A new drug that targets the cystic fibrosis transmembrane conductance regulator protein could significantly improve lung function and other symptoms in patients with cystic fibrosis.

In a phase 3 double-blind, placebo controlled crossover trial, researchers examined the effects of tezacaftor – a cystic fibrosis transmembrane conductance regulator (CFTR) corrector – in combination with the CFTR potentiator ivacaftor, compared with ivacaftor alone or placebo.

copyright Zerbor/Thinkstock

A new drug that targets the cystic fibrosis transmembrane conductance regulator protein could significantly improve lung function and other symptoms in patients with cystic fibrosis.

In a phase 3 double-blind, placebo controlled crossover trial, researchers examined the effects of tezacaftor – a cystic fibrosis transmembrane conductance regulator (CFTR) corrector – in combination with the CFTR potentiator ivacaftor, compared with ivacaftor alone or placebo.

copyright Zerbor/Thinkstock

A new drug that targets the cystic fibrosis transmembrane conductance regulator protein could significantly improve lung function and other symptoms in patients with cystic fibrosis.

In a phase 3 double-blind, placebo controlled crossover trial, researchers examined the effects of tezacaftor – a cystic fibrosis transmembrane conductance regulator (CFTR) corrector – in combination with the CFTR potentiator ivacaftor, compared with ivacaftor alone or placebo.

copyright Zerbor/Thinkstock

Substance use disorders are affecting every pediatric practice as they are major contributors to morbidity and mortality in young people. With the ongoing risks of binge drinking, the current epidemic of opioid addiction and overdose deaths in the United States, and the shifting legal status and public perception of the risk of marijuana, how to deal with substance use disorders seems to be the focus of public conversation these days. Some of the most effective and cost-effective interventions for substance abuse disorders are preventive ones, such as parent education and early recognition in pediatric practice.

Substance abuse risk

rez-art/Thinkstock

We cannot yet predict who can safely “experiment” with substances or who will develop dependency. However, there is information that we can use to identify those at greater risk. Youth who have a first-degree relative with a substance use disorder are at greater risk for developing such a disorder themselves, and this is especially so if there is a family history of alcoholism. Youth who suffer from a psychiatric illness, particularly from anxiety and mood disorders, have a special vulnerability to abusing substances, particularly when their underlying illness is untreated or incompletely treated. Youth with ADHD are at substantially elevated risk of developing substance use disorders, although there is a complex relationship between these two problems. The evidence currently suggests that for youth who began effective treatment prior to puberty, there is no elevation in risk, but for those who did not, there is a substantially elevated risk of substance use disorders. Finally, there has been research that indicates that children with a combination of sensation-seeking, high impulsivity, anxiety-sensitivity, and hopelessness are at the highest risk for substance use disorders.²
 

Prevention efforts you can make: To your patients

The first step in your prevention efforts is an open conversation about drugs and alcohol. Ask your middle schoolers about whether they have tried alcohol or any drugs. Have their friends? What are kids saying about alcohol? About marijuana? Vaping? Are there other substances that kids are talking about or trying? Be genuinely curious, warm, and nonjudgmental. Find out what they think the risks of these substances may be. If appropriate, offer them some education about known risks of substances to the developing brain, to school or athletic performance, and so on. You can teach them about other trusted resources, such as the National Institute on Drug Abuse (NIDA), which has a resource specifically for teens (teens.drugabuse.gov).

Prevention efforts you can make: To the parents

Your other prevention strategies should include parents. Studies have shown that when parents have clear rules and expectations about drug and alcohol use, and are consistent about enforcing consequences in their home, their children are significantly less likely than their peers to have experimented with drugs or alcohol by their senior year in high school. Parents of children headed to middle school should hear about this fact, alongside accurate information about the risks associated with alcohol and specific drugs for the developing brain.

References

1. Hum Genet. 2012 Jun;131(6):779-89.

2. Alcohol Clin Exp Res. 2013 Jan;37(Suppl 1):E281-90.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton Wellesley Hospital, also in Boston. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston.

Substance use disorders are affecting every pediatric practice as they are major contributors to morbidity and mortality in young people. With the ongoing risks of binge drinking, the current epidemic of opioid addiction and overdose deaths in the United States, and the shifting legal status and public perception of the risk of marijuana, how to deal with substance use disorders seems to be the focus of public conversation these days. Some of the most effective and cost-effective interventions for substance abuse disorders are preventive ones, such as parent education and early recognition in pediatric practice.

Substance abuse risk

rez-art/Thinkstock

We cannot yet predict who can safely “experiment” with substances or who will develop dependency. However, there is information that we can use to identify those at greater risk. Youth who have a first-degree relative with a substance use disorder are at greater risk for developing such a disorder themselves, and this is especially so if there is a family history of alcoholism. Youth who suffer from a psychiatric illness, particularly from anxiety and mood disorders, have a special vulnerability to abusing substances, particularly when their underlying illness is untreated or incompletely treated. Youth with ADHD are at substantially elevated risk of developing substance use disorders, although there is a complex relationship between these two problems. The evidence currently suggests that for youth who began effective treatment prior to puberty, there is no elevation in risk, but for those who did not, there is a substantially elevated risk of substance use disorders. Finally, there has been research that indicates that children with a combination of sensation-seeking, high impulsivity, anxiety-sensitivity, and hopelessness are at the highest risk for substance use disorders.²
 

Prevention efforts you can make: To your patients

The first step in your prevention efforts is an open conversation about drugs and alcohol. Ask your middle schoolers about whether they have tried alcohol or any drugs. Have their friends? What are kids saying about alcohol? About marijuana? Vaping? Are there other substances that kids are talking about or trying? Be genuinely curious, warm, and nonjudgmental. Find out what they think the risks of these substances may be. If appropriate, offer them some education about known risks of substances to the developing brain, to school or athletic performance, and so on. You can teach them about other trusted resources, such as the National Institute on Drug Abuse (NIDA), which has a resource specifically for teens (teens.drugabuse.gov).

Prevention efforts you can make: To the parents

Your other prevention strategies should include parents. Studies have shown that when parents have clear rules and expectations about drug and alcohol use, and are consistent about enforcing consequences in their home, their children are significantly less likely than their peers to have experimented with drugs or alcohol by their senior year in high school. Parents of children headed to middle school should hear about this fact, alongside accurate information about the risks associated with alcohol and specific drugs for the developing brain.

References

1. Hum Genet. 2012 Jun;131(6):779-89.

2. Alcohol Clin Exp Res. 2013 Jan;37(Suppl 1):E281-90.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton Wellesley Hospital, also in Boston. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston.

Substance use disorders are affecting every pediatric practice as they are major contributors to morbidity and mortality in young people. With the ongoing risks of binge drinking, the current epidemic of opioid addiction and overdose deaths in the United States, and the shifting legal status and public perception of the risk of marijuana, how to deal with substance use disorders seems to be the focus of public conversation these days. Some of the most effective and cost-effective interventions for substance abuse disorders are preventive ones, such as parent education and early recognition in pediatric practice.

Substance abuse risk

rez-art/Thinkstock

We cannot yet predict who can safely “experiment” with substances or who will develop dependency. However, there is information that we can use to identify those at greater risk. Youth who have a first-degree relative with a substance use disorder are at greater risk for developing such a disorder themselves, and this is especially so if there is a family history of alcoholism. Youth who suffer from a psychiatric illness, particularly from anxiety and mood disorders, have a special vulnerability to abusing substances, particularly when their underlying illness is untreated or incompletely treated. Youth with ADHD are at substantially elevated risk of developing substance use disorders, although there is a complex relationship between these two problems. The evidence currently suggests that for youth who began effective treatment prior to puberty, there is no elevation in risk, but for those who did not, there is a substantially elevated risk of substance use disorders. Finally, there has been research that indicates that children with a combination of sensation-seeking, high impulsivity, anxiety-sensitivity, and hopelessness are at the highest risk for substance use disorders.²
 

Prevention efforts you can make: To your patients

The first step in your prevention efforts is an open conversation about drugs and alcohol. Ask your middle schoolers about whether they have tried alcohol or any drugs. Have their friends? What are kids saying about alcohol? About marijuana? Vaping? Are there other substances that kids are talking about or trying? Be genuinely curious, warm, and nonjudgmental. Find out what they think the risks of these substances may be. If appropriate, offer them some education about known risks of substances to the developing brain, to school or athletic performance, and so on. You can teach them about other trusted resources, such as the National Institute on Drug Abuse (NIDA), which has a resource specifically for teens (teens.drugabuse.gov).

Prevention efforts you can make: To the parents

Your other prevention strategies should include parents. Studies have shown that when parents have clear rules and expectations about drug and alcohol use, and are consistent about enforcing consequences in their home, their children are significantly less likely than their peers to have experimented with drugs or alcohol by their senior year in high school. Parents of children headed to middle school should hear about this fact, alongside accurate information about the risks associated with alcohol and specific drugs for the developing brain.

References

1. Hum Genet. 2012 Jun;131(6):779-89.

2. Alcohol Clin Exp Res. 2013 Jan;37(Suppl 1):E281-90.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton Wellesley Hospital, also in Boston. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston.

PARIS—Interferon beta is associated with a lower risk of all-cause mortality among patients with multiple sclerosis (MS) treated in clinical practice, according to data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Participants in the study were observed for as long as 18 years. The findings were consistent across two geographically distinct regions (ie, Canada and France), said the investigators.

Interferon beta has benefits for patients with MS, but whether the treatment prolongs survival in this population is unclear. Elaine Kingwell, PhD, a research associate in the Division of Neurology at the University of British Columbia in Vancouver, and colleagues investigated the association between interferon beta treatment and all-cause mortality in the clinical setting.

The researchers accessed prospectively collected data on patients with relapsing-remitting MS at onset, including sex, birth date, Expanded Disability Status Scale (EDSS) scores, and disease modifying treatments (DMTs), from British Columbia, Canada, and Rennes, France. Data were linked to population-based administrative databases capturing death dates in both countries. In Canada, data about drug prescriptions filled, universal health care registration, hospital admissions, and physician visits also were available. Patients were treatment-naïve at study entry, and investigators followed them from the earliest of first MS clinic visit, 18th birthday, or January 1, 1996, to the earliest of death, emigration, or December 31, 2013.

