpoint in pain reduction
This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.
Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.
Continue to: The groups were observed...
The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.
Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.
WHAT’S NEW
Evidence of benefit as abortive therapy for acute migraine
This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.
CAVEATS
Single-center trial, measuring limited response time
The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.
CHALLENGES TO IMPLEMENTATION
Timolol’s systemic adverse effects require caution
Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
- Kurian A, Reghunadhan I, Thilak P, et al. Short-term efficacy and safety of topical β-blockers (timolol maleate ophthalmic solution, 0.5%) in acute migraine: a randomized crossover trial. JAMA Ophthalmol. 2020;138:1160-1166. doi: 10.1001/jamaophthalmol.2020.3676
- Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743-800. doi: 10.1016/S0140-6736(15)60692-4
- Yeh WZ, Blizzard L, Taylor BV. What is the actual prevalence of migraine? Brain Behav. 2018;8:e00950. doi: 10.1002/brb3.950
- Leonardi M, Raggi A. Burden of migraine: international perspectives. Neurol Sci. 2013;34(suppl 1):S117-S118. doi: 10.1007/s10072-013-1387-8
- Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629-808. doi: 10.1177/0333102413485658
- Ubrogepant. GoodRx. Accessed May 23, 2022. www.goodrx.com/ubrogepant
- Orr SL, Friedman BW, Christie S, et al. Management of adults with acute migraine in the emergency department: the American Headache Society evidence assessment of parenteral pharmacotherapies. Headache. 2016;56:911-940. doi: 10.1111/head.12835
- 8. Migliazzo CV, Hagan JC III. Beta blocker eye drops for treatment of acute migraine. Mo Med. 2014;111:283-288.
- 9. Cossack M, Nabrinsky E, Turner H, et al. Timolol eyedrops in the treatment of acute migraine attacks: a randomized crossover study. JAMA Neurol. 2018;75:1024-1025. doi: 10.1001/jamaneurol.2018.0970
- 10. Timolol. GoodRx. Accessed May 23, 2022. www.goodrx.com/timolol
ILLUSTRATIVE CASE
A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?
Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.2 The prevalence of migraine is between 2.6% and 21.7% across multiple countries.3 On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).4
Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs),
Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine5) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved
Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.7 Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.10 A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.8 A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.9 However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.
STUDY SUMMARY
Crossover study achieved primary endpoint in pain reduction
This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.
Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.
Continue to: The groups were observed...
The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.
Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.
WHAT’S NEW
Evidence of benefit as abortive therapy for acute migraine
This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.
CAVEATS
Single-center trial, measuring limited response time
The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.
CHALLENGES TO IMPLEMENTATION
Timolol’s systemic adverse effects require caution
Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
ILLUSTRATIVE CASE
A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?
Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.2 The prevalence of migraine is between 2.6% and 21.7% across multiple countries.3 On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).4
Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs),
Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine5) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved
Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.7 Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.10 A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.8 A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.9 However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.
STUDY SUMMARY
Crossover study achieved primary endpoint in pain reduction
This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.
Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.
Continue to: The groups were observed...
The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.
Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.
WHAT’S NEW
Evidence of benefit as abortive therapy for acute migraine
This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.
CAVEATS
Single-center trial, measuring limited response time
The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.
CHALLENGES TO IMPLEMENTATION
Timolol’s systemic adverse effects require caution
Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
- Kurian A, Reghunadhan I, Thilak P, et al. Short-term efficacy and safety of topical β-blockers (timolol maleate ophthalmic solution, 0.5%) in acute migraine: a randomized crossover trial. JAMA Ophthalmol. 2020;138:1160-1166. doi: 10.1001/jamaophthalmol.2020.3676
- Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743-800. doi: 10.1016/S0140-6736(15)60692-4
- Yeh WZ, Blizzard L, Taylor BV. What is the actual prevalence of migraine? Brain Behav. 2018;8:e00950. doi: 10.1002/brb3.950
- Leonardi M, Raggi A. Burden of migraine: international perspectives. Neurol Sci. 2013;34(suppl 1):S117-S118. doi: 10.1007/s10072-013-1387-8
- Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629-808. doi: 10.1177/0333102413485658
- Ubrogepant. GoodRx. Accessed May 23, 2022. www.goodrx.com/ubrogepant
- Orr SL, Friedman BW, Christie S, et al. Management of adults with acute migraine in the emergency department: the American Headache Society evidence assessment of parenteral pharmacotherapies. Headache. 2016;56:911-940. doi: 10.1111/head.12835
- 8. Migliazzo CV, Hagan JC III. Beta blocker eye drops for treatment of acute migraine. Mo Med. 2014;111:283-288.