Using a nested case–control design, the researchers randomly selected as many as 20 MS controls by incidence density sampling and matched them to MS cases (ie, patients who died during follow-up) by sex, age (± 5 years), calendar year, and EDSS score at study entry. The association between all-cause mortality and interferon beta exposure (greater than six months) was estimated by conditional logistic regression, expressed as odds ratios (OR), and adjusted for glatiramer acetate (greater than six months exposure), any exposure to another DMT, age, and comorbidity burden. Analyses were stratified by sex and country. The researchers examined the association with cumulative exposure to interferon beta (up to three years or more than three years).

The cohort included 7,009 patients (75% women) with relapsing-remitting MS with a median age at study entry of 42. During follow-up (median, 12.3 years), 30% of participants were exposed to interferon beta, 11% were exposed to glatiramer acetate, and 12% were exposed to other DMTs, including MS-specific immunosuppressants. As many as 20 controls were successfully matched to each of 649 cases (mean age at death, 60). The odds of exposure to interferon beta was 32% lower among cases than controls. Stratification by sex or country did not change the interpretation of findings. Compared with no or minimal exposure, a longer cumulative time on interferon beta (ie, more than three years) was associated with increased survival (OR, 0.44), whereas exposure of less than three years was not (OR, 1.00).

PARIS—Interferon beta is associated with a lower risk of all-cause mortality among patients with multiple sclerosis (MS) treated in clinical practice, according to data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Participants in the study were observed for as long as 18 years. The findings were consistent across two geographically distinct regions (ie, Canada and France), said the investigators.

Interferon beta has benefits for patients with MS, but whether the treatment prolongs survival in this population is unclear. Elaine Kingwell, PhD, a research associate in the Division of Neurology at the University of British Columbia in Vancouver, and colleagues investigated the association between interferon beta treatment and all-cause mortality in the clinical setting.

The researchers accessed prospectively collected data on patients with relapsing-remitting MS at onset, including sex, birth date, Expanded Disability Status Scale (EDSS) scores, and disease modifying treatments (DMTs), from British Columbia, Canada, and Rennes, France. Data were linked to population-based administrative databases capturing death dates in both countries. In Canada, data about drug prescriptions filled, universal health care registration, hospital admissions, and physician visits also were available. Patients were treatment-naïve at study entry, and investigators followed them from the earliest of first MS clinic visit, 18th birthday, or January 1, 1996, to the earliest of death, emigration, or December 31, 2013.

Using a nested case–control design, the researchers randomly selected as many as 20 MS controls by incidence density sampling and matched them to MS cases (ie, patients who died during follow-up) by sex, age (± 5 years), calendar year, and EDSS score at study entry. The association between all-cause mortality and interferon beta exposure (greater than six months) was estimated by conditional logistic regression, expressed as odds ratios (OR), and adjusted for glatiramer acetate (greater than six months exposure), any exposure to another DMT, age, and comorbidity burden. Analyses were stratified by sex and country. The researchers examined the association with cumulative exposure to interferon beta (up to three years or more than three years).

The cohort included 7,009 patients (75% women) with relapsing-remitting MS with a median age at study entry of 42. During follow-up (median, 12.3 years), 30% of participants were exposed to interferon beta, 11% were exposed to glatiramer acetate, and 12% were exposed to other DMTs, including MS-specific immunosuppressants. As many as 20 controls were successfully matched to each of 649 cases (mean age at death, 60). The odds of exposure to interferon beta was 32% lower among cases than controls. Stratification by sex or country did not change the interpretation of findings. Compared with no or minimal exposure, a longer cumulative time on interferon beta (ie, more than three years) was associated with increased survival (OR, 0.44), whereas exposure of less than three years was not (OR, 1.00).

PARIS—Interferon beta is associated with a lower risk of all-cause mortality among patients with multiple sclerosis (MS) treated in clinical practice, according to data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Participants in the study were observed for as long as 18 years. The findings were consistent across two geographically distinct regions (ie, Canada and France), said the investigators.

Interferon beta has benefits for patients with MS, but whether the treatment prolongs survival in this population is unclear. Elaine Kingwell, PhD, a research associate in the Division of Neurology at the University of British Columbia in Vancouver, and colleagues investigated the association between interferon beta treatment and all-cause mortality in the clinical setting.

The researchers accessed prospectively collected data on patients with relapsing-remitting MS at onset, including sex, birth date, Expanded Disability Status Scale (EDSS) scores, and disease modifying treatments (DMTs), from British Columbia, Canada, and Rennes, France. Data were linked to population-based administrative databases capturing death dates in both countries. In Canada, data about drug prescriptions filled, universal health care registration, hospital admissions, and physician visits also were available. Patients were treatment-naïve at study entry, and investigators followed them from the earliest of first MS clinic visit, 18th birthday, or January 1, 1996, to the earliest of death, emigration, or December 31, 2013.

Using a nested case–control design, the researchers randomly selected as many as 20 MS controls by incidence density sampling and matched them to MS cases (ie, patients who died during follow-up) by sex, age (± 5 years), calendar year, and EDSS score at study entry. The association between all-cause mortality and interferon beta exposure (greater than six months) was estimated by conditional logistic regression, expressed as odds ratios (OR), and adjusted for glatiramer acetate (greater than six months exposure), any exposure to another DMT, age, and comorbidity burden. Analyses were stratified by sex and country. The researchers examined the association with cumulative exposure to interferon beta (up to three years or more than three years).

The cohort included 7,009 patients (75% women) with relapsing-remitting MS with a median age at study entry of 42. During follow-up (median, 12.3 years), 30% of participants were exposed to interferon beta, 11% were exposed to glatiramer acetate, and 12% were exposed to other DMTs, including MS-specific immunosuppressants. As many as 20 controls were successfully matched to each of 649 cases (mean age at death, 60). The odds of exposure to interferon beta was 32% lower among cases than controls. Stratification by sex or country did not change the interpretation of findings. Compared with no or minimal exposure, a longer cumulative time on interferon beta (ie, more than three years) was associated with increased survival (OR, 0.44), whereas exposure of less than three years was not (OR, 1.00).

More to psychiatry than just neuroscience

In his editorial “Advancing clinical neuroscience literacy among psychiatric practitioners” (From the Editor, Current Psychiatry. September 2017, p. 17-18), Dr. Nasrallah states, “All psychiatrists are fully aware that brain pathology is the source of every psychiatric disorder they evaluate, diagnose, and treat.” Although it is true that as psychiatrists we need to be fully informed of the latest advances in neuropsychiatry—and the implications of these advances—there is still more than the reductionist aspects of neuroscience underpinning a lot of what makes our patients’ struggles in life so difficult. In current psychiatric practice, I see far more neglect of the “old-fashioned” psychological treatment skills and understanding by psychiatrists who focus solely on psycho­pharmacologic treatment.

I find that many of my patients look for more or different drugs to fix their dysfunctional patterns in life—many of which stem from their dysfunctional and traumatic childhoods. Thus, it is more than just drugs and neurochemical pathways, more than just the “dysregulated neural circuitry,” that we need to focus on in our psychiatric practice.

I finished my psychiatric residency in 1972, before we knew much about neuroscience. Since then, we have learned so much about neuroscience and the specific neuroscience mechanisms involved in the brain and mind. Those advances have done much to aid our core understanding of psychiatric disorders. However, let us not forget that there is more to the mind than just neurochemistry, and more to our practice of psychiatry than just neuroscience.

Leonard Korn, MD
Psychiatrist
Portsmouth Regional Hospital
Portsmouth, New Hampshire

Dr. Nasrallah responds

It is now widely accepted in our field that all psychological phenomena and all human behaviors are associated with neuro­biological components. All life events, especially traumatic experiences, are transduced into structural and chemical changes, often within minutes. The formation of dendritic spines to encode the memory of one’s experiences throughout waking hours is well established in neuroscience, and hundreds of studies have been published about this. 

Psychotherapy is a neurobiological intervention that induces neuroplasticity and leads to structural brain repair, because talking, listening, triggering memories, inducing insight, and “connecting the dots” in one’s behavior are all biological events.^1,2 There is no such thing as a purely psychological process independent of the brain. The mind is the product of ongoing complex, intricate activity of brain neurocircuits whose neurobiological activity is translated into thoughts, emotions, impulses, and behaviors. The mind is perpetually tethered to its neurological roots.

Thus, reductionism actually describes a scientific fact and is not a term with pejorative connotations used to shut down scientific discourse about the biological basis of human behavior. By advancing their clinical neuroscience literacy, psychiatric practitioners will understand that they deal with a specific brain pathology in every patient that they treat and that the medications and psychotherapeutic interventions they employ are synergistic biological treatments.³

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

References
1. Nasrallah HA. Repositioning psychotherapy as a neurobiological intervention. Current Psychiatry. 2013;12(12):18-19.
2. Nasrallah HA. Out-of-the-box questions about psychotherapy. Current Psychiatry. 2010;9(10):13-14.
3. Nasrallah HA. Medications with psychotherapy: a synergy to heal the brain. C urrent Psychiatry. 2006;5(10):11-12.

The impact of childhood trauma

I enjoyed Dr. Nasrallah’s article “Beyond DSM-5: Clinical and bio­logic features shared by major psy­chiatric syndromes” (From the Editor, Current Psychiatry. October 2017, p. 4,6-7), but there was only 1 mention of childhood trauma, which shares features with most of the common­alities he described, such as inflam­mation, smaller brain volumes, gene and environment interaction, short­ened telomeres, and elevated corti­sol levels. The Adverse Childhood Experiences Study1 taught us about the impact of childhood trauma on the entire organism. We need to focus on that commonality.

Susan Jones, MD
Child and Adolescent Psychiatrist
Virginia Treatment Center for Children
Assistant Professor
Virginia Commonwealth University
School of Medicine
Richmond, Virginia

Reference
1. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998;14(4):245-258

Dr. Nasrallah responds

It is worth pointing out that childhood trauma predominantly leads to psy­chotic and mood disorders in adulthood, and the criteria I mentioned would then hold true.