- 9. Cossack M, Nabrinsky E, Turner H, et al. Timolol eyedrops in the treatment of acute migraine attacks: a randomized crossover study. JAMA Neurol. 2018;75:1024-1025. doi: 10.1001/jamaneurol.2018.0970
- 10. Timolol. GoodRx. Accessed May 23, 2022. www.goodrx.com/timolol
- Kurian A, Reghunadhan I, Thilak P, et al. Short-term efficacy and safety of topical β-blockers (timolol maleate ophthalmic solution, 0.5%) in acute migraine: a randomized crossover trial. JAMA Ophthalmol. 2020;138:1160-1166. doi: 10.1001/jamaophthalmol.2020.3676
- Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743-800. doi: 10.1016/S0140-6736(15)60692-4
- Yeh WZ, Blizzard L, Taylor BV. What is the actual prevalence of migraine? Brain Behav. 2018;8:e00950. doi: 10.1002/brb3.950
- Leonardi M, Raggi A. Burden of migraine: international perspectives. Neurol Sci. 2013;34(suppl 1):S117-S118. doi: 10.1007/s10072-013-1387-8
- Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629-808. doi: 10.1177/0333102413485658
- Ubrogepant. GoodRx. Accessed May 23, 2022. www.goodrx.com/ubrogepant
- Orr SL, Friedman BW, Christie S, et al. Management of adults with acute migraine in the emergency department: the American Headache Society evidence assessment of parenteral pharmacotherapies. Headache. 2016;56:911-940. doi: 10.1111/head.12835
- 8. Migliazzo CV, Hagan JC III. Beta blocker eye drops for treatment of acute migraine. Mo Med. 2014;111:283-288.
- 9. Cossack M, Nabrinsky E, Turner H, et al. Timolol eyedrops in the treatment of acute migraine attacks: a randomized crossover study. JAMA Neurol. 2018;75:1024-1025. doi: 10.1001/jamaneurol.2018.0970
- 10. Timolol. GoodRx. Accessed May 23, 2022. www.goodrx.com/timolol
PRACTICE CHANGER
Consider timolol maleate 0.5% eyedrops as a quick and effective abortive therapy for migraine.1
STRENGTH OF RECOMMENDATION
B: Based on a single randomized controlled trial.1
Kurian A, Reghunadhan I, Thilak P, et al. Short-term efficacy and safety of topical β-blockers (timolol maleate ophthalmic solution, 0.5%) in acute migraine: a randomized crossover trial. JAMA Ophthalmol. 2020;138:1160-1166.
In utero COVID exposure tied to neurodevelopmental disorders at 1 year
Infants exposed to SARS-CoV-2 in utero are at increased risk for neurodevelopmental disorders in the first year of life, new research suggests.
But whether it is exposure to the pandemic or maternal exposure to the virus itself that may harm early childhood neurodevelopment is unclear, caution investigators, led by Roy Perlis, MD, MSc, with Massachusetts General Hospital, Boston.
“In this analysis of 222 offspring of mothers infected with SARS-CoV-2, compared with the offspring of 7,550 mothers in the control group (not infected) delivered during the same period, we observed neurodevelopmental diagnoses to be significantly more common among exposed offspring, particularly those exposed to third-trimester maternal infection,” they write.
The study was published online in JAMA Network Open.
Speech and language disorders
The study included 7,772 mostly singleton live births across six hospitals in Massachusetts between March and September 2020, including 222 (2.9%) births to mothers with SARS-CoV-2 infection confirmed by polymerase chain reaction testing during pregnancy.
In all, 14 of 222 children born to SARS-CoV-2–infected mothers (6.3%) were diagnosed with a neurodevelopmental disorder in the first year of life versus 227 of 7,550 unexposed offspring (3%) (unadjusted odds ratio, 2.17; 95% confidence interval, 1.24-3.79; P = .006).
In models adjusted for preterm delivery, as well as race, ethnicity, insurance status, child sex, and maternal age, COVID-exposed offspring were significantly more likely to receive a neurodevelopmental diagnosis in the first year of life (adjusted OR, 1.86; 95% CI, 1.03-3.36; P = .04).
The magnitude of the association with neurodevelopmental disorders was greater with third-trimester SARS-CoV-2 infection (aOR, 2.34; 95% CI, 1.23-4.44; P = .01).
The majority of these diagnoses reflected developmental disorders of motor function or speech and language.
The researchers noted that the finding of an association between prenatal SARS-CoV-2 exposure and neurodevelopmental diagnoses at 12 months is in line with a “large body of literature” linking maternal viral infection and maternal immune activation with offspring neurodevelopmental disorders later in life.