More to psychiatry than just neuroscience

In his editorial “Advancing clinical neuroscience literacy among psychiatric practitioners” (From the Editor, Current Psychiatry. September 2017, p. 17-18), Dr. Nasrallah states, “All psychiatrists are fully aware that brain pathology is the source of every psychiatric disorder they evaluate, diagnose, and treat.” Although it is true that as psychiatrists we need to be fully informed of the latest advances in neuropsychiatry—and the implications of these advances—there is still more than the reductionist aspects of neuroscience underpinning a lot of what makes our patients’ struggles in life so difficult. In current psychiatric practice, I see far more neglect of the “old-fashioned” psychological treatment skills and understanding by psychiatrists who focus solely on psycho­pharmacologic treatment.

I find that many of my patients look for more or different drugs to fix their dysfunctional patterns in life—many of which stem from their dysfunctional and traumatic childhoods. Thus, it is more than just drugs and neurochemical pathways, more than just the “dysregulated neural circuitry,” that we need to focus on in our psychiatric practice.

I finished my psychiatric residency in 1972, before we knew much about neuroscience. Since then, we have learned so much about neuroscience and the specific neuroscience mechanisms involved in the brain and mind. Those advances have done much to aid our core understanding of psychiatric disorders. However, let us not forget that there is more to the mind than just neurochemistry, and more to our practice of psychiatry than just neuroscience.

Leonard Korn, MD
Psychiatrist
Portsmouth Regional Hospital
Portsmouth, New Hampshire

Dr. Nasrallah responds

It is now widely accepted in our field that all psychological phenomena and all human behaviors are associated with neuro­biological components. All life events, especially traumatic experiences, are transduced into structural and chemical changes, often within minutes. The formation of dendritic spines to encode the memory of one’s experiences throughout waking hours is well established in neuroscience, and hundreds of studies have been published about this. 

Psychotherapy is a neurobiological intervention that induces neuroplasticity and leads to structural brain repair, because talking, listening, triggering memories, inducing insight, and “connecting the dots” in one’s behavior are all biological events.^1,2 There is no such thing as a purely psychological process independent of the brain. The mind is the product of ongoing complex, intricate activity of brain neurocircuits whose neurobiological activity is translated into thoughts, emotions, impulses, and behaviors. The mind is perpetually tethered to its neurological roots.

Thus, reductionism actually describes a scientific fact and is not a term with pejorative connotations used to shut down scientific discourse about the biological basis of human behavior. By advancing their clinical neuroscience literacy, psychiatric practitioners will understand that they deal with a specific brain pathology in every patient that they treat and that the medications and psychotherapeutic interventions they employ are synergistic biological treatments.³

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

References
1. Nasrallah HA. Repositioning psychotherapy as a neurobiological intervention. Current Psychiatry. 2013;12(12):18-19.
2. Nasrallah HA. Out-of-the-box questions about psychotherapy. Current Psychiatry. 2010;9(10):13-14.
3. Nasrallah HA. Medications with psychotherapy: a synergy to heal the brain. C urrent Psychiatry. 2006;5(10):11-12.

The impact of childhood trauma

I enjoyed Dr. Nasrallah’s article “Beyond DSM-5: Clinical and bio­logic features shared by major psy­chiatric syndromes” (From the Editor, Current Psychiatry. October 2017, p. 4,6-7), but there was only 1 mention of childhood trauma, which shares features with most of the common­alities he described, such as inflam­mation, smaller brain volumes, gene and environment interaction, short­ened telomeres, and elevated corti­sol levels. The Adverse Childhood Experiences Study1 taught us about the impact of childhood trauma on the entire organism. We need to focus on that commonality.

Susan Jones, MD
Child and Adolescent Psychiatrist
Virginia Treatment Center for Children
Assistant Professor
Virginia Commonwealth University
School of Medicine
Richmond, Virginia

Reference
1. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998;14(4):245-258

Dr. Nasrallah responds

It is worth pointing out that childhood trauma predominantly leads to psy­chotic and mood disorders in adulthood, and the criteria I mentioned would then hold true.

More to psychiatry than just neuroscience

In his editorial “Advancing clinical neuroscience literacy among psychiatric practitioners” (From the Editor, Current Psychiatry. September 2017, p. 17-18), Dr. Nasrallah states, “All psychiatrists are fully aware that brain pathology is the source of every psychiatric disorder they evaluate, diagnose, and treat.” Although it is true that as psychiatrists we need to be fully informed of the latest advances in neuropsychiatry—and the implications of these advances—there is still more than the reductionist aspects of neuroscience underpinning a lot of what makes our patients’ struggles in life so difficult. In current psychiatric practice, I see far more neglect of the “old-fashioned” psychological treatment skills and understanding by psychiatrists who focus solely on psycho­pharmacologic treatment.

I find that many of my patients look for more or different drugs to fix their dysfunctional patterns in life—many of which stem from their dysfunctional and traumatic childhoods. Thus, it is more than just drugs and neurochemical pathways, more than just the “dysregulated neural circuitry,” that we need to focus on in our psychiatric practice.

I finished my psychiatric residency in 1972, before we knew much about neuroscience. Since then, we have learned so much about neuroscience and the specific neuroscience mechanisms involved in the brain and mind. Those advances have done much to aid our core understanding of psychiatric disorders. However, let us not forget that there is more to the mind than just neurochemistry, and more to our practice of psychiatry than just neuroscience.

Leonard Korn, MD
Psychiatrist
Portsmouth Regional Hospital
Portsmouth, New Hampshire

Dr. Nasrallah responds

It is now widely accepted in our field that all psychological phenomena and all human behaviors are associated with neuro­biological components. All life events, especially traumatic experiences, are transduced into structural and chemical changes, often within minutes. The formation of dendritic spines to encode the memory of one’s experiences throughout waking hours is well established in neuroscience, and hundreds of studies have been published about this. 

Psychotherapy is a neurobiological intervention that induces neuroplasticity and leads to structural brain repair, because talking, listening, triggering memories, inducing insight, and “connecting the dots” in one’s behavior are all biological events.^1,2 There is no such thing as a purely psychological process independent of the brain. The mind is the product of ongoing complex, intricate activity of brain neurocircuits whose neurobiological activity is translated into thoughts, emotions, impulses, and behaviors. The mind is perpetually tethered to its neurological roots.

Thus, reductionism actually describes a scientific fact and is not a term with pejorative connotations used to shut down scientific discourse about the biological basis of human behavior. By advancing their clinical neuroscience literacy, psychiatric practitioners will understand that they deal with a specific brain pathology in every patient that they treat and that the medications and psychotherapeutic interventions they employ are synergistic biological treatments.³

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

References
1. Nasrallah HA. Repositioning psychotherapy as a neurobiological intervention. Current Psychiatry. 2013;12(12):18-19.
2. Nasrallah HA. Out-of-the-box questions about psychotherapy. Current Psychiatry. 2010;9(10):13-14.
3. Nasrallah HA. Medications with psychotherapy: a synergy to heal the brain. C urrent Psychiatry. 2006;5(10):11-12.

The impact of childhood trauma

I enjoyed Dr. Nasrallah’s article “Beyond DSM-5: Clinical and bio­logic features shared by major psy­chiatric syndromes” (From the Editor, Current Psychiatry. October 2017, p. 4,6-7), but there was only 1 mention of childhood trauma, which shares features with most of the common­alities he described, such as inflam­mation, smaller brain volumes, gene and environment interaction, short­ened telomeres, and elevated corti­sol levels. The Adverse Childhood Experiences Study1 taught us about the impact of childhood trauma on the entire organism. We need to focus on that commonality.

Susan Jones, MD
Child and Adolescent Psychiatrist
Virginia Treatment Center for Children
Assistant Professor
Virginia Commonwealth University
School of Medicine
Richmond, Virginia

Reference
1. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998;14(4):245-258

Dr. Nasrallah responds

It is worth pointing out that childhood trauma predominantly leads to psy­chotic and mood disorders in adulthood, and the criteria I mentioned would then hold true.

The Food and Drug Administration on Nov. 21 granted orphan drug designation to rofecoxib (TRM-201), a cyclooxygenase 2–selective nonsteroidal anti-inflammatory drug (NSAID) intended to treat patients with hemophilic arthropathy (HA).

HA, a joint disease caused by hemarthrosis, is the largest cause of morbidity for hemophilia patients. There are currently no approved treatments in the United States.

dwatson@frontlinemedcom.com

The Food and Drug Administration on Nov. 21 granted orphan drug designation to rofecoxib (TRM-201), a cyclooxygenase 2–selective nonsteroidal anti-inflammatory drug (NSAID) intended to treat patients with hemophilic arthropathy (HA).

HA, a joint disease caused by hemarthrosis, is the largest cause of morbidity for hemophilia patients. There are currently no approved treatments in the United States.

dwatson@frontlinemedcom.com

The Food and Drug Administration on Nov. 21 granted orphan drug designation to rofecoxib (TRM-201), a cyclooxygenase 2–selective nonsteroidal anti-inflammatory drug (NSAID) intended to treat patients with hemophilic arthropathy (HA).

HA, a joint disease caused by hemarthrosis, is the largest cause of morbidity for hemophilia patients. There are currently no approved treatments in the United States.

dwatson@frontlinemedcom.com

PARIS—Siponimod significantly reduces MRI activity and slows brain volume loss in patients with secondary progressive multiple sclerosis (MS), according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Effects are observable at month 12 and sustained at month 24. “These results, together with the clinically observed reduction in confirmed disability progression reported previously, corroborate the positive impact of treatment with siponimod in patients with secondary progressive MS,” said Robert Fox, MD, a researcher at the Mellen Center for Treatment and Research in MS in the Cleveland Clinic, and colleagues.

The EXPAND study demonstrated the benefits of siponimod, a selective modulator of sphingosine 1-phosphate receptor subtypes 1 and 5, on confirmed disability progression. Dr. Fox and colleagues examined these data to evaluate the effect of siponimod versus placebo on predefined MRI outcomes in patients with secondary progressive MS.

The researchers randomized patients 2:1 to receive siponimod or placebo. MRI scans were performed at baseline and every 12 months thereafter. Radiologists at a central reading center analyzed the scans. Key MRI outcomes included T2 lesion volume, number of new or enlarging T2 lesions, number of gadolinium-enhancing lesions, and brain volume loss assessed by percent brain volume change.