They cautioned, however, that whether a definitive connection exists between prenatal SARS-CoV-2 exposure and adverse neurodevelopment in offspring is not yet known, in part because children born to women infected in the first wave of the pandemic haven’t reached their second birthday – a time when neurodevelopment disorders such as autism are typically diagnosed.
There is also the risk for ascertainment bias arising from greater concern for offspring of infected mothers who were ill during pregnancy. These parents may be more inclined to seek evaluation, and clinicians may be more inclined to diagnose or refer for evaluation, the researchers noted.
Nonetheless, as reported by this news organization, the study results support those of research released at the European Psychiatric Association 2022 Congress; those results also showed an association between maternal SARS-CoV-2 infection and impaired neurodevelopment in 6-week-old infants.
Hypothesis generating
In an accompanying commentary, Torri D. Metz, MD, MS, with University of Utah Health, Salt Lake City, said the preliminary findings of Dr. Perlis and colleagues are “critically important, yet many questions remain.”
“Essentially all of what we know now about the effects of in utero exposure to maternal SARS-CoV-2 infection is from children who were exposed to the early and Alpha variants of SARS-CoV-2, as those are the only children now old enough to undergo rigorous neurodevelopmental assessments,” Dr. Metz pointed out.
Ultimately, Dr. Metz said it’s not surprising that the pandemic and in utero exposure to maternal SARS-CoV-2 infection may adversely affect neurodevelopmental outcomes in young children.
Yet, as a retrospective cohort study, the study can only demonstrate associations, not causality.
“This type of work is intended to be hypothesis generating, and that goal has been accomplished as these preliminary findings generate numerous additional research questions to explore,” Dr. Metz wrote.
Among them: Are there genetic predispositions to adverse outcomes? Will we observe differential effects by SARS-CoV-2 variant, by severity of infection, and by trimester of infection? Is it the virus itself or all of the societal changes that occurred during this period, including differences in how those changes were experienced among those with and without SARS-CoV-2?
“Perhaps the most important question is how do we intervene to help mitigate the adverse effects of the pandemic on young children,” Dr. Metz noted.
“Prospective studies to validate these findings, tease out some of the nuance, and identify those at highest risk will help health care practitioners appropriately dedicate resources to improve outcomes as we follow the life course of this generation of children born during the COVID-19 pandemic,” she added.
The study was supported by the National Institute of Mental Health and the National Institute of Child Health and Human Development. Dr. Perlis is an associate editor for JAMA Network Open but was not involved in the editorial review or decision for the study. Dr. Metz reported receiving personal fees and grants from Pfizer and grants from GestVision.
A version of this article first appeared on Medscape.com.
Infants exposed to SARS-CoV-2 in utero are at increased risk for neurodevelopmental disorders in the first year of life, new research suggests.
But whether it is exposure to the pandemic or maternal exposure to the virus itself that may harm early childhood neurodevelopment is unclear, caution investigators, led by Roy Perlis, MD, MSc, with Massachusetts General Hospital, Boston.
“In this analysis of 222 offspring of mothers infected with SARS-CoV-2, compared with the offspring of 7,550 mothers in the control group (not infected) delivered during the same period, we observed neurodevelopmental diagnoses to be significantly more common among exposed offspring, particularly those exposed to third-trimester maternal infection,” they write.
The study was published online in JAMA Network Open.
Speech and language disorders
The study included 7,772 mostly singleton live births across six hospitals in Massachusetts between March and September 2020, including 222 (2.9%) births to mothers with SARS-CoV-2 infection confirmed by polymerase chain reaction testing during pregnancy.
In all, 14 of 222 children born to SARS-CoV-2–infected mothers (6.3%) were diagnosed with a neurodevelopmental disorder in the first year of life versus 227 of 7,550 unexposed offspring (3%) (unadjusted odds ratio, 2.17; 95% confidence interval, 1.24-3.79; P = .006).
In models adjusted for preterm delivery, as well as race, ethnicity, insurance status, child sex, and maternal age, COVID-exposed offspring were significantly more likely to receive a neurodevelopmental diagnosis in the first year of life (adjusted OR, 1.86; 95% CI, 1.03-3.36; P = .04).
The magnitude of the association with neurodevelopmental disorders was greater with third-trimester SARS-CoV-2 infection (aOR, 2.34; 95% CI, 1.23-4.44; P = .01).
The majority of these diagnoses reflected developmental disorders of motor function or speech and language.
The researchers noted that the finding of an association between prenatal SARS-CoV-2 exposure and neurodevelopmental diagnoses at 12 months is in line with a “large body of literature” linking maternal viral infection and maternal immune activation with offspring neurodevelopmental disorders later in life.
They cautioned, however, that whether a definitive connection exists between prenatal SARS-CoV-2 exposure and adverse neurodevelopment in offspring is not yet known, in part because children born to women infected in the first wave of the pandemic haven’t reached their second birthday – a time when neurodevelopment disorders such as autism are typically diagnosed.
There is also the risk for ascertainment bias arising from greater concern for offspring of infected mothers who were ill during pregnancy. These parents may be more inclined to seek evaluation, and clinicians may be more inclined to diagnose or refer for evaluation, the researchers noted.
Nonetheless, as reported by this news organization, the study results support those of research released at the European Psychiatric Association 2022 Congress; those results also showed an association between maternal SARS-CoV-2 infection and impaired neurodevelopment in 6-week-old infants.
Hypothesis generating
In an accompanying commentary, Torri D. Metz, MD, MS, with University of Utah Health, Salt Lake City, said the preliminary findings of Dr. Perlis and colleagues are “critically important, yet many questions remain.”
“Essentially all of what we know now about the effects of in utero exposure to maternal SARS-CoV-2 infection is from children who were exposed to the early and Alpha variants of SARS-CoV-2, as those are the only children now old enough to undergo rigorous neurodevelopmental assessments,” Dr. Metz pointed out.
Ultimately, Dr. Metz said it’s not surprising that the pandemic and in utero exposure to maternal SARS-CoV-2 infection may adversely affect neurodevelopmental outcomes in young children.
Yet, as a retrospective cohort study, the study can only demonstrate associations, not causality.
“This type of work is intended to be hypothesis generating, and that goal has been accomplished as these preliminary findings generate numerous additional research questions to explore,” Dr. Metz wrote.
Among them: Are there genetic predispositions to adverse outcomes? Will we observe differential effects by SARS-CoV-2 variant, by severity of infection, and by trimester of infection? Is it the virus itself or all of the societal changes that occurred during this period, including differences in how those changes were experienced among those with and without SARS-CoV-2?
“Perhaps the most important question is how do we intervene to help mitigate the adverse effects of the pandemic on young children,” Dr. Metz noted.
“Prospective studies to validate these findings, tease out some of the nuance, and identify those at highest risk will help health care practitioners appropriately dedicate resources to improve outcomes as we follow the life course of this generation of children born during the COVID-19 pandemic,” she added.
The study was supported by the National Institute of Mental Health and the National Institute of Child Health and Human Development. Dr. Perlis is an associate editor for JAMA Network Open but was not involved in the editorial review or decision for the study. Dr. Metz reported receiving personal fees and grants from Pfizer and grants from GestVision.
A version of this article first appeared on Medscape.com.
Infants exposed to SARS-CoV-2 in utero are at increased risk for neurodevelopmental disorders in the first year of life, new research suggests.
But whether it is exposure to the pandemic or maternal exposure to the virus itself that may harm early childhood neurodevelopment is unclear, caution investigators, led by Roy Perlis, MD, MSc, with Massachusetts General Hospital, Boston.
“In this analysis of 222 offspring of mothers infected with SARS-CoV-2, compared with the offspring of 7,550 mothers in the control group (not infected) delivered during the same period, we observed neurodevelopmental diagnoses to be significantly more common among exposed offspring, particularly those exposed to third-trimester maternal infection,” they write.
The study was published online in JAMA Network Open.
Speech and language disorders
The study included 7,772 mostly singleton live births across six hospitals in Massachusetts between March and September 2020, including 222 (2.9%) births to mothers with SARS-CoV-2 infection confirmed by polymerase chain reaction testing during pregnancy.
In all, 14 of 222 children born to SARS-CoV-2–infected mothers (6.3%) were diagnosed with a neurodevelopmental disorder in the first year of life versus 227 of 7,550 unexposed offspring (3%) (unadjusted odds ratio, 2.17; 95% confidence interval, 1.24-3.79; P = .006).
In models adjusted for preterm delivery, as well as race, ethnicity, insurance status, child sex, and maternal age, COVID-exposed offspring were significantly more likely to receive a neurodevelopmental diagnosis in the first year of life (adjusted OR, 1.86; 95% CI, 1.03-3.36; P = .04).
The magnitude of the association with neurodevelopmental disorders was greater with third-trimester SARS-CoV-2 infection (aOR, 2.34; 95% CI, 1.23-4.44; P = .01).
The majority of these diagnoses reflected developmental disorders of motor function or speech and language.