The full analysis set comprised patients who received one or more doses of study drug as per original randomization. The per-protocol analysis set consisted of all full-analysis-set patients without major protocol deviations and included efficacy data only up to discontinuation of double-blinded treatment.

The investigators randomized 1,651 patients. A total of 1,099 patients received siponimod (2 mg), and 546 received placebo. Dr. Fox and colleagues observed treatment benefits in favor of siponimod for all key outcomes and analysis sets investigated. Post-baseline MRI data were available for more than 80% of participants.

At month 12, the adjusted mean differences in the change in T2 lesion volume from baseline versus placebo were −613 mm³  in the full analysis set and −634 mm³ in the per protocol analysis set. At month 24, the differences were −778 mm³ in the full analysis set and −830 mm³ in the per protocol analysis set.

At month 12, the adjusted mean differences in percent brain volume change were 0.175 in the full analysis set and 0.221 in the per protocol analysis set. At month 24, the differences were 0.128 in the full analysis set and 0.277 in the per protocol analysis set.

Siponimod reduced the average T1 gadolinium-enhancing lesion count over months 12 and 24 by 86.6% in the full analysis set and 91.1% in the per protocol analysis set. Siponimod reduced the average count of new or enlarging T2 lesions by 80.6% in the full analysis set and 85.3% in the per protocol analysis set.

This study was funded by Novartis Pharma, which is headquartered in Basel, Switzerland.

PARIS—Siponimod significantly reduces MRI activity and slows brain volume loss in patients with secondary progressive multiple sclerosis (MS), according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Effects are observable at month 12 and sustained at month 24. “These results, together with the clinically observed reduction in confirmed disability progression reported previously, corroborate the positive impact of treatment with siponimod in patients with secondary progressive MS,” said Robert Fox, MD, a researcher at the Mellen Center for Treatment and Research in MS in the Cleveland Clinic, and colleagues.

The EXPAND study demonstrated the benefits of siponimod, a selective modulator of sphingosine 1-phosphate receptor subtypes 1 and 5, on confirmed disability progression. Dr. Fox and colleagues examined these data to evaluate the effect of siponimod versus placebo on predefined MRI outcomes in patients with secondary progressive MS.

The researchers randomized patients 2:1 to receive siponimod or placebo. MRI scans were performed at baseline and every 12 months thereafter. Radiologists at a central reading center analyzed the scans. Key MRI outcomes included T2 lesion volume, number of new or enlarging T2 lesions, number of gadolinium-enhancing lesions, and brain volume loss assessed by percent brain volume change.

The full analysis set comprised patients who received one or more doses of study drug as per original randomization. The per-protocol analysis set consisted of all full-analysis-set patients without major protocol deviations and included efficacy data only up to discontinuation of double-blinded treatment.

The investigators randomized 1,651 patients. A total of 1,099 patients received siponimod (2 mg), and 546 received placebo. Dr. Fox and colleagues observed treatment benefits in favor of siponimod for all key outcomes and analysis sets investigated. Post-baseline MRI data were available for more than 80% of participants.

At month 12, the adjusted mean differences in the change in T2 lesion volume from baseline versus placebo were −613 mm³  in the full analysis set and −634 mm³ in the per protocol analysis set. At month 24, the differences were −778 mm³ in the full analysis set and −830 mm³ in the per protocol analysis set.

At month 12, the adjusted mean differences in percent brain volume change were 0.175 in the full analysis set and 0.221 in the per protocol analysis set. At month 24, the differences were 0.128 in the full analysis set and 0.277 in the per protocol analysis set.

Siponimod reduced the average T1 gadolinium-enhancing lesion count over months 12 and 24 by 86.6% in the full analysis set and 91.1% in the per protocol analysis set. Siponimod reduced the average count of new or enlarging T2 lesions by 80.6% in the full analysis set and 85.3% in the per protocol analysis set.

This study was funded by Novartis Pharma, which is headquartered in Basel, Switzerland.

PARIS—Siponimod significantly reduces MRI activity and slows brain volume loss in patients with secondary progressive multiple sclerosis (MS), according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Effects are observable at month 12 and sustained at month 24. “These results, together with the clinically observed reduction in confirmed disability progression reported previously, corroborate the positive impact of treatment with siponimod in patients with secondary progressive MS,” said Robert Fox, MD, a researcher at the Mellen Center for Treatment and Research in MS in the Cleveland Clinic, and colleagues.

The EXPAND study demonstrated the benefits of siponimod, a selective modulator of sphingosine 1-phosphate receptor subtypes 1 and 5, on confirmed disability progression. Dr. Fox and colleagues examined these data to evaluate the effect of siponimod versus placebo on predefined MRI outcomes in patients with secondary progressive MS.

The researchers randomized patients 2:1 to receive siponimod or placebo. MRI scans were performed at baseline and every 12 months thereafter. Radiologists at a central reading center analyzed the scans. Key MRI outcomes included T2 lesion volume, number of new or enlarging T2 lesions, number of gadolinium-enhancing lesions, and brain volume loss assessed by percent brain volume change.

The full analysis set comprised patients who received one or more doses of study drug as per original randomization. The per-protocol analysis set consisted of all full-analysis-set patients without major protocol deviations and included efficacy data only up to discontinuation of double-blinded treatment.

The investigators randomized 1,651 patients. A total of 1,099 patients received siponimod (2 mg), and 546 received placebo. Dr. Fox and colleagues observed treatment benefits in favor of siponimod for all key outcomes and analysis sets investigated. Post-baseline MRI data were available for more than 80% of participants.

At month 12, the adjusted mean differences in the change in T2 lesion volume from baseline versus placebo were −613 mm³  in the full analysis set and −634 mm³ in the per protocol analysis set. At month 24, the differences were −778 mm³ in the full analysis set and −830 mm³ in the per protocol analysis set.

At month 12, the adjusted mean differences in percent brain volume change were 0.175 in the full analysis set and 0.221 in the per protocol analysis set. At month 24, the differences were 0.128 in the full analysis set and 0.277 in the per protocol analysis set.

Siponimod reduced the average T1 gadolinium-enhancing lesion count over months 12 and 24 by 86.6% in the full analysis set and 91.1% in the per protocol analysis set. Siponimod reduced the average count of new or enlarging T2 lesions by 80.6% in the full analysis set and 85.3% in the per protocol analysis set.

This study was funded by Novartis Pharma, which is headquartered in Basel, Switzerland.

SCOTTSDALE, ARIZ. – In a small, single-center study of patients with subdiaphragmatic hemorrhage, resuscitative endovascular balloon occlusion of the aorta (REBOA) improved hemodynamic status and 30-day survival rates, compared with resuscitative thoracotomy (RT).

Although the technique was first developed during the Korean War, REBOA never really caught on, possibly because of limitations in endovascular technology. But recent advances in surgical technique have revitalized interest.

The funding source was not disclosed. Dr. Smith is on the speakers bureau for Prytime Medical and is a consultant for Boehringer Laboratory LLC.

SCOTTSDALE, ARIZ. – In a small, single-center study of patients with subdiaphragmatic hemorrhage, resuscitative endovascular balloon occlusion of the aorta (REBOA) improved hemodynamic status and 30-day survival rates, compared with resuscitative thoracotomy (RT).

Although the technique was first developed during the Korean War, REBOA never really caught on, possibly because of limitations in endovascular technology. But recent advances in surgical technique have revitalized interest.

The funding source was not disclosed. Dr. Smith is on the speakers bureau for Prytime Medical and is a consultant for Boehringer Laboratory LLC.

SCOTTSDALE, ARIZ. – In a small, single-center study of patients with subdiaphragmatic hemorrhage, resuscitative endovascular balloon occlusion of the aorta (REBOA) improved hemodynamic status and 30-day survival rates, compared with resuscitative thoracotomy (RT).

Although the technique was first developed during the Korean War, REBOA never really caught on, possibly because of limitations in endovascular technology. But recent advances in surgical technique have revitalized interest.

The funding source was not disclosed. Dr. Smith is on the speakers bureau for Prytime Medical and is a consultant for Boehringer Laboratory LLC.

Treating short-term or situational anxiety or anxiety attacks with benzodiazepines carries the risk of withdrawal and dependence. Other options include various antidepressants and buspirone. Although such medications decrease overall anxiety and can prevent anxiety from building, they are not effective for breakthrough anxiety. Other mainstays are antihistamines, antipsychotics, or newer antiepileptics such as gabapentin and pregabalin, but none of these have strong clinical literature support regarding their effectiveness for treating anxiety disorders.

PanX compounded medications are dual drug combinations of a beta blocker plus an antiemetic antimuscarinic agent.¹ They are designed and patented for as-needed treatment of anxiety disorders without using any controlled substances. Compounded medications are not FDA-approved, but are commercially available and subject to Section 503A of the Federal Food, Drug, and Cosmetics Act of 2013.²

In PanX medications, the beta blocker is intended to address the sympathetic cardiovascular symptoms of anxiety. Beta adrenergic receptor antagonists have been prescribed off-label for decades to treat social anxiety disorder, including performance anxiety. At least 7 beta blockers—atenolol, propranolol, pindolol, timolol, nadolol, betaxolol, and oxprenolol—have been reported to have anxiolytic effects, although these are limited to cardiovascular symptoms of anxiety.¹

However, there is a need to augment the limited effects of the beta blocker with another agent, such as an antimuscarinic agent, which is intended for parasympathetic noncardiovascular and CNS symptoms of anxiety. Scopolamine is a preferred antimuscarinic because it has been known for over a century to exhibit anxiolytic effects.³ Scopolamine’s mechanism of action is antagonism of acetylcholine binding to the M1 and/or M2 muscarinic receptors.⁴

We present a case of a patient who needed a nonbenzodiazepine treatment for acute anxiety. She received a compounded PanX combination of the beta-1 selective beta blocker atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, as needed for acute anxiety.

Case report

Acute anxiety, benzodiazepine abuse

Ms. L, age 30, with a family history of depression and anxiety, has had anxiety, depression, and posttraumatic stress disorder since she was in her mid-20s. She is evaluated in a 30-day rehabilitation program for alprazolam abuse. She is detoxed from alprazolam and stabilized with lurasidone, 60 mg once in the morning, gabapentin, 1,200 mg 4 times a day, and quetiapine, 125 mg as needed for sleep.