The researchers noted that the finding of an association between prenatal SARS-CoV-2 exposure and neurodevelopmental diagnoses at 12 months is in line with a “large body of literature” linking maternal viral infection and maternal immune activation with offspring neurodevelopmental disorders later in life.
They cautioned, however, that whether a definitive connection exists between prenatal SARS-CoV-2 exposure and adverse neurodevelopment in offspring is not yet known, in part because children born to women infected in the first wave of the pandemic haven’t reached their second birthday – a time when neurodevelopment disorders such as autism are typically diagnosed.
There is also the risk for ascertainment bias arising from greater concern for offspring of infected mothers who were ill during pregnancy. These parents may be more inclined to seek evaluation, and clinicians may be more inclined to diagnose or refer for evaluation, the researchers noted.
Nonetheless, as reported by this news organization, the study results support those of research released at the European Psychiatric Association 2022 Congress; those results also showed an association between maternal SARS-CoV-2 infection and impaired neurodevelopment in 6-week-old infants.
Hypothesis generating
In an accompanying commentary, Torri D. Metz, MD, MS, with University of Utah Health, Salt Lake City, said the preliminary findings of Dr. Perlis and colleagues are “critically important, yet many questions remain.”
“Essentially all of what we know now about the effects of in utero exposure to maternal SARS-CoV-2 infection is from children who were exposed to the early and Alpha variants of SARS-CoV-2, as those are the only children now old enough to undergo rigorous neurodevelopmental assessments,” Dr. Metz pointed out.
Ultimately, Dr. Metz said it’s not surprising that the pandemic and in utero exposure to maternal SARS-CoV-2 infection may adversely affect neurodevelopmental outcomes in young children.
Yet, as a retrospective cohort study, the study can only demonstrate associations, not causality.
“This type of work is intended to be hypothesis generating, and that goal has been accomplished as these preliminary findings generate numerous additional research questions to explore,” Dr. Metz wrote.
Among them: Are there genetic predispositions to adverse outcomes? Will we observe differential effects by SARS-CoV-2 variant, by severity of infection, and by trimester of infection? Is it the virus itself or all of the societal changes that occurred during this period, including differences in how those changes were experienced among those with and without SARS-CoV-2?
“Perhaps the most important question is how do we intervene to help mitigate the adverse effects of the pandemic on young children,” Dr. Metz noted.
“Prospective studies to validate these findings, tease out some of the nuance, and identify those at highest risk will help health care practitioners appropriately dedicate resources to improve outcomes as we follow the life course of this generation of children born during the COVID-19 pandemic,” she added.
The study was supported by the National Institute of Mental Health and the National Institute of Child Health and Human Development. Dr. Perlis is an associate editor for JAMA Network Open but was not involved in the editorial review or decision for the study. Dr. Metz reported receiving personal fees and grants from Pfizer and grants from GestVision.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Stimulants may not improve academic learning in children with ADHD
Extended-release methylphenidate (Concerta) had no effect on learning academic material taught in a small group of children with attention-deficit/hyperactivity disorder (ADHD), a controlled crossover study found.
As in previous studies, however, the stimulant did improve seat work productivity and classroom behavior, but these benefits did not translate into better learning of individual academic learning units, according to William E. Pelham Jr., PhD, of the department of psychology at Florida International University in Miami, and colleagues.
The results were published online in the Journal of Consulting and Clinical Psychology.
The authors said the finding raises questions about how stimulant medication leads to improved academic achievement over time. “This is important given that many parents and pediatricians believe that medication will improve academic achievement; parents are more likely to pursue medication (vs. other treatment options) when they identify academic achievement as a primary goal for treatment. The current findings suggest this emphasis may be misguided,” they wrote.
In their view, efforts to improve learning in children with ADHD should focus on delivering effective academic instruction and support such as individualized educational plans rather than stimulant therapy.
The study
The study cohort consisted of 173 children aged 7-12 (77% male, 86% Hispanic) who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for ADHD and were participating in a therapeutic summer camp classroom.
The experimental design was a triple-masked, within-subject, AB/BA crossover trial. Children completed two consecutive phases of daily, 25-minute instruction in both subject-area content (science and social studies) and vocabulary. Each phase was a standard instructional unit lasting for 3 weeks and lessons were given by credentialed teachers via small-group, evidence-based instruction.
Each child was randomized to receive daily osmotic-release oral system methylphenidate (OROS-MPH) during either the first or second instructional phase and to receive placebo during the other.
Seat work referred to the amount of work a pupil completed in a fixed duration of independent work time, and classroom behavior referred to the frequency of violating classroom rules. Learning was measured by tests, and multilevel models were fit separately to the subject and vocabulary test scores, with four observations per child: pretest and posttest in the two academic subject areas.