Ms. L improves significantly and is transferred to an intensive outpatient program. While there, she experiences increased periods of anxiety related to ruminative thoughts about relationship, occupational, and living stressors. She requests a medication for breakthrough anxiety and recognizes that, because of her history, a benzodiazepine is not medically indicated.

Ms. L signs a consent to a physician-sponsored trial of a PanX medication consisting of orally disintegrating tablets of atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, (in a polyglycol troche base plus mannitol, silica gel, and Steviol glycosides), which is prepared by a compounding pharmacy. Over 6 days, she takes the PanX combination 3 times. Immediately before she takes the medication, her symptoms are intense anxiety, nervousness, and agitation; feelings of panic; increased heart rate and palpitations; and shortness of breath. Ms. L says these symptoms developed approximately 20 minutes before she took the PanX combination. Approximately 30 minutes after taking the medication, she describes having a complete resolution of these symptoms that lasted for 4 hours. She says the medication “calmed [her] down” and had a “Klonopin or benzo-like effect.” She notes that her heart rate slowed quickly, followed by her breathing, and that she also was “more focused.” No information regarding her heart rate or blood pressure when she experienced the symptoms or after treatment is available. She denies experiencing dry mouth, dizziness, fatigue, sleepiness, blurred vision, or confusion.

Targets for future research

This case provides some preliminary clinical evidence of a rapid anxiolytic effect from a novel medication—a beta blocker plus scopolamine combination—that was beneficial in a situation where it may be likely that a benzodiazepine would have been utilized. This is our first case report documenting a trial of any PanX combination (ie, a combination of any beta blocker with any antimuscarinic agent) regarding anxiolytic efficacy and timing, tolerability, and adverse effects. With recognition that this is a report of 1 patient who took the medication 3 times, there is much that is not known.

Additional clinical studies are needed to evaluate the efficacy, tolerability, and adverse effects associated with using a beta blocker/antiemetic antimuscarinic combination to treat acute anxiety. Medication interactions also need to be considered. Whether this combination medication would be best for treating breakthrough anxiety or other acute anxiety episodes, and/or used as a regularly dosed medication is unknown. With documented risks of long-term benzodiazepine use, other novel therapeutics, such as the atenolol/scopolamine combination, may be welcome in treating acute anxiety.

Treating short-term or situational anxiety or anxiety attacks with benzodiazepines carries the risk of withdrawal and dependence. Other options include various antidepressants and buspirone. Although such medications decrease overall anxiety and can prevent anxiety from building, they are not effective for breakthrough anxiety. Other mainstays are antihistamines, antipsychotics, or newer antiepileptics such as gabapentin and pregabalin, but none of these have strong clinical literature support regarding their effectiveness for treating anxiety disorders.

PanX compounded medications are dual drug combinations of a beta blocker plus an antiemetic antimuscarinic agent.¹ They are designed and patented for as-needed treatment of anxiety disorders without using any controlled substances. Compounded medications are not FDA-approved, but are commercially available and subject to Section 503A of the Federal Food, Drug, and Cosmetics Act of 2013.²

In PanX medications, the beta blocker is intended to address the sympathetic cardiovascular symptoms of anxiety. Beta adrenergic receptor antagonists have been prescribed off-label for decades to treat social anxiety disorder, including performance anxiety. At least 7 beta blockers—atenolol, propranolol, pindolol, timolol, nadolol, betaxolol, and oxprenolol—have been reported to have anxiolytic effects, although these are limited to cardiovascular symptoms of anxiety.¹

However, there is a need to augment the limited effects of the beta blocker with another agent, such as an antimuscarinic agent, which is intended for parasympathetic noncardiovascular and CNS symptoms of anxiety. Scopolamine is a preferred antimuscarinic because it has been known for over a century to exhibit anxiolytic effects.³ Scopolamine’s mechanism of action is antagonism of acetylcholine binding to the M1 and/or M2 muscarinic receptors.⁴

We present a case of a patient who needed a nonbenzodiazepine treatment for acute anxiety. She received a compounded PanX combination of the beta-1 selective beta blocker atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, as needed for acute anxiety.

Case report

Acute anxiety, benzodiazepine abuse

Ms. L, age 30, with a family history of depression and anxiety, has had anxiety, depression, and posttraumatic stress disorder since she was in her mid-20s. She is evaluated in a 30-day rehabilitation program for alprazolam abuse. She is detoxed from alprazolam and stabilized with lurasidone, 60 mg once in the morning, gabapentin, 1,200 mg 4 times a day, and quetiapine, 125 mg as needed for sleep.

Ms. L improves significantly and is transferred to an intensive outpatient program. While there, she experiences increased periods of anxiety related to ruminative thoughts about relationship, occupational, and living stressors. She requests a medication for breakthrough anxiety and recognizes that, because of her history, a benzodiazepine is not medically indicated.

Ms. L signs a consent to a physician-sponsored trial of a PanX medication consisting of orally disintegrating tablets of atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, (in a polyglycol troche base plus mannitol, silica gel, and Steviol glycosides), which is prepared by a compounding pharmacy. Over 6 days, she takes the PanX combination 3 times. Immediately before she takes the medication, her symptoms are intense anxiety, nervousness, and agitation; feelings of panic; increased heart rate and palpitations; and shortness of breath. Ms. L says these symptoms developed approximately 20 minutes before she took the PanX combination. Approximately 30 minutes after taking the medication, she describes having a complete resolution of these symptoms that lasted for 4 hours. She says the medication “calmed [her] down” and had a “Klonopin or benzo-like effect.” She notes that her heart rate slowed quickly, followed by her breathing, and that she also was “more focused.” No information regarding her heart rate or blood pressure when she experienced the symptoms or after treatment is available. She denies experiencing dry mouth, dizziness, fatigue, sleepiness, blurred vision, or confusion.

Targets for future research

This case provides some preliminary clinical evidence of a rapid anxiolytic effect from a novel medication—a beta blocker plus scopolamine combination—that was beneficial in a situation where it may be likely that a benzodiazepine would have been utilized. This is our first case report documenting a trial of any PanX combination (ie, a combination of any beta blocker with any antimuscarinic agent) regarding anxiolytic efficacy and timing, tolerability, and adverse effects. With recognition that this is a report of 1 patient who took the medication 3 times, there is much that is not known.

Additional clinical studies are needed to evaluate the efficacy, tolerability, and adverse effects associated with using a beta blocker/antiemetic antimuscarinic combination to treat acute anxiety. Medication interactions also need to be considered. Whether this combination medication would be best for treating breakthrough anxiety or other acute anxiety episodes, and/or used as a regularly dosed medication is unknown. With documented risks of long-term benzodiazepine use, other novel therapeutics, such as the atenolol/scopolamine combination, may be welcome in treating acute anxiety.

Treating short-term or situational anxiety or anxiety attacks with benzodiazepines carries the risk of withdrawal and dependence. Other options include various antidepressants and buspirone. Although such medications decrease overall anxiety and can prevent anxiety from building, they are not effective for breakthrough anxiety. Other mainstays are antihistamines, antipsychotics, or newer antiepileptics such as gabapentin and pregabalin, but none of these have strong clinical literature support regarding their effectiveness for treating anxiety disorders.

PanX compounded medications are dual drug combinations of a beta blocker plus an antiemetic antimuscarinic agent.¹ They are designed and patented for as-needed treatment of anxiety disorders without using any controlled substances. Compounded medications are not FDA-approved, but are commercially available and subject to Section 503A of the Federal Food, Drug, and Cosmetics Act of 2013.²

In PanX medications, the beta blocker is intended to address the sympathetic cardiovascular symptoms of anxiety. Beta adrenergic receptor antagonists have been prescribed off-label for decades to treat social anxiety disorder, including performance anxiety. At least 7 beta blockers—atenolol, propranolol, pindolol, timolol, nadolol, betaxolol, and oxprenolol—have been reported to have anxiolytic effects, although these are limited to cardiovascular symptoms of anxiety.¹

However, there is a need to augment the limited effects of the beta blocker with another agent, such as an antimuscarinic agent, which is intended for parasympathetic noncardiovascular and CNS symptoms of anxiety. Scopolamine is a preferred antimuscarinic because it has been known for over a century to exhibit anxiolytic effects.³ Scopolamine’s mechanism of action is antagonism of acetylcholine binding to the M1 and/or M2 muscarinic receptors.⁴

We present a case of a patient who needed a nonbenzodiazepine treatment for acute anxiety. She received a compounded PanX combination of the beta-1 selective beta blocker atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, as needed for acute anxiety.

Case report

Acute anxiety, benzodiazepine abuse

Ms. L, age 30, with a family history of depression and anxiety, has had anxiety, depression, and posttraumatic stress disorder since she was in her mid-20s. She is evaluated in a 30-day rehabilitation program for alprazolam abuse. She is detoxed from alprazolam and stabilized with lurasidone, 60 mg once in the morning, gabapentin, 1,200 mg 4 times a day, and quetiapine, 125 mg as needed for sleep.

Ms. L improves significantly and is transferred to an intensive outpatient program. While there, she experiences increased periods of anxiety related to ruminative thoughts about relationship, occupational, and living stressors. She requests a medication for breakthrough anxiety and recognizes that, because of her history, a benzodiazepine is not medically indicated.

Ms. L signs a consent to a physician-sponsored trial of a PanX medication consisting of orally disintegrating tablets of atenolol, 25 mg, plus scopolamine hydrobromide, 0.2 mg, (in a polyglycol troche base plus mannitol, silica gel, and Steviol glycosides), which is prepared by a compounding pharmacy. Over 6 days, she takes the PanX combination 3 times. Immediately before she takes the medication, her symptoms are intense anxiety, nervousness, and agitation; feelings of panic; increased heart rate and palpitations; and shortness of breath. Ms. L says these symptoms developed approximately 20 minutes before she took the PanX combination. Approximately 30 minutes after taking the medication, she describes having a complete resolution of these symptoms that lasted for 4 hours. She says the medication “calmed [her] down” and had a “Klonopin or benzo-like effect.” She notes that her heart rate slowed quickly, followed by her breathing, and that she also was “more focused.” No information regarding her heart rate or blood pressure when she experienced the symptoms or after treatment is available. She denies experiencing dry mouth, dizziness, fatigue, sleepiness, blurred vision, or confusion.

Targets for future research

This case provides some preliminary clinical evidence of a rapid anxiolytic effect from a novel medication—a beta blocker plus scopolamine combination—that was beneficial in a situation where it may be likely that a benzodiazepine would have been utilized. This is our first case report documenting a trial of any PanX combination (ie, a combination of any beta blocker with any antimuscarinic agent) regarding anxiolytic efficacy and timing, tolerability, and adverse effects. With recognition that this is a report of 1 patient who took the medication 3 times, there is much that is not known.

Additional clinical studies are needed to evaluate the efficacy, tolerability, and adverse effects associated with using a beta blocker/antiemetic antimuscarinic combination to treat acute anxiety. Medication interactions also need to be considered. Whether this combination medication would be best for treating breakthrough anxiety or other acute anxiety episodes, and/or used as a regularly dosed medication is unknown. With documented risks of long-term benzodiazepine use, other novel therapeutics, such as the atenolol/scopolamine combination, may be welcome in treating acute anxiety.

Brain Glucose Level Is Associated With Alzheimer’s Disease Severity

Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to Alzheimer’s disease pathogenesis, according to a study published online ahead of print October 19 in Alzheimer’s & Dementia. Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, researchers measured brain glucose concentration and assessed the ratios of serine, glycine, and alanine to glucose. Investigators also quantified protein levels of the neuronal and astrocytic glucose transporters. In addition, study authors assessed the relationships between plasma glucose measured before death and brain tissue glucose. Higher brain tissue glucose concentration, reduced glycolytic flux, and lower neuronal glucose transporters were related to severity of Alzheimer’s disease pathology and the expression of Alzheimer’s disease symptoms. Longitudinal increases in fasting plasma glucose levels were associated with higher brain tissue glucose concentrations.

An Y, Varma VR, Varma S, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement. 2017 Oct 19 [Epub ahead of print].

Is it Better to Be Asleep or Awake for DBS Implantation?

Patients with Parkinson’s disease who undergo deep brain stimulation (DBS) device implantation while asleep have better communication, cognition, and speech outcomes, according to a study published November 7 in Neurology. Thirty DBS candidates with Parkinson’s disease underwent imaging-guided implantation while asleep. Their six-month outcomes were compared to those of 39 patients who previously had undergone implantation while awake. Assessments included an off-levodopa Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, the 39-item Parkinson’s Disease Questionnaire, motor diaries, and speech fluency. No difference was observed in improvement of UPDRS III or UPDRS II. Improvement in on time without dyskinesia was superior in asleep implantation. Quality of life scores improved in both groups. Improvement in summary index and subscores for cognition and communication were superior in implantation while asleep.

Brodsky MA, Anderson S, Murchison C, et al. Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease. Neurology. 2017;89(19):1944-1950.

Is Inflammation During Middle Age Linked to Brain Shrinkage Later On?

People with blood biomarkers of inflammation during midlife may have more brain shrinkage decades later than people without these biomarkers, according to a study published online ahead of print November 1 in Neurology. Plasma levels of fibrinogen, albumin, white blood cells, von Willebrand factor, and Factor VIII were assessed at baseline in 1,633 participants in the Atherosclerosis Risk in Communities Study. Each standard deviation increase in midlife inflammation composite score was associated with 1,788 mm³ greater ventricular volume, 110 mm³ smaller hippocampal volume, 519 mm³ smaller occipital volume, and 532 mm³ smaller Alzheimer disease signature region volumes and reduced episodic memory 24 years later. Compared with participants with no elevated midlife inflammatory markers, participants with elevations in three or more markers had 5% smaller hippocampal and Alzheimer’s disease signature region volumes.

Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 1 [Epub ahead of print].

Novel Wristbands Improve Seizure Detection

Wrist-worn convulsive seizure detectors provide more accurate seizure counts than previous automated detectors do, while maintaining tolerable false alarm rates (FAR) for ambulatory monitoring, according to a study published in the November issue of Epilepsia. Hand-annotated video-EEG seizure events were collected from 69 patients at six clinical sites. Two novel wristbands and one current wristband were used to record electrodermal activity and accelerometer signals, obtaining 5,928 hours of data, including 55 convulsive epileptic seizures in 22 patients. The novel wristbands consistently outperformed the current wristband. The best wristband had a sensitivity of 94.55% and an FAR of 0.2 events per day. When increasing the sensitivity to 100%, the FAR was as much as 13 times lower than with the current detector. Automatically estimated seizure durations were correlated with true durations.

Onorati F, Regalia G, Caborni C, et al. Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors. Epilepsia. 2017;58(11):1870-1879.

Focused Ultrasound Reduces Parkinson’s Disease Tremor

Focused ultrasound thalamotomy for patients with tremor-dominant Parkinson’s disease demonstrates improvement in medication-refractory tremor by Clinical Rating Scale for Tremor assessments, even in the setting of a placebo response, according to a study published online ahead of print October 30 in JAMA Neurology. Researchers randomized 20 patients to unilateral focused ultrasound thalamotomy and seven to a sham procedure. Twenty-six participants were male, and the median age was 67.8. The predefined primary outcomes were safety and difference in improvement between groups at three months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor. On-medication median tremor scores improved 62% from a baseline of 17 points following focused ultrasound thalamotomy, and 22% from a baseline of 23 points after sham procedures.

Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: a randomized clinical trial. JAMA Neurol. 2017 Oct 30 [Epub ahead of print].

Biomarker of Multiple Sclerosis Identified

MicroRNAs associated with circulating exosomes are informative biomarkers for the diagnosis of multiple sclerosis (MS) and for predicting disease subtype with a high degree of accuracy, according to a study published October 30 in Scientific Reports. Exosome-associated microRNAs in serum samples from 25 patients with MS and 11 matched healthy controls were profiled using small RNA next-generation sequencing. In addition to identifying biomarkers that distinguish healthy people from people with MS, researchers identified nine microRNA molecules that differentiate between relapsing-remitting MS and progressive MS. Study authors also validated eight out of nine microRNA molecules in an independent group of 11 patients with progressive MS. The blood test may enable earlier treatment of MS and help neurologists identify the most appropriate treatment for a patient, said the authors.

Ebrahimkhani S, Vafaee F, Young PE, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep. 2017;7(1):14293.

Does Oral Anticoagulation in Atrial Fibrillation Reduce Dementia Risk?

The risk of dementia in patients with atrial fibrillation is higher among those who do not take oral anticoagulants, compared with those who do, according to a study published online ahead of print October 24 in the European Heart Journal. This Swedish retrospective registry study included 444,106 patients with hospital diagnosis of atrial fibrillation and no previous diagnosis of dementia between 2006 and 2014. At baseline, 54% of patients were not taking oral anticoagulants. Investigators performed propensity score matching, used falsification end points, and performed intention-to-treat and on-treatment analyses. Patients on anticoagulant treatment at baseline had a 29% lower risk of dementia than patients without anticoagulant treatment, and a 48% lower risk analyzed on treatment. Direct comparison between new oral anticoagulants and warfarin showed no difference.

Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2017 Oct 24 [Epub ahead of print].

Dendritic Spine Plasticity May Protect Against Dementia

Dendritic spine plasticity protects older people with Alzheimer’s disease pathology from developing dementia, according to a study published in the October issue of Annals of Neurology. Researchers compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 of the dorsolateral prefrontal cortex in 12 age-matched healthy controls, eight controls with Alzheimer’s disease pathology (CAD), and 21 people with Alzheimer’s disease. The investigators created digital reconstructions of dendritic structure for morphologic analyses. Spine density was similar among control and CAD cases, but was reduced significantly in Alzheimer’s disease. Thin and mushroom spines were reduced significantly in Alzheimer’s disease, compared with CAD brains, and stubby spine density was decreased significantly in CAD and Alzheimer’s disease, compared with controls.

Boros BD, Greathouse KM, Gentry EG, et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 2017;82(4):602-614.

Opioid Versus Nonopioid Treatment for Acute Migraine

IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the emergency department and should not be used as first-line therapy, according to a study published online ahead of print October 18 in Neurology. This study was conducted in two emergency departments and included patients who met international criteria for migraine if they had not used an opioid within the previous month. Participants received hydromorphone (1 mg) or prochlorperazine (10 mg) and diphenhydramine (25 mg). The primary outcome was achieving a headache level of mild or none within two hours of treatment and maintaining that level for 48 hours without rescue medication. Approximately 60% of the prochlorperazine arm achieved the primary outcome, compared with 31% of the hydromorphone arm.

Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017 Oct 18 [Epub ahead of print].

Frontotemporal Degeneration Entails High Economic Burden

The economic burden of frontotemporal degeneration may be twice as high as that of Alzheimer’s disease, according to a study published online ahead of print October 4 in Neurology. An Internet survey was administered to 674 primary caregivers of patients with behavioral-variant frontotemporal degeneration, primary progressive aphasia, frontotemporal degeneration with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. Direct costs for these disorders equaled $47,916, and indirect costs equaled $71,737. Patients age 65 or older, those with later stages of disease, and those with behavioral-variant frontotemporal degeneration had higher direct costs, while patients younger than 65 and men had higher indirect costs. Mean household income ranged from $75,000 to $99,000 at 12 months before frontotemporal degeneration diagnosis, but declined to $50,000 to $59,999 after diagnosis.

Galvin JE, Howard DH, Denny SS, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Oct 4 [Epub ahead of print].

FDA Approves Vimpat for Partial-Onset Seizures in Pediatric Epilepsy

The FDA has approved a label extension for Vimpat (lacosamide) CV as an oral option for the treatment of partial-onset seizures in pediatric patients age 4 and older. The safety and efficacy profile of Vimpat as monotherapy and adjunctive therapy for the treatment of partial-onset seizures in adults was previously established in four multicenter, randomized, controlled clinical trials. The expanded indication for Vimpat is based on extrapolation of efficacy data from adults to children and is supported by safety and pharmacokinetics data collected in children. Adverse reactions in pediatric patients are similar to those in adult patients. UCB, which markets Vimpat, is headquartered in Brussels.