The results showed that medication had large, salutary, statistically significant effects on children’s academic seat work productivity and classroom behavior on every single day of the instructional period.
Pupils completed 37% more arithmetic problems per minute when taking OROS-MPH and committed 53% fewer rule violations per hour. In terms of learning the material taught during instruction, however, tests showed that children learned the same amount of subject-area and vocabulary content whether they were taking OROS-MPH or placebo during the instructional period.
Consistent with previous studies, medication slightly helped to improve test scores when taken on the day of a test, but not enough to boost most children’s grades. For example, medication helped children increase on average 1.7 percentage points out of 100 on science and social studies tests.
“This finding has relevance for parents deciding whether to medicate their child for occasions such as a psychoeducational evaluation or high-stakes academic testing – while the effect size was small, findings suggest being medicated would improve scores,” the investigators wrote.
Sharing his perspective on the study but not involved in it, Herschel R. Lessin, MD, a pediatrician at The Children’s Medical Group in Poughkeepsie, N.Y., and coauthor of the American Academy of Pediatrics (AAP) guidelines on ADHD, said, “If you ignore the sensationalized headlines, this study is an interesting but preliminary first step, and justifies further research on the topic. It also has several potential defects, which the authors in fact address in the supplements.” The cohort size was small, for example, the doses of medication were very low, and the study took place in a controlled therapeutic setting – not the everyday classroom.
Furthermore, Dr. Lessin added, the study’s conclusions “are contrary to my 40 years of experience in treating ADHD. If they had used standard measures of assessment, as in previous studies, they would have found medication did impact learning. More research is clearly needed.”
In other comments, Holly K. Harris, MD, assistant professor of pediatrics-development at Baylor College of Medicine and Texas Children’s Hospital in Houston, said the core symptoms of ADHD are primarily behavioral in nature, not academic learning related.
“Stimulant medications are targeting these core behavioral symptoms of ADHD ... but the goal of treatment is more than just the reduction of symptoms; it is to improve a child’s overall functioning so that they succeed at what is expected of them and avoid developing even more impairments,” Dr. Harris said, adding that symptom improvement can sometimes allow a child to learn better in the classroom and achieve more academically.
Children with ADHD may have diagnosed or undiagnosed comorbid learning disabilities, with one 2013 study suggesting a rate of 31%-45%.
With such learning disabilities being distinct from core behavioral symptoms, stimulant medications would not be expected to address a child’s learning disability. “In fact, best practice is for a child with ADHD who is not responding to stimulant medication (doctors might refer to this as complex ADHD) to undergo full individual evaluations either through the school system or an outside psychological assessment to assess for potential learning disabilities or other comorbid developmental/learning or psychiatric diagnosis,” Dr. Harris said.
Rather than changing prescribing patterns, she continued, pediatricians could consider advising parents to request learning evaluations through the school system if the child continues to struggle academically with no change in learning outcomes despite improvement in some behavioral outcomes.
As a reference, Dr. Harris recommended the Society for Developmental and Behavioral Pediatrics guidelines for complex ADHD.
This study was funded by the National Institute on Mental Health with additional support from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the Institute of Education Sciences. Coauthor James Waxmonsky, MD, has received research funding from the National Institutes of Health, Supernus, and Pfizer and served on the advisory board for Iron Shore, NLS Pharma, and Purdue Pharma.
Extended-release methylphenidate (Concerta) had no effect on learning academic material taught in a small group of children with attention-deficit/hyperactivity disorder (ADHD), a controlled crossover study found.
As in previous studies, however, the stimulant did improve seat work productivity and classroom behavior, but these benefits did not translate into better learning of individual academic learning units, according to William E. Pelham Jr., PhD, of the department of psychology at Florida International University in Miami, and colleagues.
The results were published online in the Journal of Consulting and Clinical Psychology.
The authors said the finding raises questions about how stimulant medication leads to improved academic achievement over time. “This is important given that many parents and pediatricians believe that medication will improve academic achievement; parents are more likely to pursue medication (vs. other treatment options) when they identify academic achievement as a primary goal for treatment. The current findings suggest this emphasis may be misguided,” they wrote.
In their view, efforts to improve learning in children with ADHD should focus on delivering effective academic instruction and support such as individualized educational plans rather than stimulant therapy.
The study
The study cohort consisted of 173 children aged 7-12 (77% male, 86% Hispanic) who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for ADHD and were participating in a therapeutic summer camp classroom.
The experimental design was a triple-masked, within-subject, AB/BA crossover trial. Children completed two consecutive phases of daily, 25-minute instruction in both subject-area content (science and social studies) and vocabulary. Each phase was a standard instructional unit lasting for 3 weeks and lessons were given by credentialed teachers via small-group, evidence-based instruction.
Each child was randomized to receive daily osmotic-release oral system methylphenidate (OROS-MPH) during either the first or second instructional phase and to receive placebo during the other.
Seat work referred to the amount of work a pupil completed in a fixed duration of independent work time, and classroom behavior referred to the frequency of violating classroom rules. Learning was measured by tests, and multilevel models were fit separately to the subject and vocabulary test scores, with four observations per child: pretest and posttest in the two academic subject areas.
The results showed that medication had large, salutary, statistically significant effects on children’s academic seat work productivity and classroom behavior on every single day of the instructional period.
Pupils completed 37% more arithmetic problems per minute when taking OROS-MPH and committed 53% fewer rule violations per hour. In terms of learning the material taught during instruction, however, tests showed that children learned the same amount of subject-area and vocabulary content whether they were taking OROS-MPH or placebo during the instructional period.
Consistent with previous studies, medication slightly helped to improve test scores when taken on the day of a test, but not enough to boost most children’s grades. For example, medication helped children increase on average 1.7 percentage points out of 100 on science and social studies tests.
“This finding has relevance for parents deciding whether to medicate their child for occasions such as a psychoeducational evaluation or high-stakes academic testing – while the effect size was small, findings suggest being medicated would improve scores,” the investigators wrote.
Sharing his perspective on the study but not involved in it, Herschel R. Lessin, MD, a pediatrician at The Children’s Medical Group in Poughkeepsie, N.Y., and coauthor of the American Academy of Pediatrics (AAP) guidelines on ADHD, said, “If you ignore the sensationalized headlines, this study is an interesting but preliminary first step, and justifies further research on the topic. It also has several potential defects, which the authors in fact address in the supplements.” The cohort size was small, for example, the doses of medication were very low, and the study took place in a controlled therapeutic setting – not the everyday classroom.
Furthermore, Dr. Lessin added, the study’s conclusions “are contrary to my 40 years of experience in treating ADHD. If they had used standard measures of assessment, as in previous studies, they would have found medication did impact learning. More research is clearly needed.”
In other comments, Holly K. Harris, MD, assistant professor of pediatrics-development at Baylor College of Medicine and Texas Children’s Hospital in Houston, said the core symptoms of ADHD are primarily behavioral in nature, not academic learning related.
“Stimulant medications are targeting these core behavioral symptoms of ADHD ... but the goal of treatment is more than just the reduction of symptoms; it is to improve a child’s overall functioning so that they succeed at what is expected of them and avoid developing even more impairments,” Dr. Harris said, adding that symptom improvement can sometimes allow a child to learn better in the classroom and achieve more academically.
Children with ADHD may have diagnosed or undiagnosed comorbid learning disabilities, with one 2013 study suggesting a rate of 31%-45%.
With such learning disabilities being distinct from core behavioral symptoms, stimulant medications would not be expected to address a child’s learning disability. “In fact, best practice is for a child with ADHD who is not responding to stimulant medication (doctors might refer to this as complex ADHD) to undergo full individual evaluations either through the school system or an outside psychological assessment to assess for potential learning disabilities or other comorbid developmental/learning or psychiatric diagnosis,” Dr. Harris said.
Rather than changing prescribing patterns, she continued, pediatricians could consider advising parents to request learning evaluations through the school system if the child continues to struggle academically with no change in learning outcomes despite improvement in some behavioral outcomes.
As a reference, Dr. Harris recommended the Society for Developmental and Behavioral Pediatrics guidelines for complex ADHD.
This study was funded by the National Institute on Mental Health with additional support from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the Institute of Education Sciences. Coauthor James Waxmonsky, MD, has received research funding from the National Institutes of Health, Supernus, and Pfizer and served on the advisory board for Iron Shore, NLS Pharma, and Purdue Pharma.
Extended-release methylphenidate (Concerta) had no effect on learning academic material taught in a small group of children with attention-deficit/hyperactivity disorder (ADHD), a controlled crossover study found.
As in previous studies, however, the stimulant did improve seat work productivity and classroom behavior, but these benefits did not translate into better learning of individual academic learning units, according to William E. Pelham Jr., PhD, of the department of psychology at Florida International University in Miami, and colleagues.
The results were published online in the Journal of Consulting and Clinical Psychology.