—Kimberly Williams

Brain Glucose Level Is Associated With Alzheimer’s Disease Severity

Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to Alzheimer’s disease pathogenesis, according to a study published online ahead of print October 19 in Alzheimer’s & Dementia. Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, researchers measured brain glucose concentration and assessed the ratios of serine, glycine, and alanine to glucose. Investigators also quantified protein levels of the neuronal and astrocytic glucose transporters. In addition, study authors assessed the relationships between plasma glucose measured before death and brain tissue glucose. Higher brain tissue glucose concentration, reduced glycolytic flux, and lower neuronal glucose transporters were related to severity of Alzheimer’s disease pathology and the expression of Alzheimer’s disease symptoms. Longitudinal increases in fasting plasma glucose levels were associated with higher brain tissue glucose concentrations.

An Y, Varma VR, Varma S, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement. 2017 Oct 19 [Epub ahead of print].

Is it Better to Be Asleep or Awake for DBS Implantation?

Patients with Parkinson’s disease who undergo deep brain stimulation (DBS) device implantation while asleep have better communication, cognition, and speech outcomes, according to a study published November 7 in Neurology. Thirty DBS candidates with Parkinson’s disease underwent imaging-guided implantation while asleep. Their six-month outcomes were compared to those of 39 patients who previously had undergone implantation while awake. Assessments included an off-levodopa Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, the 39-item Parkinson’s Disease Questionnaire, motor diaries, and speech fluency. No difference was observed in improvement of UPDRS III or UPDRS II. Improvement in on time without dyskinesia was superior in asleep implantation. Quality of life scores improved in both groups. Improvement in summary index and subscores for cognition and communication were superior in implantation while asleep.

Brodsky MA, Anderson S, Murchison C, et al. Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease. Neurology. 2017;89(19):1944-1950.

Is Inflammation During Middle Age Linked to Brain Shrinkage Later On?

People with blood biomarkers of inflammation during midlife may have more brain shrinkage decades later than people without these biomarkers, according to a study published online ahead of print November 1 in Neurology. Plasma levels of fibrinogen, albumin, white blood cells, von Willebrand factor, and Factor VIII were assessed at baseline in 1,633 participants in the Atherosclerosis Risk in Communities Study. Each standard deviation increase in midlife inflammation composite score was associated with 1,788 mm³ greater ventricular volume, 110 mm³ smaller hippocampal volume, 519 mm³ smaller occipital volume, and 532 mm³ smaller Alzheimer disease signature region volumes and reduced episodic memory 24 years later. Compared with participants with no elevated midlife inflammatory markers, participants with elevations in three or more markers had 5% smaller hippocampal and Alzheimer’s disease signature region volumes.

Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 1 [Epub ahead of print].

Novel Wristbands Improve Seizure Detection

Wrist-worn convulsive seizure detectors provide more accurate seizure counts than previous automated detectors do, while maintaining tolerable false alarm rates (FAR) for ambulatory monitoring, according to a study published in the November issue of Epilepsia. Hand-annotated video-EEG seizure events were collected from 69 patients at six clinical sites. Two novel wristbands and one current wristband were used to record electrodermal activity and accelerometer signals, obtaining 5,928 hours of data, including 55 convulsive epileptic seizures in 22 patients. The novel wristbands consistently outperformed the current wristband. The best wristband had a sensitivity of 94.55% and an FAR of 0.2 events per day. When increasing the sensitivity to 100%, the FAR was as much as 13 times lower than with the current detector. Automatically estimated seizure durations were correlated with true durations.

Onorati F, Regalia G, Caborni C, et al. Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors. Epilepsia. 2017;58(11):1870-1879.

Focused Ultrasound Reduces Parkinson’s Disease Tremor

Focused ultrasound thalamotomy for patients with tremor-dominant Parkinson’s disease demonstrates improvement in medication-refractory tremor by Clinical Rating Scale for Tremor assessments, even in the setting of a placebo response, according to a study published online ahead of print October 30 in JAMA Neurology. Researchers randomized 20 patients to unilateral focused ultrasound thalamotomy and seven to a sham procedure. Twenty-six participants were male, and the median age was 67.8. The predefined primary outcomes were safety and difference in improvement between groups at three months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor. On-medication median tremor scores improved 62% from a baseline of 17 points following focused ultrasound thalamotomy, and 22% from a baseline of 23 points after sham procedures.

Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: a randomized clinical trial. JAMA Neurol. 2017 Oct 30 [Epub ahead of print].

Biomarker of Multiple Sclerosis Identified

MicroRNAs associated with circulating exosomes are informative biomarkers for the diagnosis of multiple sclerosis (MS) and for predicting disease subtype with a high degree of accuracy, according to a study published October 30 in Scientific Reports. Exosome-associated microRNAs in serum samples from 25 patients with MS and 11 matched healthy controls were profiled using small RNA next-generation sequencing. In addition to identifying biomarkers that distinguish healthy people from people with MS, researchers identified nine microRNA molecules that differentiate between relapsing-remitting MS and progressive MS. Study authors also validated eight out of nine microRNA molecules in an independent group of 11 patients with progressive MS. The blood test may enable earlier treatment of MS and help neurologists identify the most appropriate treatment for a patient, said the authors.

Ebrahimkhani S, Vafaee F, Young PE, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep. 2017;7(1):14293.

Does Oral Anticoagulation in Atrial Fibrillation Reduce Dementia Risk?

The risk of dementia in patients with atrial fibrillation is higher among those who do not take oral anticoagulants, compared with those who do, according to a study published online ahead of print October 24 in the European Heart Journal. This Swedish retrospective registry study included 444,106 patients with hospital diagnosis of atrial fibrillation and no previous diagnosis of dementia between 2006 and 2014. At baseline, 54% of patients were not taking oral anticoagulants. Investigators performed propensity score matching, used falsification end points, and performed intention-to-treat and on-treatment analyses. Patients on anticoagulant treatment at baseline had a 29% lower risk of dementia than patients without anticoagulant treatment, and a 48% lower risk analyzed on treatment. Direct comparison between new oral anticoagulants and warfarin showed no difference.

Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2017 Oct 24 [Epub ahead of print].

Dendritic Spine Plasticity May Protect Against Dementia

Dendritic spine plasticity protects older people with Alzheimer’s disease pathology from developing dementia, according to a study published in the October issue of Annals of Neurology. Researchers compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 of the dorsolateral prefrontal cortex in 12 age-matched healthy controls, eight controls with Alzheimer’s disease pathology (CAD), and 21 people with Alzheimer’s disease. The investigators created digital reconstructions of dendritic structure for morphologic analyses. Spine density was similar among control and CAD cases, but was reduced significantly in Alzheimer’s disease. Thin and mushroom spines were reduced significantly in Alzheimer’s disease, compared with CAD brains, and stubby spine density was decreased significantly in CAD and Alzheimer’s disease, compared with controls.

Boros BD, Greathouse KM, Gentry EG, et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 2017;82(4):602-614.

Opioid Versus Nonopioid Treatment for Acute Migraine

IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the emergency department and should not be used as first-line therapy, according to a study published online ahead of print October 18 in Neurology. This study was conducted in two emergency departments and included patients who met international criteria for migraine if they had not used an opioid within the previous month. Participants received hydromorphone (1 mg) or prochlorperazine (10 mg) and diphenhydramine (25 mg). The primary outcome was achieving a headache level of mild or none within two hours of treatment and maintaining that level for 48 hours without rescue medication. Approximately 60% of the prochlorperazine arm achieved the primary outcome, compared with 31% of the hydromorphone arm.

Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017 Oct 18 [Epub ahead of print].

Frontotemporal Degeneration Entails High Economic Burden

The economic burden of frontotemporal degeneration may be twice as high as that of Alzheimer’s disease, according to a study published online ahead of print October 4 in Neurology. An Internet survey was administered to 674 primary caregivers of patients with behavioral-variant frontotemporal degeneration, primary progressive aphasia, frontotemporal degeneration with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. Direct costs for these disorders equaled $47,916, and indirect costs equaled $71,737. Patients age 65 or older, those with later stages of disease, and those with behavioral-variant frontotemporal degeneration had higher direct costs, while patients younger than 65 and men had higher indirect costs. Mean household income ranged from $75,000 to $99,000 at 12 months before frontotemporal degeneration diagnosis, but declined to $50,000 to $59,999 after diagnosis.

Galvin JE, Howard DH, Denny SS, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Oct 4 [Epub ahead of print].

FDA Approves Vimpat for Partial-Onset Seizures in Pediatric Epilepsy

The FDA has approved a label extension for Vimpat (lacosamide) CV as an oral option for the treatment of partial-onset seizures in pediatric patients age 4 and older. The safety and efficacy profile of Vimpat as monotherapy and adjunctive therapy for the treatment of partial-onset seizures in adults was previously established in four multicenter, randomized, controlled clinical trials. The expanded indication for Vimpat is based on extrapolation of efficacy data from adults to children and is supported by safety and pharmacokinetics data collected in children. Adverse reactions in pediatric patients are similar to those in adult patients. UCB, which markets Vimpat, is headquartered in Brussels.

—Kimberly Williams

Brain Glucose Level Is Associated With Alzheimer’s Disease Severity

Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to Alzheimer’s disease pathogenesis, according to a study published online ahead of print October 19 in Alzheimer’s & Dementia. Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, researchers measured brain glucose concentration and assessed the ratios of serine, glycine, and alanine to glucose. Investigators also quantified protein levels of the neuronal and astrocytic glucose transporters. In addition, study authors assessed the relationships between plasma glucose measured before death and brain tissue glucose. Higher brain tissue glucose concentration, reduced glycolytic flux, and lower neuronal glucose transporters were related to severity of Alzheimer’s disease pathology and the expression of Alzheimer’s disease symptoms. Longitudinal increases in fasting plasma glucose levels were associated with higher brain tissue glucose concentrations.

An Y, Varma VR, Varma S, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement. 2017 Oct 19 [Epub ahead of print].

Is it Better to Be Asleep or Awake for DBS Implantation?

Patients with Parkinson’s disease who undergo deep brain stimulation (DBS) device implantation while asleep have better communication, cognition, and speech outcomes, according to a study published November 7 in Neurology. Thirty DBS candidates with Parkinson’s disease underwent imaging-guided implantation while asleep. Their six-month outcomes were compared to those of 39 patients who previously had undergone implantation while awake. Assessments included an off-levodopa Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, the 39-item Parkinson’s Disease Questionnaire, motor diaries, and speech fluency. No difference was observed in improvement of UPDRS III or UPDRS II. Improvement in on time without dyskinesia was superior in asleep implantation. Quality of life scores improved in both groups. Improvement in summary index and subscores for cognition and communication were superior in implantation while asleep.

Brodsky MA, Anderson S, Murchison C, et al. Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease. Neurology. 2017;89(19):1944-1950.

Is Inflammation During Middle Age Linked to Brain Shrinkage Later On?

People with blood biomarkers of inflammation during midlife may have more brain shrinkage decades later than people without these biomarkers, according to a study published online ahead of print November 1 in Neurology. Plasma levels of fibrinogen, albumin, white blood cells, von Willebrand factor, and Factor VIII were assessed at baseline in 1,633 participants in the Atherosclerosis Risk in Communities Study. Each standard deviation increase in midlife inflammation composite score was associated with 1,788 mm³ greater ventricular volume, 110 mm³ smaller hippocampal volume, 519 mm³ smaller occipital volume, and 532 mm³ smaller Alzheimer disease signature region volumes and reduced episodic memory 24 years later. Compared with participants with no elevated midlife inflammatory markers, participants with elevations in three or more markers had 5% smaller hippocampal and Alzheimer’s disease signature region volumes.

Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 1 [Epub ahead of print].

Novel Wristbands Improve Seizure Detection

Wrist-worn convulsive seizure detectors provide more accurate seizure counts than previous automated detectors do, while maintaining tolerable false alarm rates (FAR) for ambulatory monitoring, according to a study published in the November issue of Epilepsia. Hand-annotated video-EEG seizure events were collected from 69 patients at six clinical sites. Two novel wristbands and one current wristband were used to record electrodermal activity and accelerometer signals, obtaining 5,928 hours of data, including 55 convulsive epileptic seizures in 22 patients. The novel wristbands consistently outperformed the current wristband. The best wristband had a sensitivity of 94.55% and an FAR of 0.2 events per day. When increasing the sensitivity to 100%, the FAR was as much as 13 times lower than with the current detector. Automatically estimated seizure durations were correlated with true durations.

Onorati F, Regalia G, Caborni C, et al. Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors. Epilepsia. 2017;58(11):1870-1879.

Focused Ultrasound Reduces Parkinson’s Disease Tremor

Focused ultrasound thalamotomy for patients with tremor-dominant Parkinson’s disease demonstrates improvement in medication-refractory tremor by Clinical Rating Scale for Tremor assessments, even in the setting of a placebo response, according to a study published online ahead of print October 30 in JAMA Neurology. Researchers randomized 20 patients to unilateral focused ultrasound thalamotomy and seven to a sham procedure. Twenty-six participants were male, and the median age was 67.8. The predefined primary outcomes were safety and difference in improvement between groups at three months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor. On-medication median tremor scores improved 62% from a baseline of 17 points following focused ultrasound thalamotomy, and 22% from a baseline of 23 points after sham procedures.

Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: a randomized clinical trial. JAMA Neurol. 2017 Oct 30 [Epub ahead of print].

Biomarker of Multiple Sclerosis Identified

MicroRNAs associated with circulating exosomes are informative biomarkers for the diagnosis of multiple sclerosis (MS) and for predicting disease subtype with a high degree of accuracy, according to a study published October 30 in Scientific Reports. Exosome-associated microRNAs in serum samples from 25 patients with MS and 11 matched healthy controls were profiled using small RNA next-generation sequencing. In addition to identifying biomarkers that distinguish healthy people from people with MS, researchers identified nine microRNA molecules that differentiate between relapsing-remitting MS and progressive MS. Study authors also validated eight out of nine microRNA molecules in an independent group of 11 patients with progressive MS. The blood test may enable earlier treatment of MS and help neurologists identify the most appropriate treatment for a patient, said the authors.

Ebrahimkhani S, Vafaee F, Young PE, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep. 2017;7(1):14293.

Does Oral Anticoagulation in Atrial Fibrillation Reduce Dementia Risk?

The risk of dementia in patients with atrial fibrillation is higher among those who do not take oral anticoagulants, compared with those who do, according to a study published online ahead of print October 24 in the European Heart Journal. This Swedish retrospective registry study included 444,106 patients with hospital diagnosis of atrial fibrillation and no previous diagnosis of dementia between 2006 and 2014. At baseline, 54% of patients were not taking oral anticoagulants. Investigators performed propensity score matching, used falsification end points, and performed intention-to-treat and on-treatment analyses. Patients on anticoagulant treatment at baseline had a 29% lower risk of dementia than patients without anticoagulant treatment, and a 48% lower risk analyzed on treatment. Direct comparison between new oral anticoagulants and warfarin showed no difference.

Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2017 Oct 24 [Epub ahead of print].

Dendritic Spine Plasticity May Protect Against Dementia

Dendritic spine plasticity protects older people with Alzheimer’s disease pathology from developing dementia, according to a study published in the October issue of Annals of Neurology. Researchers compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 of the dorsolateral prefrontal cortex in 12 age-matched healthy controls, eight controls with Alzheimer’s disease pathology (CAD), and 21 people with Alzheimer’s disease. The investigators created digital reconstructions of dendritic structure for morphologic analyses. Spine density was similar among control and CAD cases, but was reduced significantly in Alzheimer’s disease. Thin and mushroom spines were reduced significantly in Alzheimer’s disease, compared with CAD brains, and stubby spine density was decreased significantly in CAD and Alzheimer’s disease, compared with controls.

Boros BD, Greathouse KM, Gentry EG, et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 2017;82(4):602-614.

Opioid Versus Nonopioid Treatment for Acute Migraine

IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the emergency department and should not be used as first-line therapy, according to a study published online ahead of print October 18 in Neurology. This study was conducted in two emergency departments and included patients who met international criteria for migraine if they had not used an opioid within the previous month. Participants received hydromorphone (1 mg) or prochlorperazine (10 mg) and diphenhydramine (25 mg). The primary outcome was achieving a headache level of mild or none within two hours of treatment and maintaining that level for 48 hours without rescue medication. Approximately 60% of the prochlorperazine arm achieved the primary outcome, compared with 31% of the hydromorphone arm.

Friedman BW, Irizarry E, Solorzano C, et al. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017 Oct 18 [Epub ahead of print].

Frontotemporal Degeneration Entails High Economic Burden

The economic burden of frontotemporal degeneration may be twice as high as that of Alzheimer’s disease, according to a study published online ahead of print October 4 in Neurology. An Internet survey was administered to 674 primary caregivers of patients with behavioral-variant frontotemporal degeneration, primary progressive aphasia, frontotemporal degeneration with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. Direct costs for these disorders equaled $47,916, and indirect costs equaled $71,737. Patients age 65 or older, those with later stages of disease, and those with behavioral-variant frontotemporal degeneration had higher direct costs, while patients younger than 65 and men had higher indirect costs. Mean household income ranged from $75,000 to $99,000 at 12 months before frontotemporal degeneration diagnosis, but declined to $50,000 to $59,999 after diagnosis.

Galvin JE, Howard DH, Denny SS, et al. The social and economic burden of frontotemporal degeneration. Neurology. 2017 Oct 4 [Epub ahead of print].

FDA Approves Vimpat for Partial-Onset Seizures in Pediatric Epilepsy

The FDA has approved a label extension for Vimpat (lacosamide) CV as an oral option for the treatment of partial-onset seizures in pediatric patients age 4 and older. The safety and efficacy profile of Vimpat as monotherapy and adjunctive therapy for the treatment of partial-onset seizures in adults was previously established in four multicenter, randomized, controlled clinical trials. The expanded indication for Vimpat is based on extrapolation of efficacy data from adults to children and is supported by safety and pharmacokinetics data collected in children. Adverse reactions in pediatric patients are similar to those in adult patients. UCB, which markets Vimpat, is headquartered in Brussels.

—Kimberly Williams

SAN DIEGO – The first validation study of proposed new classification criteria for systemic lupus erythematosus (SLE) yielded a sensitivity of 98% and a specificity of 97%.

The development is part of a four-phase joint effort by the American College of Rheumatology and the European League Against Rheumatism, first launched in 2014, to improve classification of patients with SLE for the purposes of clinical trials of new therapies and clinical research into the causes and outcomes of the disease. “The ACR and EULAR have long recognized the importance of classification criteria, so that we have more homogeneous groups in these research studies, and then we can compare results from studies,” Sindhu Johnson, MD, PhD, said during a press briefing at the annual meeting of the American College of Rheumatology.

Doug Brunk/Frontline Medical News

dbrunk@frontlinemedcom.com

SAN DIEGO – The first validation study of proposed new classification criteria for systemic lupus erythematosus (SLE) yielded a sensitivity of 98% and a specificity of 97%.

The development is part of a four-phase joint effort by the American College of Rheumatology and the European League Against Rheumatism, first launched in 2014, to improve classification of patients with SLE for the purposes of clinical trials of new therapies and clinical research into the causes and outcomes of the disease. “The ACR and EULAR have long recognized the importance of classification criteria, so that we have more homogeneous groups in these research studies, and then we can compare results from studies,” Sindhu Johnson, MD, PhD, said during a press briefing at the annual meeting of the American College of Rheumatology.

Doug Brunk/Frontline Medical News

dbrunk@frontlinemedcom.com

SAN DIEGO – The first validation study of proposed new classification criteria for systemic lupus erythematosus (SLE) yielded a sensitivity of 98% and a specificity of 97%.

The development is part of a four-phase joint effort by the American College of Rheumatology and the European League Against Rheumatism, first launched in 2014, to improve classification of patients with SLE for the purposes of clinical trials of new therapies and clinical research into the causes and outcomes of the disease. “The ACR and EULAR have long recognized the importance of classification criteria, so that we have more homogeneous groups in these research studies, and then we can compare results from studies,” Sindhu Johnson, MD, PhD, said during a press briefing at the annual meeting of the American College of Rheumatology.

Doug Brunk/Frontline Medical News

dbrunk@frontlinemedcom.com