The authors said the finding raises questions about how stimulant medication leads to improved academic achievement over time. “This is important given that many parents and pediatricians believe that medication will improve academic achievement; parents are more likely to pursue medication (vs. other treatment options) when they identify academic achievement as a primary goal for treatment. The current findings suggest this emphasis may be misguided,” they wrote.
In their view, efforts to improve learning in children with ADHD should focus on delivering effective academic instruction and support such as individualized educational plans rather than stimulant therapy.
The study
The study cohort consisted of 173 children aged 7-12 (77% male, 86% Hispanic) who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for ADHD and were participating in a therapeutic summer camp classroom.
The experimental design was a triple-masked, within-subject, AB/BA crossover trial. Children completed two consecutive phases of daily, 25-minute instruction in both subject-area content (science and social studies) and vocabulary. Each phase was a standard instructional unit lasting for 3 weeks and lessons were given by credentialed teachers via small-group, evidence-based instruction.
Each child was randomized to receive daily osmotic-release oral system methylphenidate (OROS-MPH) during either the first or second instructional phase and to receive placebo during the other.
Seat work referred to the amount of work a pupil completed in a fixed duration of independent work time, and classroom behavior referred to the frequency of violating classroom rules. Learning was measured by tests, and multilevel models were fit separately to the subject and vocabulary test scores, with four observations per child: pretest and posttest in the two academic subject areas.
The results showed that medication had large, salutary, statistically significant effects on children’s academic seat work productivity and classroom behavior on every single day of the instructional period.
Pupils completed 37% more arithmetic problems per minute when taking OROS-MPH and committed 53% fewer rule violations per hour. In terms of learning the material taught during instruction, however, tests showed that children learned the same amount of subject-area and vocabulary content whether they were taking OROS-MPH or placebo during the instructional period.
Consistent with previous studies, medication slightly helped to improve test scores when taken on the day of a test, but not enough to boost most children’s grades. For example, medication helped children increase on average 1.7 percentage points out of 100 on science and social studies tests.
“This finding has relevance for parents deciding whether to medicate their child for occasions such as a psychoeducational evaluation or high-stakes academic testing – while the effect size was small, findings suggest being medicated would improve scores,” the investigators wrote.
Sharing his perspective on the study but not involved in it, Herschel R. Lessin, MD, a pediatrician at The Children’s Medical Group in Poughkeepsie, N.Y., and coauthor of the American Academy of Pediatrics (AAP) guidelines on ADHD, said, “If you ignore the sensationalized headlines, this study is an interesting but preliminary first step, and justifies further research on the topic. It also has several potential defects, which the authors in fact address in the supplements.” The cohort size was small, for example, the doses of medication were very low, and the study took place in a controlled therapeutic setting – not the everyday classroom.
Furthermore, Dr. Lessin added, the study’s conclusions “are contrary to my 40 years of experience in treating ADHD. If they had used standard measures of assessment, as in previous studies, they would have found medication did impact learning. More research is clearly needed.”
In other comments, Holly K. Harris, MD, assistant professor of pediatrics-development at Baylor College of Medicine and Texas Children’s Hospital in Houston, said the core symptoms of ADHD are primarily behavioral in nature, not academic learning related.
“Stimulant medications are targeting these core behavioral symptoms of ADHD ... but the goal of treatment is more than just the reduction of symptoms; it is to improve a child’s overall functioning so that they succeed at what is expected of them and avoid developing even more impairments,” Dr. Harris said, adding that symptom improvement can sometimes allow a child to learn better in the classroom and achieve more academically.
Children with ADHD may have diagnosed or undiagnosed comorbid learning disabilities, with one 2013 study suggesting a rate of 31%-45%.
With such learning disabilities being distinct from core behavioral symptoms, stimulant medications would not be expected to address a child’s learning disability. “In fact, best practice is for a child with ADHD who is not responding to stimulant medication (doctors might refer to this as complex ADHD) to undergo full individual evaluations either through the school system or an outside psychological assessment to assess for potential learning disabilities or other comorbid developmental/learning or psychiatric diagnosis,” Dr. Harris said.
Rather than changing prescribing patterns, she continued, pediatricians could consider advising parents to request learning evaluations through the school system if the child continues to struggle academically with no change in learning outcomes despite improvement in some behavioral outcomes.
As a reference, Dr. Harris recommended the Society for Developmental and Behavioral Pediatrics guidelines for complex ADHD.
This study was funded by the National Institute on Mental Health with additional support from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the Institute of Education Sciences. Coauthor James Waxmonsky, MD, has received research funding from the National Institutes of Health, Supernus, and Pfizer and served on the advisory board for Iron Shore, NLS Pharma, and Purdue Pharma.
FROM JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY